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WO2011109784A1 - Formulation de conjugués peptidiques insulinotropiques - Google Patents

Formulation de conjugués peptidiques insulinotropiques Download PDF

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Publication number
WO2011109784A1
WO2011109784A1 PCT/US2011/027311 US2011027311W WO2011109784A1 WO 2011109784 A1 WO2011109784 A1 WO 2011109784A1 US 2011027311 W US2011027311 W US 2011027311W WO 2011109784 A1 WO2011109784 A1 WO 2011109784A1
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Prior art keywords
concentration
conjugate
formulation
pharmaceutical formulation
pluronic
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PCT/US2011/027311
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English (en)
Inventor
Mariéve CARRIER
Karen Thibaudeau
Martin Robitaille
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Conjuchem LLC
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Conjuchem LLC
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Publication of WO2011109784A1 publication Critical patent/WO2011109784A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • compositions comprising an insulinotropic peptide conjugate and methods of administration thereof are provided.
  • the formulations are useful in the treatment of diabetes and other insulinotropic peptide related diseases.
  • Insulinotropic peptides have been investigated as a possible therapeutic agent for the management of type II non-insulin-dependent diabetes mellitus as well as related metabolic disorders, such as obesity. See, e.g., U.S. Patent No. 6,329,336; and U.S. Patent No. 7,153,825. Recently, it has been shown that conjugation of insulinotropic peptides to albumin can provide longer duration of action in vivo while maintaining their low toxicity and therapeutic advantages. See, e.g., Giannoukakis, Curr Opin Investig Drugs.
  • compositions capable of providing stability and maintaining the biological activity of insulinotropic peptide conjugates.
  • the pharmaceutical formulations provided herein include liquid and lyophilized formulations, unit dosage forms and multi-use dosage forms, and combinations thereof.
  • the pharmaceutical formulations can be suitable for administration via parenteral routes such as subcutaneous, intravenous, intramuscular, transdermal, intra-arterial, intra-peritoneal, or via oral routes, topical routes, or inhalation routes etc.
  • an insulinotropic peptide conjugate comprising an insulinotropic peptide conjugate.
  • the insulinotropic peptide conjugate can comprise any insulinotropic peptide known to those of skill in the art.
  • it can be any peptide that can stimulate, or cause the stimulation of, synthesis or expression of the hormone insulin.
  • the insulinotropic peptide is selected from the group consisting of glucagon-like peptide 1, exendin-3 and exendin-4 and their precursors, derivatives or fragments.
  • the insulinotropic peptide is or comprises exendin-4 or a derivative thereof.
  • the insulinotropic peptides in the conjugates can be conjugated to albumin.
  • the insulinotropic peptide is conjugated to human serum albumin.
  • the insulinotropic peptide is conjugated to recombinant human albumin.
  • compositions comprising a conjugate of albumin to exendin-4, or a derivative thereof, at a concentration from about 1 mg/ml to about 100 mg/ml.
  • the pharmaceutical formulation comprises a conjugate of albumin to exendin-4, or a derivative thereof, at a concentration from about 1 mg/ml to about 100 mg/ml, a tonicity modifier, a stabilizer, a surfactant, optionally a buffer, and optionally a preservative, wherein said formulation has a pH from about 4 to about 8.
  • the formulation has a pH of about 4.0 to 9.0. In some embodiments, the formulation has a pH of about 4.5 to 7.0. In some embodiments, the formulation has a pH of about 4.0 to 6.0. In some embodiments, the formulation has a pH of about 6.0 to 8.0. In some embodiments, the formulation has a pH of about 6.0 to 9.0. In some embodiments, the formulation has a pH of about 6.5 to 8.0. In some embodiments, the formulation has a pH of about 5.0 to 7.0. In some embodiments, the formulation has a pH of about 4.5 to 6.0. In some embodiments, the formulation has a pH of about 5.0 to 6.0.
  • the formulation has a pH of about 5.5 to 6.5. In some embodiments, the formulation has a pH of about 6.5 to 7.5. In some embodiments, the formulation has a pH of about 5.1 to 6.0, about 5.2 to 6.0, about 5.3 to 6.0, about 5.4 to 6.0, about 5.5 to 6.0, about 5.6 to 6.0, about 5.7 to 6.0, or about 5.8 to 6.0. In some embodiments, said formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,
  • the formulation has a pH of about 4.5.
  • the formulation has a pH of about 5.0.
  • the formulation has a pH of about 5.5.
  • the formulation has a pH of about 6.0.
  • the formulation has a pH of about 6.5.
  • the formulation has a pH of about 7.0.
  • the formulation has a pH of about 7.5.
  • the formulation has a pH of about 8.0.
  • the conjugate of albumin to exendin-4 is exendin-4(l-39)- Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate.
  • exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate refers to a conjugate made by covalently bonding a compound of the formula:
  • exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate can be formed by covalently linking the cysteine 34 side chain thiol of albumin to a [2-[2-[2- maleimidopropionamido(ethoxy)ethoxy] acetic acid linker, which in turn is covalently linked to the epsilon amino of the carboxy terminal lysine, i.e., lysine 40, of exendin-4(l-39) Lys 40 -NH 2 .
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, and optionally a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.5.
  • a buffer having a concentration of "no more than 0.05 M” includes a buffer having a concentration in the range of about 0 to 0.05 M, e.g., about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, and 0.05 M.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, and optionally a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.5.
  • a buffer having a concentration of "no more than 0.05 mM” includes a buffer having a concentration in the range of about 0 to 0.05 mM, e.g., about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04 mM.
  • the pharmaceutical formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-and 200 mM sodium chloride, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 20 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 20 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.5.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.5.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 15 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM succinate buffer at about pH 4.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM succinate buffer at about pH 4.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEAMPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, and 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEE A-MPA)-NH 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM citrate-phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM citrate-phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer containing 1- 20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-N3 ⁇ 4 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEE A-MPA)-NH 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate- phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about ph 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate- phosphate buffer at pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM L-histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM L-histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • exendin-4(l-39) Lys 40 ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride and a optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and a optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride and a optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68 and a optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68 and a optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM phosphate buffer at about pH 6.5-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM phosphate buffer at about pH 6.5-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 6.5-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 6.5-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at pH 6.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68. .
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the present invention provides methods for treating diabetes, obesity or other diseases or conditions treatable with an insulinotropic peptide, such as pre-diabetes (e.g., impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)), diabetes, e.g., type I diabetes, type II diabetes, late autoimmune diabetes in adults (“LADA") also known as late onset autoimmune diabetes of adulthood, slow onset type I diabetes, type 1.5 diabetes, steroid induced diabetes, Human Immunodeficiency Virus (HIV) Treatment-Induced Diabetes, diabetes development in subjects with congenital or HIV-Associated Lipodystrophy ("Fat Redistribution Syndrome"), obesity (i.e., BMI of 30 kg/m 2 or greater), overweight (i.e., BMI between 25 kg/m 2 and 30 kg/m 2 ), metabolic syndrome (Syndrome X), nervous system disorders, insulin resistance, hypoglycemia unawareness, restrictive lung disease, gastrointestinal disorders, e.g., irritable bowel syndrome, etc.
  • the present invention provides methods for treating diabetes, obesity, or other disorders treatable with an insulinotropic peptide by administering to a subject an effective amount of an insulinotropic peptide conjugate, e.g., in a pharmaceutical formulation described herein in combination with one or more second therapeutic agents.
  • the second therapeutic agent is an anti-diabetic agent.
  • the anti-diabetic agent is an oral antidiabetic agent (OAD), e.g., a biguanide, e.g., metformin.
  • OAD oral antidiabetic agent
  • kits comprising pharmaceutical formulations and dosage forms of the invention.
  • subject refers to an animal such as a mammal, including but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse and the like.
  • a primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • mouse and the like.
  • the subject is human.
  • the subject is a non-human animal, for instance, a non-human animal such as a cow, sheep, goat or horse.
  • the subject can be male or female.
  • insulinotropic means having insulinotropic activity, i.e., the ability to stimulate, or to cause the stimulation of, the synthesis or expression of the hormone insulin.
  • Insulinotropic peptides include, but are not limited to, GLP-1, exendin-3, exendin-4, and precursors, derivatives, or fragments of peptides such as GLP-1, exendin-3 and exendin-4 and other peptides with insulinotropic activity.
  • Glucagon-Like Peptide- 1 (“GLP-1”) and “GLP- 1 derivatives” are intestinal hormones and derivatives thereof, respectively, that generally simulate insulin secretion during hyperglycemia, suppress glucagon secretion, stimulate (pro) insulin biosynthesis and decelerate gastric emptying and acid secretion.
  • the glucagon-like peptide is GLP- 1(7- 37).
  • the glucagon-like peptide is GLP-l(7-36).
  • Exendin-3 is a naturally occurring GLP-1 agonist that can be isolated from salivary secretions of Heloderma horridum, the Mexican bearded lizard, and shares a 53% overlap with mammalian GLP-1 amino acid sequence, as disclosed in U.S. Pat. No. 5,424,286, which is incorporated by reference herein in its entirety.
  • the amino acid sequence of exendin-3 is
  • exendin-3 can refer either to exendin-3 purified from a natural source, or it can refer to chemically synthesized exendin-3, or exendin-3 produced by recombinant techniques.
  • Exendin-4" is a naturally occurring GLP-1 agonist that can be isolated from salivary gland venom of Heloderma suspectum, the Gila monster, and shares a 53% overlap with mammalian GLP-1 amino acid sequence as disclosed in U.S. Pat. No. 5,424,286, which is incorporated by reference herein in its entirety.
  • the amino acid sequence of exendin-4 is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 17).
  • Exendin-4 decreases glucagons and/or increases insulin secretion in a glucose-dependent manner, and mimics certain actions of GLP-1, including binding to and activating the human GLP-1 receptor.
  • Exendin-4 improves glycemic control by reducing fasting and postprandial glucose
  • exendin-4" can refer either to exendin-4 purified from a natural source, or it can refer to chemically synthesized exendin-4, or exendin-4 produced by recombinant techniques.
  • Reactive groups are chemical groups capable of forming a covalent bond. Such reactive agents can be coupled or bonded to an insulinotropic peptide of interest to form a modified insulinotropic peptide.
  • Reactive groups can generally be carboxy, phosphoryl, or acyl groups, either as an ester or a mixed anhydride, or an imidate, thereby capable of forming a covalent bond with functionalities such as an amino group, a hydroxy or a thiol at the target site on albumin.
  • the esters will include phenolic compounds, or be thiol esters, alkyl esters, phosphate esters, or the like.
  • Reactive groups include succinimidyl and maleimido groups.
  • “Functionalities” are groups on albumin with which reactive groups on modified insulinotropic peptides are capable of reacting to form covalent bonds. Functionalities include hydroxyl groups for bonding to ester reactive entities; thiol groups for bonding to maleimides and maleimido groups, imidates and thioester groups; and amino groups for bonding to carboxy, phosphoryl or acyl groups on reactive entities.
  • Linking groups are chemical moieties that can be used to connect reactive groups to insulinotropic peptides.
  • Linking groups can comprise one or more alkyl groups such as methyl, ethyl, propyl, butyl, etc. groups, alkoxy groups, alkenyl groups, alkynyl groups or amino group substituted by alkyl groups, cycloalkyl groups, polycyclic groups, aryl groups, polyaryl groups, substituted aryl groups, heterocyclic groups, and substituted heterocyclic groups.
  • Linking groups can also comprise poly ethoxy aminoacids such as AEA ((2-amino) ethoxy acetic acid) or a preferred linking group AEEA ([2-(2-amino)ethoxy)]ethoxy acetic acid).
  • AEA ((2-amino) ethoxy acetic acid)
  • AEEA [2-(2-amino)ethoxy)]ethoxy acetic acid
  • albumin refers to the most abundant protein in blood plasma having a molecular weight of approximately between 65 and 67 kilodaltons in its monomeric form, depending on the species of origin.
  • the term “albumin” is used interchangeably with “serum albumin” and is not meant to define the source of the albumin which forms a conjugate with the insulinotropic peptides of the invention.
  • the term “albumin” as used herein can refer either to albumin purified from a natural source such as blood or serous fluids, or it can refer to chemically synthesized albumin, or albumin produced by recombinant techniques. Exemplary forms of albumin of the insulinotropic peptide albumin conjugates described herein are provided in section V, E, i below.
  • an "insulinotropic peptide conjugate” comprises an insulinotropic peptide that has been conjugated to a protein such as albumin, transferrin, immunoglobulin, immunoglobulin Fc fragment, human chorionic gonadotropin, pseudo-PEG unstructured polypeptide, and elastin-like peptide, etc., or a polymer such as poly-ethylene glycol or other polymer via a covalent bond formed between the insulinotropic peptide and a functionality on the protein or polymer, respectively.
  • the insulinotropic peptide is coupled to the protein or polymer via a linking group.
  • the insulinotropic peptide has been modified to contain a reactive group to which a protein or polymer is covalently bound.
  • the reactive group is coupled to the insulinotropic peptide via a linking group.
  • An "insulinotropic peptide albumin conjugate” comprises an insulinotropic peptide that has been conjugated to albumin via a covalent bond formed between the insulinotropic peptide and a functionality on albumin.
  • the insulinotropic peptide has been modified to contain a reactive group to which albumin is covalently bound.
  • the reactive group is coupled to the insulinotropic peptide via a linking group.
  • Stability can be measured at a selected temperature for a selected time period.
  • the formulation is stable at room temperature (about 25 °C) or at 40 °C for at least 1, 2, 3, 4, 5, 6, 9, 12, 24 or 36 months and/or stable at about 2-8 °C for at least 1, 2, 3, 4, 5, 6, 9, 12, 24 or 36 months.
  • the formulation is preferably stable following freezing ⁇ e.g., -70 °C ).
  • the criteria for stability are as follows: (1) the formulation remains clear by visual analysis; (2) the concentration, pH and osmolality of the formulation has no more than about ⁇ 10% change; (3) no more than about 10%, more preferably no more than about 5%, or most preferably no more than about 1% of aggregate forms as measured by SEC-HPLC; and (4) no more than 10%, more preferably no more than about 5%, or most preferably no more than 1 % of peptide or peptide conjugate breaks down as measured by SDS-PAGE or RP-HPLC.
  • a peptide or peptide conjugate "retains its physical stability" in a pharmaceutical formulation if it shows substantially no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
  • the peptide of a peptide-conjugate retains its physical stability in a pharmaceutical formulation where less than about 10%, more preferably less than about 5, or most preferably less than about 1% of the peptide or peptide conjugate is present as an aggregate in the formulation.
  • a peptide or peptide conjugate "retains its chemical stability" in a pharmaceutical formulation if the chemical stability at a given time is such that the peptide is considered to retain its biological activity as defined below.
  • Chemical stability can be assessed by detecting and quantifying chemically altered forms of the peptide.
  • Chemical alteration may involve size modification (e.g. clipping) which can be evaluated using size exclusion chromatography, SDS- PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), for example.
  • Other types of chemical alteration include charge alteration (e.g. occurring as a result of deamidation) which can be evaluated by ion-exchange
  • a peptide or peptide conjugate "retains its biological activity" in a pharmaceutical formulation, if the peptide in a pharmaceutical formulation is biologically active for its intended purpose. For example, biological activity is retained if the biological activity of the peptide in the pharmaceutical formulation is at least about 70%, at least about 80%, or more preferably, at least about 90% (within the errors of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared.
  • the biological activity for a particular peptide will be the biological activity of the peptide known to those of skill in the art.
  • the biological activity of GLP-1 includes, but is not limited to, stimulation of insulin secretion during hyperglycemia, suppression of glucagon secretion, stimulation of (pro) insulin biosynthesis, deceleration of gastric emptying and acid secretion, and reduction of blood glucose levels.
  • a buffer refers to a substance that resists changes in pH and maintains the pH value of a solution in an acceptable range by the action of its acid-base conjugate components.
  • a buffered formulation described herein has a pH in the range from about 4 to about 8; preferably from about 5 to about 7; and most preferably has a pH in the range from about 5 to about 6.
  • the pH of the buffered formulation is about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0.
  • buffers that will control the pH in this range include acetate (e.g. sodium acetate), phosphate (e.g.
  • a "tonicity modifier” refers to a compound which, in appropriate amount, renders the formulation isotonic, such as, for example, sodium chloride, calcium chloride, magnesium chloride, lactose, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine and the like.
  • Isotonic is meant that the formulation of interest has essentially the same osmolarity as human blood. Isotonic formulations will generally have an osmolarity from about 250 to 350 mOsm, preferably from about 250 to about 330 mOsm. Osmolarity can be measured using a vapor pressure or ice-freezing type osmometer, for example.
  • a "surfactant” refers to a compound that reduces interfacial tension between a liquid and a solid when dissolved in solution, which can be added to the formulation to reduce aggregation of the reconstituted protein and/or reduce the formation of particulates in the reconstituted formulation.
  • surfactants useful for the formulations and methods described herein include polysorbates (e.g. polysorbates 20 or 80); poloxamers (e.g.
  • poloxamer 188 (pluronic F68)); Triton; sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g.
  • lauroamidopropyl myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUATTM series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol, etc.
  • a “stabilizer” refers to a compound that stabilizes the peptide or conjugate during fluctuations in storage temperature and minimizes degradation products, peptide degradants and aggregation.
  • Useful stabilizers in the formulations of the invention include, but are not limited to, sodium octanoate, myristic acid, Na-N-acetyltryptophan, L-glutamic acid, arginine, nitrogen and combinations thereof.
  • the stabilizer is sodium octanoate.
  • the stabilizer is myristic acid.
  • a "preservative” refers to a compound which can be added to the formulation to essentially reduce bacterial activity therein, thus facilitating the production of a multi-use formulation, for example.
  • useful preservatives include m-cresol, benzyl alcohol, methanol, ethanol, iso-propanol, butyl paraben, ethyl paraben, methyl paraben, phenol, glycerol, xylitol, resorcinol, cathechol, 2, 6-dimethylcyclohexanol, 2-methyl-2,4-pentadiol, dextran, polyvinylpyrrolidone, 2-chlorophenol, benzethonium chloride, merthiolate (thimersosal), benzoic acid (propyl paraben) MW 180.2, benzoic acid MW 122.12, benzalkonium chloride, chlorobutanol, sodium benzoate, sodium prop
  • a "bulking agent” refers to a compound which can add mass to a lyophilized mixture and contributes to the physical structure of a lyophilized cake (e.g. facilitates the production of an essentially uniform lyophilized cake which maintains an open pore structure).
  • Exemplary bulking agents include mannitol, glycine, polyethylene glycol and xorbitol.
  • bulking agents also typically impart useful qualities to the lyophilized composition such as modifying the collapse temperature, providing freeze-thaw protection, further enhancing the protein stability over long-term storage, and the like. These agents can also serve as tonicity modifiers.
  • a "reducing sugar” is one which contains a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins and a "non- reducing sugar” is one which does not have these properties of a reducing sugar.
  • reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose.
  • Nonreducing sugars include sucrose, trehalose, sorbose, melezitose and raffinose.
  • lyophilized pharmaceutical formulations as described herein are lyophilized in the absence of reducing sugars, or in the presence of only non-reducing sugars.
  • a "pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administration to mammals, preferably humans.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly injurious (e.g., fatal) to the subject.
  • the pharmaceutically acceptable carrier is approved for administration to humans by a government regulatory agency such as the Food and Drug Administration (FDA) or the European Medicines Agency (EMEA).
  • FDA Food and Drug Administration
  • EMEA European Medicines Agency
  • prevention refers to a reduction in the risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • prevention refers to the use of a compound or composition in a subject not yet affected by the disease or disorder or not yet exhibiting a symptom of the disease or disorder, for instance a subject not yet diabetic or not yet exhibiting the symptoms of diabetes.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) that exists in a subject.
  • “treating” or “treatment” refers to ameliorating at least one physical parameter of the disease or disorder, which may be indiscernible by the subject.
  • “treating or treatment” refers to beneficially modulating the disease, either physically (e.g., stabilization of a discernable symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • an "effective amount,” with respect to treatment means an amount of an insulinotropic peptide conjugate that when, administered to a subject for treating a disease is sufficient to treat the disease.
  • An effective amount can vary depending on, inter alia, the insulinotropic peptide used, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • the present invention provides pharmaceutical formulations of insulinotropic peptide conjugates.
  • the formulations can be suitable for administration via a parenteral route such as subcutaneous, intravenous, intramuscular, transdermal, intra-arterial, or intraperitoneal routes, or via other routes such as oral, topical, or inhalation routes.
  • the insulinotropic peptide in the conjugate can be any insulinotropic peptide known to those of skill in the art. It can be any peptide that is capable of stimulating, or causing the stimulation of, synthesis or expression of the hormone insulin.
  • the insulinotropic peptide is selected from the group consisting of glucagonlike peptide 1, exendin-3 and exendin-4 and their precursors, derivatives or fragments.
  • the insulinotropic peptide is exendin-4 or a derivative. Exemplary derivatives are described in detail below.
  • the insulinotropic peptide is conjugated to albumin. In some embodiments, the insulinotropic peptide is conjugated to serum albumin. In some embodiments, the insulinotropic peptide is conjugated to human serum albumin. In some embodiments, the insulinotropic peptide is conjugated to recombinant human albumin.
  • the insulinotropic peptide and insulinotropic peptide conjugate are described in detail in Section V below.
  • free albumin may be present in the formulations, at a concentration of about 80, 70, 60, 50, 40, 30, 25, 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 mg/ml. In certain embodiments, free albumin is present at less than about 80, 70, 60, 50, 40, 30, 20, 25, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 mg/ml. Preferably, free albumin is present at less than or equal to about 15 mg/ml, more preferably free albumin is present at less than or equal to 10 mg/ml, and most preferably less than 5 mg/ml. In some embodiments, the free albumin present in the formulations described herein is less than or equal to 10 mg/ml. In some embodiments, the free albumin present in the free albumin present in the free albumin present in the
  • the free albumin present in the formulations described herein is less than or equal to 1 mg/ml. In some embodiments, the free albumin present in the formulations described herein is less than or equal to 0.5 mg/ml. In some embodiments, the free albumin present in the formulations described herein is less than or equal to 0.1 mg/ml. In some embodiments, the free albumin present in the formulations described herein is less than or equal to 0.05 mg/ml. In other embodiments, no free albumin is detectable, e.g. , by one or more of the methods described below for quantifying free albumin, e.g. , by hydrophobic interaction chromatography, gel electrophoresis, LCMS, or reverse phase HPLC.
  • insulinotropic peptide conjugates in the formulations of the present invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • the formulations according to the present invention are suitable for subcutaneous administration of an insulinotropic peptide conjugate to a subject in need thereof.
  • the subject is administered a dose of the insulinotropic peptide conjugate in an amount between about 500 ⁇ g and 7000 ⁇ g (e.g.
  • the dosage of insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate
  • the insulinotropic peptide conjugate formulation which may be effective to treat a disease or condition described herein for a particular subject is administered to the subject in accordance with a weekly dosing regime.
  • the subject can be administered a total weekly dosage of the insulinotropic peptide conjugate over a number of weeks to achieve the desired therapeutic response.
  • the total weekly dose is administered in a single administration during the week, i.e., once a week, and the total weekly dose comprises the insulinotropic peptide conjugate in an amount of between about lOOC ⁇ g and 700C ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 150C ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g.
  • the total weekly dose is
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 3000 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 3500 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 4000 ⁇ g.
  • the total weekly dose is
  • the dose comprises the insulinotropic peptide conjugate in an amount of 4500 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 5000 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of between about 1000 ⁇ g and 3500 ⁇ g, amounting to a total weekly dose of between about 2000 ⁇ g and 7000 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each
  • administration comprises the insulinotropic peptide conjugate in an amount of 1000 ⁇ g, amounting to a total weekly dose of 2000 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1100 ⁇ g, amounting to a total weekly dose of 2200 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1200 ⁇ g, amounting to a total weekly dose of 2400 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1225 ⁇ g, amounting to a total weekly dose of 2500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1300 ⁇ g, amounting to a total weekly dose of 2600 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1400 ⁇ g, amounting to a total weekly dose of 2800 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g, amounting to a total weekly dose of 3000 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1600 ⁇ g, amounting to a total weekly dose of 3200 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1700 ⁇ g, amounting to a total weekly dose of 3400 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1750 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1800 ⁇ g, amounting to a total weekly dose of 3600 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1900 ⁇ g, amounting to a total weekly dose of 3800 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g, amounting to a total weekly dose of 4000 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2225 ⁇ g, amounting to a total weekly dose of 4500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g, amounting to a total weekly dose of 5000 ⁇ .
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1000 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 1500 ⁇ g, amounting to a total weekly dose of 2500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 1000 ⁇ g, amounting to a total weekly dose of 2500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2000 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 1500 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2500 ⁇ g, amounting to a total weekly dose of 4500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2000 ⁇ g, amounting to a total weekly dose of 4500 ⁇ g.
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • a method of treating a human subject having a fasting blood glucose level characteristic of the presence of diabetes comprising: (a) determining a value of the fasting blood glucose level of said subject, by a method comprising measuring said fasting blood glucose level, wherein said determining is performed by said subject;
  • the increased amount is too large practically to administer to the subject; wherein if the subject experiences one or more of said (i) - (iii) above, the next occurrence of said administering step comprises administering to the subject an amount of said compound that is the same or decreased relative to the amount of said compound most recently administered to said subject.
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the method comprising:
  • the value of the fasting blood glucose level of the subject is determined in an occurrence of said determining step to be below said fasting blood glucose level characteristic of the presence of pre-diabetes;
  • the increased amount is too large practically to administer to the subject; wherein if the subject experiences one or more of said (i) - (iii) above, the next occurrence of said administering step comprises administering to the subject an amount of said compound that is the same or decreased relative to the amount of said compound most recently administered to said subject.
  • the concentration of the insulinotropic peptide conjugate (without free albumin) in the formulations is from about 0.1 mg/ml to about 100 mg/ml, from about 0.1 mg/ml to about 75 mg/ml, from about 0.1 mg/ml to about 50 mg/ml, from about 0.1 mg/ml to about 40 mg/ml, from about 0.1 mg/ml to about 30 mg/ml, from about 1 mg/ml to about 100 mg/ml, from about 5 mg/ml to about 50 mg/ml, or from about 10 mg/ml to 20 mg/ml.
  • the concentration of the insulinotropic peptide conjugate in the formulations is higher than about 10 mg/ml, about 20 mg/ml, about 50 mg/ml, about 100 mg/ml, about 200 mg/ml, or about 500 mg/ml. In some embodiments, the concentration of the insulinotropic peptide conjugate in the formulations is lower than about 100 mg/ml, about 50 mg/ml, about 40 mg/ml, about 30 mg/ml, about 20 mg/ml, about 10 mg/ml, about 5 mg/ml, about 1 mg/ml, or about 0.1 mg/ml.
  • the concentration of the insulinotropic peptide conjugate in the formulations is about 1 mg/ml to about 50 mg/ml, from about 1 mg/ml to about 40 mg/ml, from about 1 mg/ml to about 20 mg/ml, or from about 1 to about 15 mg/ml. In particularly preferred embodiments, the concentration of the insulinotropic peptide conjugate in the formulations is about 1 mg/ml. In other particularly preferred embodiments, the concentration of the insulinotropic peptide conjugate in the formulations is about 2.5 mg/ml. In other particularly preferred embodiments, the concentration of the insulinotropic peptide conjugate in the formulations is about 5 mg/ml.
  • the concentration of the insulinotropic peptide conjugate in the formulations is about 10 mg/ml. In other particularly preferred embodiments, the concentration of the insulinotropic peptide conjugate in the formulations is about 20 mg/ml. In some embodiments, the amount of the insulinotropic peptide conjugate administered is about any of 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, or 1.0 mis or does not exceed 1.0 ml, the concentration of the insulinotropic peptide conjugate is greater than 10 mg/ml (e.g., 10 mg/ml to about 40 mg/ml), and the conjugate is administered subcutaneously. [0065] In certain embodiments, the formulations herein can be administered as monotherapy. In other words, the formulations herein can be provided as the sole administration of an active agent for treatment of one or more conditions provided herein.
  • the formulations herein can also be administered in combination with or can comprise one or more second therapeutic agents useful for the particular indication being treated, preferably those with complementary activities that do not adversely affect the insulinotropic peptide conjugate of the formulation.
  • second therapeutic agents can be present with the insulinotropic peptide conjugate in amounts that are effective for the purpose intended.
  • the second therapeutic agent is an anti-diabetic agent, e.g., an oral anti-diabetic agent, e.g., a biguanide, e.g., metformin.
  • the pharmaceutical formulations comprise a buffer that maintains a physiologically suitable pH. Exemplary physiologically suitable pH ranges are provided below.
  • the buffer can serve to enhance isotonicity and chemical stability of the formulation.
  • the pharmaceutical formulations do not comprise a buffer.
  • the formulation has a pH of about 3.0 to 8.0. In some embodiments, the formulation has a pH of about 4.0 to 8.0. In some embodiments, the
  • the formulation has a pH of about 4.5 to 7.0. In some embodiments, the formulation has a pH of about 4.0 to 6.0. In some embodiments, the formulation has a pH of about 6.0 to 8.0. In some embodiments, the formulation has a pH of about 6.0 to 9.0. In some embodiments, the
  • the formulation has a pH of about 6.5 to 8.0. In some embodiments, the formulation has a pH of about 5.0 to 7.0. In some embodiments, the formulation has a pH of about 4.5 to 6.0. In some embodiments, the formulation has a pH of about 5.0 to 6.0. In some embodiments, the
  • the formulation has a pH of about 5.5 to 6.5. In some embodiments, the formulation has a pH of about 6.5 to 7.5. In some embodiments, the formulation has a pH of about 5.1 to 6.0, about 5.2 to 6.0, about 5.3 to 6.0, about 5.4 to 6.0, about 5.5 to 6.0, about 5.6 to 6.0, about 5.7 to 6.0, or about 5.8 to 6.0.
  • said formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9 or 9.0.
  • the formulation has a pH of about 4.5.
  • a particular embodiment the formulation has a pH of about 4.5.
  • the formulation has a pH of about 5.0. In a particular embodiment, the formulation has a pH of about 5.5. In another particular embodiment, the formulation has a pH of about 6.0. In a particular embodiment, the formulation has a pH of about 6.5. In another particular embodiment, the formulation has a pH of about 7.0. In another particular embodiment, the formulation has a pH of about 7.5.
  • the pH can be adjusted as necessary by techniques known in the art. For example, hydrochloric acid or sodium hydroxide can be added as necessary to adjust the pH to desired levels.
  • Useful buffers in the buffered formulations described herein include, but are not limited to, acetate, phosphate, maleate, succinate, histidine (e.g., L-histidine),
  • the formulation can further comprise any counter-ion deemed suitable, such as sodium or calcium.
  • the buffer is present in an amount sufficient to maintain suitable pH. In some embodiments, the buffer is present in the formulations from about 0.1 mM to about 100 mM, from about 0.1 mM to about 50 mM, from about 0.1 mM to about 30 mM, about 0.1 mM to about 25 mM, from about 0.1 mM to about 20 mM, or from about 5 mM to about 15 mM. In certain embodiments, the buffer is at about 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, or 15 mM. In some embodiments, the buffer is a sodium acetate buffer or a succinate buffer at about 10 mM.
  • the formulations can comprise a tonicity modifier that contributes to maintain the isotonicity of the formulation.
  • the formulation is isotonic, i.e., the formulation possesses the same or about the same osmotic pressure as blood plasma. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm, preferably from about 250 to about 330 mOsm.
  • the formulation is hypertonic.
  • the formulation is hypotonic.
  • the tonicity modifier can be any tonicity modifier apparent to one of skill, such as a salt, a sugar, a sugar alcohol, a polyol or an amino acid.
  • exemplary tonicity modifiers include but are not limited to a salt such as sodium chloride, calcium chloride or magnesium chloride, a sugar or polyol such as lactose, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine and combinations thereof.
  • the tonicity modifier is sodium chloride.
  • the tonicity modifier is sorbitol.
  • combined tonicity modifiers yield a total osmolarity that is isotonic as described above.
  • salts or non-reducing sugars are preferred as tonicity modifiers.
  • a "non-reducing sugar” is one which does not contain a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins.
  • Non-reducing sugars include sucrose, trehalose, sorbose, melezitose and raffinose.
  • Non-reducing sugars can prevent or reduce chemical and/or physical instability of the peptides upon lyophilization and subsequent storage.
  • the tonicity modifier is present in the formulation in an amount to maintain desired tonicity of the formulation.
  • the tonicity modifier is present at about 0.1 % to about 50 % (w/v), about 0.5 % to about 20 % (w/v), about 1 % to about 10 % (w/v), or about 4 % to about 6 % (w/v). In some embodiments, the tonicity modifier is present at about 5 % (w/v). In some embodiments, the tonicity modifier is present at a concentration of at least 1 mM. In some embodiments, the tonicity modifier is present at about 1 mM to about 200 mM, from about 10 mM to about 150 mM or from about 50 mM to about 100 mM. In some preferred
  • the formulation comprises about 135 mM sodium chloride. In other preferred embodiments, the formulation comprises about 150 mM sodium chloride. In other preferred embodiments, the formulation comprises about 5% sorbitol (w/v).
  • the formulations can also comprise a stabilizer to stabilize the conjugate during fluctuations in storage temperature and to minimize degradation products, peptide degradants and aggregation.
  • Useful stabilizers in the formulations of the invention include, but are not limited to, sodium octanoate, myristic acid, Na-N-acetyltryptophan, L-glutamic acid, arginine, nitrogen and combinations thereof.
  • the stabilizer is sodium octanoate.
  • the stabilizer is myristic acid.
  • the stabilizer is present in the formulation at about 0.1 mM to 30 mM, about 0.5 mM and 20 mM, about 1 mM to about 15 mM, or about 5 mM to about 10 mM. In certain embodiments, the stabilizer is present in the formulation at about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 1 1 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM or 20 mM.
  • the stabilizer is sodium octanoate at about 5 mM. In another particular embodiment, the stabilizer is sodium octanoate at about 15 mM. In another particular embodiment, the stabilizer is myristic acid at about 0.1 mM.
  • the formulations can also comprise a surfactant.
  • Surfactants are compounds that reduce interfacial tension between a liquid and a solid when dissolved in solution, and can be added to the formulation to reduce aggregation of the reconstituted protein and/or reduce the formation of particulates in the reconstituted formulation.
  • Exemplary surfactants include polysorbates (e.g. polysorbates 20 or 80); poloxamers (e.g.
  • poloxamer 188 (pluronic F68)); Triton; sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl- betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g.
  • lauroamidopropyl myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUAT series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol, etc.
  • the amount of surfactant is such that it reduces aggregation of the formulated peptides or peptide conjugates and/or minimizes the formation of particulates in the formulation and/or reduces adsorption.
  • the surfactant can be present in the formulation in an amount of about 0.001-1 % (w/v), and preferably, about 0.01-0.5% (w/v).
  • the formulation comprises a surfactant which is a poloxamer.
  • the formulation comprises pluronic F68.
  • the formulation comprises between about 0.01% (w/v) and about 1% (w/v) pluronic F68, more preferably about 0.1% (w/v) pluronic F68.
  • the formulations comprise the above-identified agents (i.e. insulinotropic peptide conjugates, buffer, tonicity modifier, stabilizer and surfactant) and are free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol and benzethonium chloride.
  • a preservative can be included in the formulations, particularly where the formulations are multi-use formulations.
  • preservatives include but are not limited to m-cresol, benzyl alcohol, methanol, ethanol, isopropanol, butyl paraben, ethyl paraben, methyl paraben, phenol, glycerol, xylitol, resorcinol, cathechol, 2, 6- dimethylcyclohexanol, 2-methyl-2,4-pentadiol, dextran, polyvinylpyrrolidone, 2-chlorophenol, benzethonium chloride, merthiolate (thimerosal), benzoic acid (propyl paraben) MW 180.2, benzoic acid MW 122.12, benzalkonium chloride, chlorobutanol, sodium benzoate, sodium propionate, and cetylpyridinium chloride.
  • the preservatives are mercury- free. Any of these preservatives can be used as a sole preservative or in combination with each other in the
  • preservatives that are compatible with the buffer and other components of the formulations (i.e., the solution is clear) are used.
  • the buffer is sodium acetate or sodium phosphate
  • compatible preservatives include methanol, ethanol, iso-propanol, glycerol, resorcinol, 2-methyl-2,4-pentadiol, merthiolate (thimerosal), benzalkonium chloride, sodium benzoate, cetylpyridinium chloride.
  • the concentration of the preservative used in the formulations can be determined according to the judgment of those of skill in the art. In some embodiments, about 0.005 to 10% (w/v), about 0.1 to 1.0 % (w/v), or about 0.3 to 0.7 % (w/v) of the preservative is present in the formulations. In some embodiments, about 0.005, 0.1, 0.3, 0.5, 0.7, or 1.0 % (w/v) of the preservative is present in the formulations.
  • a bulking agent can be included in a lyophilized formulation to facilitate the production of an essentially uniform lyophilized cake which maintains an open pore structure.
  • Exemplary bulking agents include mannitol, glycine, polyethylene glycol and xorbitol. Bulking agents can also serve as a tonicity modifier as well.
  • One or more other pharmaceutically acceptable carriers, excipients or stabilizers for example, such as described in Remington's Pharmaceutical Sciences 19th edition, Genarro, A. Ed. (1995) can be included in the formulations provided that they do not significantly adversely affect the desired characteristics of the formulation.
  • Additional constituent elements of the formulations of the present invention can include water, e.g., water for injection, vegetable oil, a thickening agent such as methylcellulose antiadsorbant, a wetting agent, antioxidants including ascorbic acid and methionine, chelating agents such as EDTA, metal complexes (e.g. Zn-protein complexes), biodegradable polymers such as polyesters, and/or salt-forming counterions such as sodium etc.
  • Acceptable carriers, excipients or stabilizers are present in an amount such that they are nontoxic to subjects at the dosages and concentrations employed.
  • the optimal formulation according to the present invention can vary depending on factors such as the amount of time the formulation will be stored, conditions under which the formulation will be stored and used, the particular subject population to which the formulation may be administered, etc.
  • the formulations as described herein can be contained in a vial, bottle, tube, syringe or other container for single or multiple administrations.
  • Such containers can be made of glass or a polymer material such as polypropylene, polyethylene, polyvinylchloride, or polyolefin, for example.
  • the containers can include a seal, or other closure system, such as a rubber stopper that can be penetrated by a needle in order to withdraw a single dose and then re-seal upon removal of the needle.
  • the container is a 2-chamber syringe.
  • the container is a pen-type delivery apparatus comprising a single dose or multiple doses, i.e., it can be used for a single administration or multiple administration events.
  • a pen-type delivery apparatus can be permanent, e.g., a permanent pen that houses a disposable cartridge containing a single dose or multiple doses, or the entire apparatus can be disposable, e.g., a disposable pen that contains a single dose or multiple doses.
  • the dose can be pre-set, i.e., fixed.
  • the cartridge is a 2-chamber cartridge.
  • the dose can be a flexible dose, i.e., dialed-in by the user.
  • the pen-type delivery apparatus comprises a luer-lock, luer-cone, or other needle fitting connector that facilitates attachment of a disposable needle.
  • the pen-type delivery apparatus comprises a staked, i.e., permanent needle.
  • the container is a syringe.
  • the syringe comprises a luer-lock, luer-cone, or other needle fitting connector that facilitates attachment of a disposable needle.
  • the syringe comprises a staked, i.e., permanent, needle.
  • the syringe is prefilled with a single dose or multiple doses.
  • the formulations provided herein can be formulated in a variety of concentrations in various vial sizes for various administration dosages.
  • the dosages can be formulated in a 0.25, 0.5, 1, 2, or 3 ml vial, or any other size vial or other container known by one of skill in the art.
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to, or following, preparation of the formulation. Alternatively, sterility of the entire formulation can be accomplished by autoclaving the ingredients, except for protein, at about 120°C for about 30 minutes, for example.
  • the present invention provides a pharmaceutical formulation comprising a conjugate of albumin to exendin-4, or a derivative thereof, at a concentration from about 1 mg/ml to about 100 mg/ml, a buffer, a tonicity modifier, a stabilizer, a surfactant and optionally a preservative, wherein said formulation has a pH from about 4 to about 8.
  • the pharmaceutical formulation comprises, or alternatively consists of, a conjugate of albumin and an insulinotropic peptide, said insulinotropic peptide comprising a sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a buffer; a tonicity modifier, wherein the tonicity modifier is at a concentration of at least 1 mM; a stabilizer; and a surfactant, wherein said formulation has a pH from about 4 to about 8.
  • the exendin-4 albumin conjugate comprises recombinant human albumin cysteine 34 thiol covalently linked to a [2- [2- [2
  • the exendin-4 albumin conjugate is at a concentration of about 10 mg/ml to 20 mg/ml.
  • the buffer is a succinate, maleate, citrate -phosphate, L-histidine, or a sodium phosphate buffer or combinations thereof with a pH of about 4.0 to 7.0.
  • the tonicity modifier is sodium chloride.
  • the stabilizer is sodium octanoate or myristic acid.
  • the surfactant is pluronic F68.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, and optionally a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, and optionally a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, and optionally a preservative, wherein the formulation has a pH of about4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, and optionally a preservative, wherein the formulation has a pH of about4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 4.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.5.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.5 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 15 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 15 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.5.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 160 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.5.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.5.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M, wherein the formulation has a pH of about 6.5.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 5.5.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.5.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, optionally a preservative, and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 mM, wherein the formulation has a pH of about 6.5.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate and 0.1% (w/v) pluronic F68, wherein the formulation has a pH of about 6.5.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 4.0 to 7.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 5.5.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.0.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate, 150 mM sodium chloride, 15 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative, wherein the formulation has a pH of about 6.5.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM succinate buffer at about pH 4.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM succinate buffer at about pH 4.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM succinate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM succinate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a pre
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM succinate buffer at about pH 4.0 to 7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM succinate buffer at about pH 4.0 to 7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 1-15 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of exendin-4, or a derivative thereof, in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of exendin-4, or a derivative thereof, in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.0 to 7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 4.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM succinate buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM succinate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, and 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the formulation comprises 10 mg/ml of an
  • insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM maleate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM maleate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM maleate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM citrate-phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM citrate- phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chlor
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM citrate -phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM citrate -phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer containing 1- 20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate -phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM citrate -phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM citrate- phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM citrate -phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM citrate-phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM citrate -phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM citrate -phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM citrate -phosphate buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM citrate-phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM L-histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM L-histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chlor
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the formulation comprises 10 mg/ml of an
  • insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM L- histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM L-histidine buffer at about pH 5.0-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L- histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM L-histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L- histidine buffer at about pH 5.0-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 5.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM L-histidine buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and
  • insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 5.5-7.0, containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer containing 1-20 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 1-15 mM sodium octanoate, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 5.5-7.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 5 mM sodium octanoate, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 5-30 mM sodium phosphate buffer at about pH 6.0-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100- 200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 5-30 mM sodium phosphate buffer at about pH 6.0-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg
  • the formulation comprises 10 mg/ml of an
  • the formulation comprises 10 mg/ml of an
  • insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the pharmaceutical formulation comprises about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 6.0-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 5-30 mM sodium phosphate buffer at about pH 6.0-8.0, containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative, wherein said formulation has a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5-8.0 containing 0.01-5.0 mM myristic acid, 0.05 to 0.2% (w/v) pluronic F68, 100-200 mM sodium chloride, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation comprises 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and optionally a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l- 39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid and 0.1% (w/v) pluronic F68.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of an insulinotropic peptide conjugate in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml of a conjugate of albumin to exendin-4, or a derivative thereof, in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consists of or consists essentially of about 1 mg/ml to about 100 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0-8.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consist of or consists essentially of 10 mg/ml exendin- 4(1-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 6.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.0 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the formulation consist of or consists essentially of 10 mg/ml exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 albumin conjugate in 10 mM sodium phosphate buffer at about pH 7.5 containing 150 mM sodium chloride, 0.1 mM myristic acid, 0.1% (w/v) pluronic F68, and a preservative.
  • the pharmaceutical formulations provided herein can be in any form deemed useful to those of skill in the art. For instance, they can be in the form of liquid or lyophilized formulations, unit dosage forms or multi-use dosage forms and combinations thereof. Thus, the formulations include liquid unit dosage forms, liquid multi-use forms, lyophilized unit dosage forms and lyophilized multi-use dosage forms.
  • the formulation is a liquid formulation.
  • the formulation is a lyophilized formulation. Lyophilization is a commonly employed technique for preserving proteins which serves to remove water from the peptide preparation of interest. An excipient can be included in pre-lyophilized formulations to enhance stability during the freeze- drying process and/or to improve stability of the lyophilized product upon storage. See Pikal, M. 1990, Biopharm. 3(9):26-30 and Arakawa et al. 1991, Pharm. Res. 8(3):285-291.
  • Lyophilized formulations can be reconstituted according to the judgment of those of skill in the art.
  • a lyophilized formulation is provided which, when reconstituted, e.g., with water for injection, results in one of the liquid formulations described herein.
  • the present invention also provides a method of reconstituting a lyophilized formulation of an insulinotropic peptide conjugate comprising providing the lyophilized formulation, and reconstituting the lyophilized formulation to form an insulinotropic peptide conjugate formulation described herein.
  • the lyophilized formulation can be reconstituted with a diluent such that the protein concentration in the reconstituted formulation is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 25, 30, 35, 40, 45, 50 mg/ml.
  • the protein concentration in the reconstituted formulation is from about 1 mg/ml to about 100 mg/ml, from about 1 mg/ml to about 50 mg/ml, or from about 1 mg/ml to about 15 mg/ml.
  • the lyophilized formulation can be reconstituted with a diluent such that the protein concentration in the reconstituted formulation is about 45-55 mg/ml. In preferred embodiments, the lyophilized formulation can be reconstituted with a diluent such that the protein concentration in the reconstituted formulation is about 50 mg/ml.
  • the diluent can be any diluent deemed suitable by one of skill, e.g., water for injection, and the like.
  • the pharmaceutical formulations provided herein include both unit dosage forms and multi-use dosage forms.
  • the formulations are in unit dosage forms.
  • Unit dosage form refers to a packaged form of the pharmaceutical formulation in an amount that is intended for a single administration to a subject.
  • the formulations are in unit dosage forms.
  • the unit dosage comprises about 10-100,000 ⁇ g, 100- 50,000 ⁇ g, 1000-10,000 ⁇ g, or 1000-5000 ⁇ g insulinotropic peptide conjugate.
  • the unit dosages comprise about 100, 200, 300, 400, 500, 750, 1000, 20,000, 30,000, 40,000, 50,000, 75,000 or 100,000 ⁇ g insulinotropic peptide conjugate.
  • Such unit dosages can be prepared according to techniques known to those of skill in the art.
  • the formulations are in multi-use dosage forms. Multi-use formulations can facilitate ease of use for subjects, reduce waste by allowing complete use of vial contents and result in significant cost savings for manufacture. Multi-use pharmaceutical formulations can be contained in multi-dose containers, e.g., vials, ampoules, etc., that allow for the extraction of partial amounts of the formulations at various times. One or more preservatives compatible with the buffer in the formulations can be present in multi-use formulations as described in detail above.
  • the formulations of the present invention are stable.
  • the formulations are stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or more than 36 months at a temperature of about 4 °C.
  • the formulations are stable for at least about 1, 2 or 3 weeks, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
  • the formulations are stable for at least about 1, 2 or 3 weeks, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
  • the present invention provides methods of preparing pharmaceutical formulations of insulinotropic peptide conjugates.
  • the methods comprise combining the specified components as described herein so as to achieve the pharmaceutical formulations provided herein.
  • Formulations provided herein can be prepared by any technique apparent to one of skill in the art.
  • a formulation can be prepared by contacting an insulinotropic peptide conjugate with other components of the formulation under conditions suitable for preparation of the formulation.
  • the insulinotropic peptide conjugate can be mixed with the other components, dialyzed with the other components, diafiltered with the other components, or contacted with the other components by any technique apparent to one of skill in the art.
  • the insulinotropic peptide conjugate can be prepared by any technique apparent to one of skill in the art. Exemplary techniques are described herein.
  • the insulinotropic peptide conjugate can be purified according to any method deemed suitable by one of skill in the art. Exemplary methods are described herein.
  • the insulinotropic peptide conjugates of the formulations of the present invention can be purified according to any purification method known in the art prior to formulation in a desired formulation composition.
  • the conjugate is purified by hydrophobic interaction chromatography (HIC).
  • HIC can be any HIC technique known to those of skill.
  • the conjugate can be purified by two HIC purifications, e.g., two HIC purifications in sequence.
  • a first purification step comprises contacting an insulinotropic peptide conjugate with phenyl sepharose, i.e., a bead-formed agarose-based gel filtration matrix covalently coupled to a phenyl group.
  • this step separates non-conjugated insulinotropic peptide from albumin species, whether free or conjugated.
  • the phenyl sepharose is equilibrated with a phosphate buffer of pH 6.0 comprising 5 mM sodium octanoate and 5 mM ammonium sulfate. Under these conditions, non-conjugated compound is capable of binding to the phenyl sepharose while the conjugate is capable of flowing through the phenyl sepharose. The conjugate can then be collected as the flow through fraction for further purification.
  • purification of the conjugate further comprises a second HIC step wherein the phenyl sepharose flow-through is contacted with butyl sepharose, i.e., a bead- formed agarose-based gel filtration matrix covalently coupled to a butyl group, to further purify the conjugate from non-conjugated albumin, dimeric non-conjugated albumin, and residual non- conjugated compound.
  • the butyl sepharose is equilibrated in a buffer at or near pH 6.0 comprising 5 mM sodium octanoate and 750 mM ammonium sulfate.
  • elution of the conjugate can be achieved using either a linear or stepwise decreasing salt gradient, or a combination thereof, wherein non-conjugated albumin can be eluted with about 750 mM ammonium sulfate, dimeric non-conjugated albumin can be eluted with about 550 mM ammonium sulfate, compound-albumin conjugates (the desired species) can be eluted with about 100 mM ammonium sulfate, and unconjugated compound and other species can be eluted with water or an equivalent thereof.
  • these species can include, for example, dimeric, trimeric, or polymeric albumin conjugates, or albumin conjugate products comprising a stoichiometry of compound to albumin greater than 1 : 1.
  • purification of the conjugate further comprises washing and concentrating the conjugate by ultrafiltration following HIC.
  • sterile water, saline, or buffer can be used to remove ammonium sulfate and buffer components from the purified conjugate.
  • insulinotropic peptide conjugates can be purified according to the purification methods described in U.S. Pat. App. No. 11/645,297 (Publication No.
  • the conjugate can be reformulated in a desired formulation composition, e.g., a formulation of the present invention by any technique apparent to one of skill. See Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
  • liquid formulations can be prepared by mixing the components in a container and adding water or buffers to the desired volume and concentration.
  • Other exemplary techniques include dialysis, ultrafiltration, diafiltration, size exclusion chromatography, etc.
  • the conjugate can be contacted with formulation components under conditions that yield a formulation provided herein.
  • reformulation of the purified insulinotropic peptide conjugate comprises pooling into a suitable container fractions which contain the insulinotropic peptide conjugate eluted from the second HIC purification step described above, i.e., following butyl sepharose chromatography.
  • the pooled material can then be concentrated using any of
  • the pooled material can be concentrated using an ultrafiltration membrane and pumping system until a protein concentration of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more than 100 mg/ml is achieved. In a particular embodiment, the pooled material is concentrated to a protein concentration of about 70 mg/ml.
  • the concentrated product can then be diafiltered against at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 volumes of water, wherein the volume of the solution containing insulinotropic peptide conjugate is kept constant. In particular embodiments, the concentrated product is diafiltered against at least 10 volumes of water.
  • the diafiltered solution comprising the insulinotropic peptide conjugate can then be contacted, i.e., mixed with a desired formulation composition to achieve a formulation composition comprising the insulinotropic peptide conjugate.
  • a 5X concentration of the desired formulation composition can be prepared, and 4 parts solution containing the insulinotropic peptide conjugate can be mixed with 1 part 5X formulation solution to achieve an insulinotropic peptide conjugate formulation described herein.
  • the protein concentration of the resulting solution can be measured, and the protein concentration can be adjusted as required with formulation buffer to achieve a desired concentration of the insulinotropic peptide conjugate in IX formulation buffer.
  • the final concentration of the insulinotropic peptide conjugate in IX formulation buffer is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more than 100 mg/ml. In particular embodiments, the final concentration of the insulinotropic peptide conjugate in IX formulation buffer is about 10 mg/ml. In another particular embodiment, the final concentration of the insulinotropic peptide conjugate in IX formulation buffer is about 50 mg/ml.
  • the product can be further filtered according to any method known in the art before preparing for storage. [0140]
  • reformulation of the purified insulinotropic peptide conjugate can comprise the following steps. By way of example and not limitation the following is presented.
  • the concentrated product can then be diafiltered against at least 10 volumes of a diafiltration buffer comprising a desired formulation composition of the present invention, wherein the formulation composition does not include the surfactant poloxamer 188 (pluronic F68).
  • the concentrated product can be diafiltered against at least 10 volumes of diafiltration buffer, wherein the volume of the solution containing insulinotropic peptide conjugate is kept constant.
  • a "5X poloxamer 188 solution,” comprising a 5X concentration of the surfactant poloxamer 188, e.g., 0.5% (w/v) poloxamer 188, can then be prepared in the diafiltration buffer described above, and 4 parts solution containing the insulinotropic peptide conjugate can be mixed with 1 part 5X poloxamer 188 solution.
  • the protein concentration of the resulting solution can be measured, and the protein concentration can be adjusted as required with formulation buffer to achieve a concentration of about 50 mg/ml insulinotropic peptide conjugate in IX formulation buffer.
  • the product can be further filtered according to any method known in the art before preparing for storage.
  • lyophilized formulations can be prepared by contacting the peptide or peptide conjugate with other components and lyophilizing the resulting mixture.
  • Many freeze-dryers are available for this purpose such as Hull50TM (Hull, USA) or GT20TM (Leybold- Heraeus, Germany) freeze-dryers. Freeze-drying can be accomplished by freezing the formulation and subsequently subliming ice from the frozen content at a temperature suitable for primary drying. Under this condition, the product temperature is below the eutectic point or the collapse temperature of the formulation.
  • the shelf temperature for the primary drying will range from about -30 to -5 °C (provided the product remains frozen during primary drying) at a suitable pressure, ranging typically from about 50 to 250 mTorr.
  • the formulation, size and type of the container holding the sample (e.g., glass vial) and the volume of liquid will mainly dictate the time required for drying, which can range from a few hours to several days (e.g. 40-60 hrs).
  • a secondary drying stage can be carried out at about 0 to 40°C depending primarily on the type and size of container and the type of protein employed. However, in certain embodiments, a secondary drying step might not be necessary.
  • the shelf temperature throughout the entire water removal phase of lyophilization can be from about -30 to -5°C.
  • the time and pressure required for secondary drying will be that which produces a suitable lyophilized cake, dependent, e.g., on the temperature and other parameters.
  • the secondary drying time is dictated by the desired residual moisture level in the product and typically takes at least about 5 hours (e.g. 10-15 hours).
  • the pressure can be the same as that employed during the primary drying step. Freeze-drying conditions can be varied depending on the formulation and vial size.
  • the formulation is stable at room temperature (about 25 °C) or at 40 °C for at least 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 or 36 months and/or stable at about 2-8 °C for at least 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 or 36 months.
  • the formulation is preferably stable following freezing (e.g., -70 °C ).
  • the criteria for stability are as follows: (1) the formulation remains clear by visual analysis; (2) the concentration, pH and osmolality of the formulation has no more than about ⁇ 10% change; (3) no more than about 10%, more preferably no more than about 5%, or most preferably no more than about 1% of aggregate forms as measured by SEC-HPLC; and (4) no more than 10%, more preferably no more than about 5%, or most preferably no more than 1% of peptide or peptide conjugate breaks down as measured by SDS-PAGE or RP-HPLC.
  • the invention provides methods of evaluating a sample of an
  • the methods comprise: determining a value for the amount of one or more species in a sample containing an
  • insulinotropic peptide conjugate e.g., exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate; and comparing the value to a reference value, thereby evaluating the sample.
  • the reference value can be any predetermined value or range of values, e.g., a value which has been set by a government agency, e.g., the FDA, or another party, e.g., the manufacturer of an approved preparation of the insulinotropic peptide conjugate or by a compendial authority, e.g., the USP.
  • the species can be any species that one of skill in the art might evaluate in the sample. Examples include, but are not limited to, the insulinotropic peptide conjugate, unconjugated albumin and unconjugated insulinotropic peptide, or any derivative of such species.
  • the derivative of the unconjugated insulinotropic peptide can be a degraded peptide, for e.g. an oxidized peptide, e.g. oxidized at a methionine residue, a deaminated peptide, e.g. deaminated at an asparagine or glutamine residue, or an oxidized and deaminated peptide.
  • the species is a conjugate of multiple insulinotropic peptides with a macromolecule (for example; albumin), e.g. 2: 1 peptide to macromolecule or 3: 1 peptide to macromolecule or 4: 1 peptide to macromolecule.
  • a macromolecule for example; albumin
  • the species is exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate.
  • the species evaluated is unconjugated albumin.
  • the amount of unconjugated albumin in the sample is ⁇ 10.0 mg/ml.
  • the species evaluated is unconjugated exendin-4(l- 39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 .
  • the amount of unconjugated exendin-4(l- 39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 100 ⁇ . In some embodiments the amount of
  • unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 50 ⁇ g/ml. In some embodiments the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 40 ⁇ g/ml. In some embodiments the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 30 ⁇ g/ml. In some embodiments the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 is ⁇ 25 ⁇ g/ml.
  • the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 20 ⁇ g/ml. In some embodiments the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 10 ⁇ . In some embodiments the amount of unconjugated exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 5 ⁇ g/ml.
  • the species evaluated is degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 .
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 1000 ⁇ .
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 500 ⁇ .
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 400 ⁇ .
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 300 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 200 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- NH 2 is ⁇ 150 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 is ⁇ 100 ⁇ g/ml.
  • the amount of degraded exendin-4(l- 39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 90 ⁇ . In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ )- ⁇ 2 is ⁇ 80 ⁇ . In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 70 ⁇ . In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 60 ⁇ g/ml.
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 50 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- NH 2 is ⁇ 40 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - AEEA-MPA)-NH 2 is ⁇ 30 ⁇ g/ml. In some embodiments, the amount of degraded exendin-4(l- 39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 25 ⁇ .
  • the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 20 ⁇ . In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 15 ⁇ . In some embodiments, the amount of degraded exendin-4(l-39) Lys ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 10 gg/ml. In some embodiments, the amount of degraded exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 is ⁇ 5 ⁇ g/ml.
  • the species evaluated is exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - MPA)-NH 2 conjugated to albumin at a ratio of 2: 1.
  • the species evaluated is exendin-4(l-39) Lys 40 ( ⁇ - MPA)-NH 2 conjugated to albumin at a ratio of 3 : 1.
  • any method known in the art can be used to determine the amount of a species in a sample comprising an insulinotropic peptide conjugate.
  • the amount of an unconjugated species in a sample is determined by gel electrophoresis, liquid chromatography- mass spectrometry (LCMS), hydrophobic interaction chromatography, high performance liquid chromatography (HPLC), reverse phase chromatography, e.g. reverse phase HPLC, circular diochroism, melting temperature, osmolality, or ultraviolet absorbance, e.g. absorbance at 280 nm.
  • hydrophobic interaction chromatography is useful for detecting or quantifying conjugate, unconjugated albumin, unconjugated peptide and/or conjugates of multiple insulinotropic peptides with a macromolecule.
  • gel electrophoresis is useful for detecting or quantifying conjugate, unconjugated albumin, unconjugated peptide and/or conjugates of multiple
  • gel electrophoresis can be combined with immunological detection, e.g. western blot or enzyme-linked immunosorbent assay, to facilitate detection.
  • immunological detection e.g. western blot or enzyme-linked immunosorbent assay
  • LCMS is useful for detecting conjugate, unconjugated albumin, unconjugated peptide and/or conjugates of multiple insulinotropic peptides with a
  • reverse phase HPLC is useful for detecting or quantifying unconjugated peptide and/or derivatives of unconjugated peptide.
  • the disorder or condition treatable with an insulinotropic peptide is obesity.
  • the disorder or condition treatable with an insulinotropic peptide is diabetes.
  • the pharmaceutical formulations provided herein will normalize hyperglycemia through glucose-dependent, insulin-dependent and insulin-independent mechanisms.
  • the pharmaceutical formulations are useful as primary agents for the treatment of type II diabetes mellitus and as adjunctive agents for the treatment of type I diabetes mellitus.
  • the disorder or condition treatable with an insulinotropic peptide is type II diabetes.
  • the methods comprise the step of administering to the subject a therapeutically effective amount of an insulinotropic peptide conjugate formulation described herein.
  • the insulinotropic peptide conjugate is a conjugate of albumin to exendin-4, or a derivative thereof.
  • the subject is a human.
  • the pharmaceutical formulations are especially suited for the treatment of subjects with diabetes, both type I and type II, in that the action of the peptide is dependent on the glucose concentration of the blood, and thus the risk of hypoglycemic side effects are greatly reduced over the risks in using current methods of treatment.
  • the formulation comprises a conjugate of albumin and an insulinotropic peptide, said insulinotropic peptide comprising a sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a buffer; a tonicity modifier; a stabilizer; and a surfactant, wherein said formulation has a pH from about 4 to about 8.
  • the method comprises administering to a subject having type II diabetes mellitus a formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human albumin cysteine 34 thiol covalently linked to a [2- [2- [2 maleimidopropionamido(ethoxy)ethoxy] acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(l-39)Lys 40 - N3 ⁇ 4.
  • the method comprises administering to a subject having type II diabetes mellitus a formulation comprising a conjugate of the formula:
  • the pharmaceutical formulations of the present invention can also be used for the treatment of subjects with obesity.
  • the pharmaceutical formulations of the present invention can also be used for the treatment of subjects with any disorder or disease treatable with an insulinotropic peptide.
  • the subject is an animal, for example, a mammal, e.g., a non-human primate.
  • the subject is a human.
  • the subject can be a male or female subject.
  • the subject is a non-human animal, such as, for instance, a cow, sheep, goat, horse, cat or dog.
  • the subject is at risk for a disorder or a condition treatable with an insulinotropic peptide including, but not limited to, obesity and type II diabetes. In some embodiments the subject is at risk for obesity. In some embodiments the subject is at risk for type II diabetes.
  • the subject is not healthy. In some embodiments the subject has or suffers from a condition treatable with an insulinotropic peptide including, but not limited to, obesity or type II diabetes.
  • the subject is obese. In some embodiments, the subject is a human and has a Body Mass Index (BMI) of 30 kg/m 2 or greater. In some embodiments, the subject is a human and has a BMI between 30 kg/m 2 and 35 kg/m 2 . In some embodiments, the subject is a human and has a BMI of 35 kg/m 2 or greater. In some embodiments, the subject is a human and has a BMI of 40 kg/m 2 or greater. In some embodiments, the subject weighs more than 120% of the normal weight for its age and height and/or ethnicity.
  • BMI Body Mass Index
  • the subject has type II diabetes. In some embodiments, the subject has abnormal glucose levels. In particular embodiments, the subject has a high glucose level. In some embodiments, the subject is a human and has an average whole blood glucose level of 8 mmol/L (138 mg/dl) or greater, and/or an average plasma blood glucose level of 9.0 mmol/L (154 mg/dl) or greater. In some embodiments, the subject is a human and has an average whole blood glucose level between 8 mmol/L (138 mg/dl) and 16 mmol/L (281 mg/dl), and/or an average plasma blood glucose level between 9.0 mmol/L (154 mg/dl) and 17 mmol/L (314 mg/dl). In some embodiments, the subject is a human and has an average whole blood glucose level greater than 16 mmol/L (281 mg/dl), and/or an average plasma blood glucose level greater than 17 mmol/L (314 mg/dl).
  • the subject is a human and has a glycosylated hemoglobin (HbAlc) level of 6.5% or greater. In some embodiments, the subject is a human and has a HbAlc level between 6.5% and 11%. In some embodiments, the subject is human and has a HbAlc level of 11% or greater. In certain embodiments, the subject has a disease, disorder or condition treatable with an insulinotropic peptide, e.g., an insulinotropic peptide conjugate. For instance, the subject has Metabolic Syndrome.
  • HbAlc glycosylated hemoglobin
  • a subject with Metabolic Syndrome has three or more of the following criteria: (1) waist circumference of greater than 102 cm for men and greater than 88 cm for women; (2) serum triglycerides of greater than 1.7 mmol/1; (3) blood pressure of greater than 130/85 mmHg; (4) HDL-cholesterol of less than 1.0 mmol/1 in men and less than 1.3 mmol/1 in women; and (5) serum glucose of greater than 6.1 mmol/1 (greater than 5.6 mmol/1 may be applicable).
  • a subject with Metabolic Syndrome has diabetes or impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or insulin resistance (assessed by clamp studies), plus at least two of the following criteria: (1) waist-to-hip ratio of greater than 0.90 in men or greater than 0.85 in women; (2) serum triglycerides of greater than 1.7 mmol/1 or HDL-cholesterol of less than 0.9 mmol/1 in men and less than 1.0 mmol/1 in women; (3) blood pressure of greater than 140/90 mmHg; (4) urinary albumin excretion rate of greater than 20 micrograms/minute or
  • the subject has pre-diabetes (e.g., impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)).
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • the subject has diabetes, e.g., type I diabetes, type II diabetes.
  • the subject has late autoimmune diabetes in adults ("LADA") also known as late onset autoimmune diabetes of adulthood.
  • LADA late autoimmune diabetes in adults
  • the subject has slow onset type I diabetes.
  • the subject has type 1.5 diabetes.
  • the subject has steroid induced diabetes.
  • the subject has Human Immunodeficiency Virus (HIV) Treatment-Induced Diabetes.
  • HIV Human Immunodeficiency Virus
  • the subject has congenital or HIV-Associated Lipodystrophy ("Fat Redistribution Syndrome") related diabetes.
  • the subject has a nervous system disorder.
  • the subject has insulin resistance.
  • the subject has hypoglycemia unawareness.
  • the subject has restrictive lung disease.
  • the subject has a gastrointestinal disorder, e.g., irritable bowel syndrome (IBS), functional dyspepsia, or pain associated with gastrointestinal disorders, e.g., pain associated with IBS and functional dyspepsia.
  • the subject has inflammatory bowel disease (IBD), e.g., Crohn's disease and ulcerative colitis, or pain associated with IBD.
  • IBD inflammatory bowel disease
  • the subject has hyperglycemia, e.g., hyperglycemia associated with surgery (e.g., a major surgical procedure, e.g., coronary bypass surgery) e.g., hyperglycemia associated with surgery on subjects with diabetes, e.g., type II diabetes or metabolic syndrome.
  • the subject has coronary heart failure (CHF).
  • CHF coronary heart failure
  • the subject has a disorder associated with beta cell dysfunction, disorders associated with the absence of beta cells, or disorders associated with insufficient numbers of beta cells. .
  • the subject has a condition or disorder associated with toxic hypervolemia, such as renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension.
  • the subject is in need for altering his lipoprotein particle size and subclass composition or his concentration in fibrinogen.
  • the subject is obese. In some embodiments, the subject is obese but neither diabetic nor pre-diabetic; obese and diabetic or pre-diabetic; obese but not affected by metabolic syndrome; obese and affected by the metabolic syndrome; overweight but neither diabetic nor pre-diabetic; overweight and diabetic or pre-diabetic; overweight but not affected by metabolic syndrome; overweight and affected by metabolic syndrome; affected by metabolic syndrome but neither diabetic nor pre-diabetic (depending on the definition of metabolic syndrome); affected by metabolic syndrome but neither obese nor overweight.
  • the subject has one or more of the following characteristics: (1) diabetes or pre-diabetes; (2) overweight or obesity; and (3) metabolic syndrome.
  • the subject is naive to anti-diabetic agents.
  • the subject is naive to other anti-diabetic agents or naive to oral anti-diabetic agents (OAD).
  • OAD oral anti-diabetic agents
  • the subject has been previously treated with one or more other antidiabetic agents, e.g., an OAD.
  • the subject has been previously treated with metformin, a sulfonylurea, a thiazolidinedione or a combination thereof.
  • the subject is being treated with, i.e., on an active treatment regimen with an OAD.
  • the subject has been administered an OAD, e.g., metformin within 1 week, 2 days, or 1 day prior to the administration of the insulinotropic peptide conjugate.
  • the subject has been on a stable dose of >1000 mg metformin daily for at least 3 months. Exemplary OADs are provided below.
  • the subject is currently being treated with, i.e., on an active treatment regimen with metformin.
  • the subject has been administered metformin within 1 week, 2 days, or 1 day prior to the administration of the insulinotropic peptide conjugate.
  • the subject has been on a stable dose of >1000 mg metformin daily for at least 3 months.
  • the formulations herein can be administered as monotherapy.
  • the formulations herein can be provided as the sole administration of an active agent for treatment of one or more conditions provided herein.
  • an insulinotropic peptide conjugate can be used with or combined with one or more second therapeutic agents in the treatment or prevention of diabetes, obesity, or disorders treatable with an insulinotropic peptide, e.g., an insulinotropic peptide conjugate.
  • the combinations of these agents can produce a more effective treatment for such diseases or disorders than with either single treatment alone.
  • a formulation provided herein can be combined with a second therapeutic agent by any means deemed suitable by a practitioner of skill in the art.
  • the formulation can be administered as described herein, and the second therapeutic agent can be administered according to any means and according to any schedule and dose suitable for that agent.
  • Methods of administration, doses, and dose schedules are within the skill of those in the art and can be determined based on knowledge of the second active agent.
  • doses and dose schedules can be adjusted for combination therapy by those of skill in the art.
  • the formulation and the second agent need not be administerered together. However, in certain embodiments, where suitable, the formulation and the second agent can be administered together where appropriate.
  • the formulation can comprise the second agent in addition to the insulinotropic peptide where appropriate.
  • Second therapeutic agents can be used together with an insulinotropic peptide conjugate in the methods provided herein.
  • Second therapeutic agents include anti-diabetic agents, including oral-anti-diabetic agents (OADs) or anti-obesity agents.
  • OADs oral-anti-diabetic agents
  • anti-obesity agents include anti-diabetic agents, including oral-anti-diabetic agents (OADs) or anti-obesity agents.
  • Exemplary OADs which find use in the combination therapies provided herein include, but are not limited to, sulfonylureas, e.g. tolbutamide (Orinase), acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide, (Diabinese), glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), glibenclamide, glimepiride (Amaryl) or gliclazide (Diamicron); biguanides, e.g.
  • sulfonylureas e.g. tolbutamide (Orinase), acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide, (Diabinese), glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), glibenclamide
  • metformin, phenformin or buformin glinide, e.g., Starlix (nateglinide), Prandin (repaglinide), Glufast (mitiglinide); meglitinides, e.g. repaglinide (Prandin) or nateglinide (Starlix);
  • thiazolidinediones e.g. rosiglitazone (Avandia), pioglitazone (Actos) or troglitazone (Rezulin); or Alpha-glucosidase inhibitors, e.g. miglitol (Glyset) or acarbose (Precose/Glucobay).
  • the second therapeutic agent which finds use in the combination therapies provided herein is a dipeptidyl peptidase IV inhibitor (DPP IV inhibitor).
  • DPP IV inhibitor can be any compound that exhibits inhibition of the enzymatic activity of DPP-IV. Examples of DPP-IV inhibitors are described, for example, in (i) D. J. Drucker, 2003, Exp. Opin. Invest. Drugs, 12:87-100; (ii) K. Augustyns, et al., 2003, Exp. Opin. Ther. Patents, 13:499-510; (iii) C. F. Deacon, et al., 2004, Exp. Opin. Investig.
  • the DPP IV inhibitor is orally available or orally administered
  • the DPP IV inhibitor is an OAD as described herein.
  • OADs can include some or all DPP IV inhibitors described herein.
  • DPP-IV inhibitors include, but are not limited to, dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide, isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl, O-benzoyl hydroxylamine, as described e.g. in U.S. Pat. Nos.
  • DPP-IV inhibitors can be found in Application Publication Nos. WO 07/054577, WO 07/053865, WO 05/116029, WO 05/087235, WO 05/082348, WO
  • JP 2003238566 JP 2002531547, JP 2002527504, JP 2002517401, JP 2002516318, JP 2002363157, JP 2002356472, JP 2002356471, JP 2002265439, JP 2001510442, JP
  • the DPP-IV inhibitor is a small molecule with a molecular weight of less than 1000, 700 or 500 Daltons, e.g., an organic molecule other than a nucleic acid, or a protein or peptide.
  • the DPP-IV inhibitor is a ⁇ -aminoacid derivative, such as 3(R)- Amino-l-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a- ]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan-l-one (MK-0431 ; sitagliptin, Januvia), or its pharmaceutical salt, hydrate or polymorph, which are described in detail in U.S. Pat. No. 6,699,871, EP 1412357, WO 03/04498, and US 2003100563, the contents of each of which are incorporated by reference herein in their entireties.
  • MK-0431 sitagliptin, Januvia
  • the DPP-IV inhibitor is sitagliptin.
  • Sitagliptin is described as an orally active and selective DPP-IV inhibitor and was recently approved in the U.S. and in Europe for the treatment of diabetes alone or in combination with metformin or sulfonylurea or a PPARy agonist. See U.S. Pat. No. 6,699,871, Kim et al., 2005, J. Med. Chem. 48: 141-151, the contents of each of which are incorporated by reference herein in their entireties.
  • the DPP-IV inhibitor is cyanopyrrolidide, such as (l-[[3- hydroxy-l-adamantyl)amino] acetyl] -2-cyano-(S)-pyrrolidine (LAF237 or vildagliptin, Galvus), l-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728), or (lS,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[-3.1.0]hexane-3- carbonitrile (saxagliptin or BMS-47718, Onglyza), which are disclosed in detail, for example, in U.S.
  • cyanopyrrolidide such as (l-[[3- hydroxy-l-
  • the DPP-IV inhibitor is vildagliptin.
  • the DPP-IV inhibitor is NVP-DPP728.
  • Vildagliptin and NVP-DPP728 are described as an orally active and selective DPP-IV inhibitor. See Villhauer et al, 2002, J Med Chem 45:2362-2365, Villhauer et al, 2003, J Med Chem 46:2774-2789, the contents of each of which are incorporated by reference herein in their entireties.
  • Vildagliptin (LAF 237) is currently undergoing Phase III clinical trial in the United States. It is approved for use in Europe in combination in combination with metformin or sulfonylurea or a thiazolidinedione.
  • the DPP-IV inhibitor is saxagliptin. Saxagliptin is currently in Phase III clinical trail in the U.S. and Europe for the treatment of type II diabetes. See Augeri et al., 2005, J. Med. Chem. 48(5):5025-5037, the contents of which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is 3-(L-Isoleucyl)thiazolidine (isoleucine- thiazolidide or PSN-9301). Isoleucine-thiazolidide can be found in JP 2001510442, WO
  • Isoleucine-thiazolidide is described as an orally active and selective DPP-IV inhibitor. See Pederson et al, 1998, Diabetes 47: 1253-1258; Epstein et al., 2007, Curr. Opion. Investig. Drugs, 8(4):331-337, the contents of each of which are incorporated by reference herein in their entireties.
  • the DPP-IV inhibitor is SYR-322 (TAK-622, alogliptin) or SYR-472 such as described in U.S. Pat. Nos. 7, 169,926 and 7,034,039, the contents of each of which are incorporated by reference herein in their entireties.
  • the DPP-IV inhibitor is valine-pyrrolidide, such as disclosed in Deacon et al, Diabetes (1998) 47:764769; which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is [l-[2(S)-Amino-3- methylbutyryl]pyrrolidin-2(R)-yl]boronic acid (PT-100).
  • the DPP-IV inhibitor is ⁇ -phenethylamine, such as described in Nordhoff et al., 2006, Bioorganic Medical Chemistry Letters 16: 1744-1748, is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is PT-630 (DB-160), such as described in Application Publication No. WO 06/034435, which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is ABT-341 , such as described in Pei et al, J. Med. Chem. 2006 Nov 2; 49(22):6439-42, which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is ABT-279, such as described in Madar et al, J. Med. Chem. 2006 Oct 19; 49(21):6416-20, which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is BI- 1356 (Ondero, linagliptin), such as described in Application Publication No. WO 04/18468, which is incorporated by reference herein in its entirety.
  • the DPP-IV inhibitor is SYR-619.
  • the DPP-IV inhibitor is GSK-823093.
  • the DPP-IV inhibitor is PSN 9301.
  • the DPP-IV inhibitor is TA-6666.
  • the DPP-IV inhibitor is CR- 14023. [0200] In certain embodiments, the DPP- -IV inhibitor is CR- 14025.
  • the DPP- -IV inhibitor is CR- 14240.
  • the DPP- -IV inhibitor is CR- 13651.
  • the DPP- -IV inhibitor is NNC-72-2138.
  • the DPP- -IV inhibitor is NN-7201.
  • the DPP- -IV inhibitor is PHX-1149.
  • the DPP- -IV inhibitor is PHX-1004.
  • the DPP- -IV inhibitor is SNT- 189379.
  • the DPP- -IV inhibitor is GRC-8087.
  • the DPP- -IV inhibitor is SK-0403.
  • the DPP- -IV inhibitor is GSK-825964.
  • the DPP- -IV inhibitor is TS-021.
  • the DPP- -IV inhibitor is GRC-8200, melogliptin.
  • the DPP- -IV inhibitor is GRC-8116.
  • the DPP- -IV inhibitor is FE 107542.
  • the DPP- -IV inhibitor is MP-513, tenegliptin.
  • the DPP- -IV inhibitor is BI356.
  • the DPP- -IV inhibitor is ALS 2-0426, AMG-222.
  • the DPP- -IV inhibitor is ABT279.
  • the DPP- -IV inhibitor is TS-201.
  • the DPP- -IV inhibitor is KRP-104.
  • the DPP- -IV inhibitor is R1579, carmegliptin.
  • the DPP- -IV inhibitor is LY2463665.
  • the DPP- -IV inhibitor is ARI-2243.
  • the DPP- -IV inhibitor is SSR-162369.
  • the second therapeutic agent is an insulin receptor agonist.
  • the insulin receptor agonist is human insulin or insulin analog; basal insulin such as Lantus (insulin glargine), Levemir (insulin detemir), insulin degludec (SIBA; NN1250), insulin degludec plus (insulin degludec + aspart mix; SIAC; NN5401), NN-344, LY-2,605,541, SuliXen (PolyXen insulin), SAR- 161,271, InsuLAR (ProPhase insulin), BIOD-Adjustable Basal insulin, Albulin-G (insulin albumin fusion protein), PC-DAC:insulin, or DACdnsulin; or fast acting insulin such as Novolog (insulin aspart), Humalog (insulin lispro), Apidra (insulin glulisine); or non-injectable formulations of insulin such as Afresa (technosphere inhaled insulin) or
  • the second therapeutic agent is glucose-dependent insulinotropic peptide/ gastric inhibitory polypeptide (GIP) analog; glucagon receptor (GCGR) antagonist such as BAY-27-9955, Cpd G, or ISIS-325,568; glucocorticoid receptor (GCCR) antagonist such as ISIS-377, 131 ; a chromium and vanadium salt or derivative; 1 lbeta-hydroxy steroid
  • dehydrogenase (1 lbeta-HSDl and 1 lbeta-HSD2) dehydrogenase and reductase inhibitor such as BVT-3498; a protein tyrosine phosphatase lb (PTP lb) inhibitor; glucose transporter (GLUT) and isoforms (GLUT1, GLUT4) inhibitor; sodium-glucose cotransporter and isoforms (SGLT1, SGLT2) inhibitor such as dapaglifozin, sergilfozin, remogliflozin, BI-10,733, JNJ-28431754/ TA-7284, LX-4211, and AVE-2268; sirtuin (SIRT) and isoforms agonist (SIRT1) such as resveratrol, SRT-501 ; a PPAR gamma/ delta agonist; a PPAR alpha/ gamma agonist such as tesaglitasar, muragli
  • GK glucokinase activator
  • GNK glycogen phosphates
  • GP glycogen phosphates
  • INGAP beta-cell growth factor
  • CD- 3 antagonist such as teplizumab, GAD65 antagonist such as Diamyd, DiaPep277, interleukin- 1 inhibitor (IL-1) such as XOMA-052, jun N-terminal kinase (JNK) inhibitor, tolerogen such as NBI-6024, TRX4.
  • the second therapeutic agent is an anti-obesity agent.
  • the anti-obesity agent is a cannabinoid 1 receptor (CB 1 R) inverse agonist and antagonist such as Acomplia/ Zimulti (rimonabant), Meridia (Sibutramine), or Xenical (Orlistad).
  • CBD 1 R cannabinoid 1 receptor
  • the second therapeutic agent is a gastro-intestinal hormone analog.
  • the gastro-intestinal hormone analog is a glucagon-like peptide-2 (GLP-2) analog such as Gattex (teduglutide); a peptide YY analog such as PYY(l-36), PYY(3- 36); a pancreatic polypeptide (PP) analog; or a gastrin analog.
  • GLP-2 glucagon-like peptide-2
  • Gattex teduglutide
  • a peptide YY analog such as PYY(l-36), PYY(3- 36
  • PP pancreatic polypeptide
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has been previously treated with an anti-diabetic agent.
  • Previous treatments with any antidiabetic agent known in the art can serve as a basis for identifying a subject for treatment with an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate described herein.
  • Exemplary anti-diabetic agents are provided above.
  • the anti-diabetic agent is an oral anti-diabetic agent (OAD).
  • the subject is identified for treatment if the subject has not been previously treated with an antidiabetic agent, e.g., an OAD. In other embodiments, the subject is identified for treatment if the subject has previously been treated with an anti-diabetic agent, e.g., an OAD. Whether a subject has been previously treated with an anti-diabetic agent, e.g., an OAD, can be determined according to the judgment of the practitioner in the art. In certain embodiments, the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has experienced hypoglycemia with the other anti-diabetic agent.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has undergone previous treatment and experienced weight gain or undesirable weight gain.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has been previously treated with a second active agent, e.g., an OAD such as sulfonylurea, metformin or a thiazolidinedione, the method can further comprise determining whether administration of the anti-diabetic agent resulted in a desirable therapeutic outcome, for example, acceptable control of the subject's glucose levels as determined by a practitioner of skill in the art.
  • a second active agent e.g., an OAD such as sulfonylurea, metformin or a thiazolidinedione
  • Acceptable glycemic control can be indicated by, but limited to, a decrease in whole blood glucose, a decrease in plasma blood glucose, a decrease in interstitial glucose (IG), and/or a decrease in HbAlc levels.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been administered an anti-diabetic agent, e.g., an OAD, e.g., resulting in acceptable control of the subject's glucose levels.
  • an anti-diabetic agent e.g., an OAD
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been administered an anti-diabetic agent, e.g., an OAD, not resulting in acceptable control of the subject's glucose levels.
  • the foregoing methods can further comprise administering to the identified subject the insulinotropic peptide conjugate or formulation.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has been administered an antidiabetic agent, e.g., an OAD, prior to the first administration of the insulinotropic peptide conjugate.
  • the OAD is metformin.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has been administered another antidiabetic agent, e.g., an OAD, not more than 30, 25, 20, 15, 10 or 5 days ago (as measured from the time of the identifying), said method further comprising administering the insulinotropic peptide conjugate or formulation within 30, 25, 20, 15, 10 or 5 days of the administration of the other antidiabetic agent.
  • another antidiabetic agent e.g., an OAD
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has not been administered an effective amount of another antidiabetic agent, e.g., an OAD, and then administering the other antidiabetic agent at the time (e.g. within the same hour or the same day as) of the first administration of the insulinotropic peptide conjugate.
  • another antidiabetic agent e.g., an OAD
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has not been administered an effective amount of another antidiabetic agent, e.g., an OAD, and then administering to the subject a first administration of the insulinotropic peptide conjugate or formulation.
  • an antidiabetic agent e.g., an OAD
  • the present invention provides methods for treating a subject having pre-diabetes, e.g., impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), comprising administering to said subject an insulinotropic peptide conjugate, e.g., an ITT peptide conjugate, e.g., an ITT peptide conjugate, e.g., an ITT peptide conjugate, e.g., an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate, e.g.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has has IFG and/or IGT. In some embodiments, the methods comprise identifying a subject that has a diagnosis of IFG by a practitioner in the art. In some
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has that has fasting plasma glucose levels of > 100 mg/dl (5.6 mmol/1) but ⁇ 126 mg/dl (7.0 mmol/1).
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has that has a diagnosis of IGT by a practitioner in the art.
  • the methods comprise identifying a subject that has 2-hour oral glucose tolerance test levels of > 140 mg/dl (7.8 mmol/1) but ⁇ 200 mg/dl (11.1 mmol/1).
  • the foregoing methods can further comprise administering to the identified subject the insulinotropic peptide conjugate or formulation.
  • the present invention provides methods for treating a subject who is obese but neither diabetic nor pre-diabetic, comprising administering to said subject an insulinotropic peptide conjugate, e.g., an insulinotropic peptide conjugate formulation described herein, in an amount effective to treat obesity.
  • an insulinotropic peptide conjugate e.g., an insulinotropic peptide conjugate formulation described herein
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that is obese but neither diabetic nor pre-diabetic for treatment with an insulinotropic peptide conjugate, wherein the methods comprise identifying a subject that has been previously treated with an anti-obesity agent.
  • the anti-obesity agent is Orlistat.
  • the anti-obesity agent is Sibutramine.
  • the anti-obesity agent is Liraglutide (NN2211). Liraglutide (NN2211) is a GLP-1 analog having the structure
  • the subject is selected for treatment if the subject has not been previously treated with Liraglutide.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been treated with Liraglutide. The foregoing methods can further comprise administering to the identified subject the insulinotropic peptide conjugate or formulation.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been administered Liraglutide resulting in a desirable therapeutic outcome, for example, weight loss amounting to greater than 5% of the subject's baseline weight, as determined by a practitioner of skill.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been administered Liraglutide resulting in weight loss amounting to greater than 5% of the subject's baseline weight.
  • the present invention provides methods of selecting a subject for treatment with an insulinotropic peptide conjugate or formulation provided herein, comprising identifying a subject that has previously been administered Liraglutide not resulting in weight loss amounting to greater than 5% of the subject's baseline weight.
  • the foregoing methods can further comprise administering to the identified subject the insulinotropic peptide conjugate or formulation.
  • the insulinotropic peptide conjugates and formulations provided herein provided herein can be used as a sedative.
  • a method of sedating a mammalian subject having an abnormality resulting in increased activation of the central or peripheral nervous system comprises administering a pharmaceutical formulation comprising an insulinotropic peptide conjugate described herein to the subject in an amount sufficient to produce a sedative or anxiolytic effect on the subject.
  • the pharmaceutical formulation can be administered intracerebroventricularly, orally, subcutaneously,
  • Such methods are useful to treat or ameliorate nervous system conditions such as anxiety, movement disorder, aggression, psychosis, seizures, panic attacks, hysteria and sleep disorders.
  • the invention encompasses a method of increasing the activity of a mammalian subject, comprising administering a pharmaceutical formulation comprising an insulinotropic peptide conjugate described herein to the subject in an amount sufficient to produce an activating effect on the subject.
  • a pharmaceutical formulation comprising an insulinotropic peptide conjugate described herein to the subject in an amount sufficient to produce an activating effect on the subject.
  • the subject has a condition resulting in decreased activation of the central or peripheral nervous system.
  • the pharmaceutical formulations can be used in the treatment of an insulinotropic peptide-related disease or condition.
  • the pharmaceutical formulations can be used in the treatment or amelioration of depression, schizoaffective disorders, sleep apnea, attention deficit syndromes with poor concentration, memory loss, forgetfulness, and narcolepsy, to name just a few conditions in which arousal of the central nervous system may be advantageous.
  • the insulinotropic peptide conjugates and formulations provided herein provided herein can also be used to induce arousal for the treatment or amelioration of depression, schizoaffective disorders, sleep apnea, attention deficit syndromes with poor concentration, memory loss, forgetfulness, and narcolepsy.
  • the therapeutic efficacy of the treatment can be monitored by subject interview to assess their condition, by psychological/neurological testing, or by amelioration of the symptoms associated with these conditions.
  • treatment of narcolepsy can be assessed by monitoring the occurrence of narcoleptic attacks.
  • effects of modified ITPs on the ability of a subject to concentrate, or on memory capacity can be tested using any of a number of diagnostic tests well known to those of skill in art.
  • the insulinotropic peptide conjugates and formulations provided herein provided herein can be utilized for post surgery treatments.
  • a subject is in need of a pharmaceutical formulation comprising a conjugated insulinotropic peptide described herein for about 1-16 hours before surgery is performed on the subject, during surgery on the subject, and after the subject's surgery for a period of not more than about 5 days.
  • the pharmaceutical formulations are administered from about sixteen hours to about one hour before surgery begins.
  • the length of time before surgery when the compounds used in the present invention should be administered in order to reduce catabolic effects and insulin resistance is dependent on a number of factors. These factors are generally known to the physician of ordinary skill, and include, most importantly, whether the subject is fasted or supplied with a glucose infusion or beverage, or some other form of sustenance during the preparatory period before surgery. Other important factors include the subject's sex, weight and age, the severity of any inability to regulate blood glucose, the underlying causes of any inability to regulate blood glucose, the expected severity of the trauma caused by the surgery, the route of administration and bioavailability, the persistence in the body, the formulation, and the potency of the compound administered.
  • a preferred time interval within which to begin administration of the modified insulinotropic peptides used in the present invention is from about one hour to about ten hours before surgery begins. The most preferred interval to begin administration is between two hours and eight hours before surgery begins.
  • Insulin resistance following a particular type of surgery is most profound on the first post-operative day, lasts at least five days, and may take up to three weeks to normalize.
  • the post-operative subject may be in need of administration of the pharmaceutical formulations of the present invention for a period of time following the trauma of surgery that will depend on factors that the physician of ordinary skill will comprehend and determine.
  • the subject is fasted or supplied with a glucose infusion or beverage, or some other form of sustenance following surgery, and also, without limitation, the subject's sex, weight and age, the severity of any inability to regulate blood glucose, the underlying causes of any inability to regulate blood glucose, the actual severity of the trauma caused by the surgery, the route of administration and bioavailability, the persistence in the body, the formulation, and the potency of the compound administered.
  • the preferred duration of administration of the compounds used in the present invention is not more than five days following surgery.
  • the insulinotropic peptide conjugates and formulations provided herein provided herein can be utilized to treat insulin resistance independently from their use in post surgery treatment.
  • Insulin resistance may be due to a decrease in binding of insulin to cell-surface receptors, or to alterations in intracellular metabolism.
  • the first type characterized as a decrease in insulin sensitivity
  • the second type characterized as a decrease in insulin responsiveness, cannot be overcome by large quantities of insulin.
  • Insulin resistance following trauma can be overcome by doses of insulin that are proportional to the degree of insulin resistance, and thus is apparently caused by a decrease in insulin sensitivity.
  • the insulinotropic peptide conjugates and formulations provided herein can be used in the treatment of an insulinotropic peptide related disease or condition while reducing nausea side effect such as described in U.S. Pat. App. No. 11/595,576 (Publication No. 2007/0207958), entitled “Method of Treatment of Diabetes and/or Obesity with Reduced Nausea Effect,” filed November 9, 2006, which is incorporated by reference herein in its entirety.
  • the insulinotropic peptide conjugates and formulations provided herein can be used to alter the concentration of fibrinogen in a subject in need thereof.
  • Provided herein are methods of decreasing the concentration of fibrinogen in a subject with an elevated level of fibrinogen the methods comprising administering to the subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the concentration of fibrinogen is decreased in the subject.
  • Provided herein are methods of providing an improved cardiovascular risk profile of a subject with an elevated level of fibrinogen comprising administering to the subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein and measuring a decrease in the concentration of fibrinogen in the subject, wherein the cardiovascular risk profile of the subject is improved.
  • methods of treating a subject with an elevated level of fibrinogen comprising administering to the subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the concentration of fibrinogen in the subject is decreased.
  • the insulinotropic peptide conjugates and formulations provided herein can be used to alter the lipoprotein particle size or subclass composition in a subject in need thereof.
  • Provided herein are methods for increasing the concentration of large LDL, large HDL, total HDL or any combination of said lipoproteins in a subject in need thereof comprising administering to said subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the concentration of large LDL, large HDL, total HDL, or any combination of said lipoproteins is increased in said subject.
  • kits for increasing the concentration of large LDL, large HDL, total HDL or any combination of said lipoproteins in a subject who has a decreased large LDL, large HDL, total HDL level, or any combination thereof comprising administering to said subject a an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the concentration of large LDL, large HDL, total HDL, or any combination of said lipoproteins is increased in said subject.
  • methods for decreasing the concentration of small LDL, very small LDL, total LDL or any combination of said lipoproteins in a subject who has an elevated level of small LDL, very small LDL, total LDL or any combination thereof comprising administering to said subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the concentration of small LDL is decreased.
  • methods for providing an improved cardiovascular risk profile of a subject who has a decreased level of large LDL, large HDL, total HDL or any combination thereof comprising administering to said subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein and measuring an increased concentration of large LDL, large HDL, total HDL or any combination of said lipoproteins, wherein the cardiovascular risk profile of said subject is improved.
  • methods for increasing the average particle size of LDL or HDL in a subject in need thereof comprising administering to said subject an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the particle size of LDL or HDL is increased in said subject.
  • kits for increasing the average particle size of LDL or HDL in a subject who has an elevated level of small LDL, a decreased level of large HDL, a decreased level of total HDL or any combination thereof comprising administering to said subject a an effective amount of an insulinotropic peptide conjugate or formulation provided herein, wherein the particle size of LDL or HDL is increased in said subject.
  • insulinotropic peptide conjugates e.g., insulintropic peptide conjugate
  • the insulinotropic peptide conjugates can be administered according to any technique deemed suitable by one of skill in the art.
  • the insulinotropic peptide conjugates e.g., insulinotropic peptide conjugate formulations
  • enterally e.g.,
  • insulinotropic peptide conjugates e.g., insulinotropic peptide conjugate formulations
  • the insulinotropic peptide conjugate is administered
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • a needle e.g., a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, a 31-gauge needle, a 32-gauge needle, or a 33-gauge needle, or a higher gauge needle.
  • the dosage and frequency of administration of the insulinotropic peptide conjugates e.g., insulinotropic peptide conjugate formulations, can be determined by one skilled in the art.
  • an insulinotropic peptide conjugate that will be effective in the treatment of a disorder or condition will vary with the nature and severity of the disorder or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the severity of the disorder or condition, the route of administration, as well as age, body weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • Exemplary doses of an insulinotropic peptide conjugate include milligram or microgram amounts of the insulinotropic peptide conjugate per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 50 microgram per kilogram, e.g., about 10 microgram per kilogram to about 30 microgram per kilogram).
  • the dosage of insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate
  • insulinotropic peptide conjugate formulation which may be effective to achieve the desired therapeutic response for a particular subject is administered to the subject in accordance with a weekly dosing regime administered over a number of weeks.
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation can be administered twice a week (e.g., as two of the same or different doses).
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation can be administered two times every 9, 10, 11, 12, 13 or 14 day period.
  • the dose is administered once a week or twice a week and the dose comprises the insulinotropic peptide conjugate in an amount between about 500 ⁇ g and 6000 ⁇ g (e.g., 525 ⁇ g, 550 ⁇ g, 575 ⁇ g, 600 ⁇ g, 625 ⁇ g, 650 ⁇ g, ,675 ⁇ g, 700 ⁇ g, 725 ⁇ g, 750 ⁇ g, 775 ⁇ ⁇ , 800 ⁇ ⁇ , 825 ⁇ ⁇ , 850 ⁇ ⁇ , 875 ⁇ ⁇ , 900 ⁇ ⁇ , 925 ⁇ ⁇ , 950 ⁇ ⁇ , 975 ⁇ ⁇ , 1000 ⁇ ⁇ , 1025 ⁇ g, 1050 ⁇ g, 1075 ⁇ g, ⁇ ⁇ , 1125 ⁇ , 115( ⁇ g, 1175 ⁇ g, 1200 ⁇ g, 1225 ⁇ g, 1250 ⁇ g, 1275 ⁇ g, 1300 ⁇ g
  • the total weekly dose is administered in a single administration during the week, i.e., once a week, and the total weekly dose comprises the insulinotropic peptide conjugate in an amount of 1000 ⁇ g or 1500 ⁇ g. In certain embodiments, the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g. In certain embodiments, the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g. In certain embodiments, the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 3000 ⁇ g. In certain embodiments, the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 3500 ⁇ g. In certain embodiments, the total weekly dose is
  • the dose comprises the insulinotropic peptide conjugate in an amount of 4000 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 4500 ⁇ g.
  • the total weekly dose is administered once a week, and the dose comprises the insulinotropic peptide conjugate in an amount of 5000 ⁇ .
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, with two equal doses or two unequal doses.
  • the total weekly dose is administered twice a week with two unequal doses, wherein the smaller of the two unequal doses is administered prior to the larger of the two unequal doses.
  • the total weekly dose is administered twice a week with two unequal doses, wherein the larger of the two unequal doses is administered prior to the smaller of the two unequal doses.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1000 ⁇ g, amounting to a total weekly dose of 2000 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1100 ⁇ g, amounting to a total weekly dose of 2200 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 120C ⁇ g, amounting to a total weekly dose of 2400 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1225 ⁇ g, amounting to a total weekly dose of 2500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 1000 ⁇ g, amounting to a total weekly dose of 2500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1300 ⁇ g, amounting to a total weekly dose of 2600 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1400 ⁇ g, amounting to a total weekly dose of 2800 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g, amounting to a total weekly dose of 3000 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1600 ⁇ g, amounting to a total weekly dose of 3200 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1700 ⁇ g, amounting to a total weekly dose of 3400 ⁇ g. In certain embodiments, the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2000 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1750 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 1500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2000 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 1500 ⁇ g, amounting to a total weekly dose of 3500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1800 ⁇ g, amounting to a total weekly dose of 3600 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 1900 ⁇ g, amounting to a total weekly dose of 3800 pg.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g, amounting to a total weekly dose of 4000 ⁇ g.
  • the total weekly dose is administered over two administrations during the week, i.e., twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2225 ⁇ g, amounting to a total weekly dose of 4500 ⁇ g.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2000 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2500 ⁇ g, amounting to a total weekly dose of 4500 pg.
  • the total weekly dose is administered twice a week, wherein the first administration comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g and the second administration comprises the insulinotropic peptide in an amount of 2000 ⁇ g, amounting to a total weekly dose of 4500 ⁇ g.
  • the total weekly dose is administered twice a week, and each administration comprises the insulinotropic peptide conjugate in an amount of 2500 ⁇ g, amounting to a total weekly dose of 5000 ⁇ g.
  • these dosages, or other exemplary dosages described herein can be provided in a delivery device for convenient administration of the dose to the subject.
  • a delivery device for convenient administration of the dose to the subject.
  • the delivery device is a syringe configured for subcutaneous delivery, e.g. a 0.3, 0.5, 1, 2, 3 or greater than 3 ml syringe having a 25, 26, 27, 28, 29, 30, 31, 32, 33, or larger than 33-gauge needle.
  • insulinotropic peptide conjugate may be applicable for different disorders and conditions, as will be readily known by those of ordinary skill in the art.
  • administration of the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulations, provided herein can be repeated, and the administrations can be separated by at least 12 hours, one day, 36 hours, two days, 60 hours, three days, 84 hours, four days, five days, six days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 4 weeks, 6 weeks, 2 months, 75 days, 3 months, or 6 months.
  • the repeated administration of the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation, is separated by three or four days, by one week, or by two weeks.
  • the methods can be practiced, and the formulations can be given, as a single, one time dose, or chronically.
  • chronic / chronically is meant that the formulations of the invention are administered more than once to a given individual.
  • chronic administration can be multiple doses of a formulation administered to a subject, on a weekly basis, a biweekly basis, monthly basis, or more or less frequently, as will be apparent to those of skill in the art.
  • Chronic administration can continue for weeks, months, or years if appropriate according to the judgment of the practitioner of skill in the art.
  • the practioner can reduce the dose to reduce such profiles.
  • the dose as described herein can be reduced from a 1500 ⁇ g dose to a 1000 ⁇ g dose
  • a 2000 ⁇ g dose can be reduced to a 1500 ⁇ g dose
  • a 2500 ⁇ g dose can be reduced to a 2000 ⁇ g dose
  • a 3000 ⁇ g dose can be reduced to a 2500 ⁇ g dose
  • a 3500 ⁇ g dose can be reduced to a 3000 ⁇ g dose
  • a 4000 ⁇ g dose can be reduced to a 3500 ⁇ g dose
  • a 4500 ⁇ g dose can be reduced to a 4000 ⁇ g dose
  • a 5000 ⁇ g dose can be reduced to a 4500 ⁇ g dose.
  • the dose of insulinotropic peptide conjugate administered over the course of repeated administrations can be held constant, or can be varied, e.g., increased or decreased, relative to the dose of insulinotropic peptide conjugate administered in earlier administrations. In certain embodiments, the dose of insulinotropic peptide conjugate administered over the course of repeated administrations is held constant.
  • a weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 1500 ⁇ g per week.
  • a weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 2000 ⁇ g per week.
  • a weekly dose of 2500 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 2500 ⁇ g per week.
  • a weekly dose of 3000 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 3000 ⁇ g per week.
  • a weekly dose of 3500 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 3500 ⁇ g per week.
  • a weekly dose of 4000 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 4000 ⁇ g per week.
  • a weekly dose of 4500 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 4500 ⁇ g per week.
  • a weekly dose of 5000 ⁇ g of insulinotropic peptide conjugate is administered to the subject, and administration is repeated on a weekly basis at 5000 ⁇ g per week.
  • a weekly dose of 3000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 1500 ⁇ g is administered to the subject, and twice-a-week administration is repeated on a weekly basis at a total weekly dose of 3000 ⁇ g of insulinotropic peptide conjugate per week.
  • a weekly dose of 4000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 2000 ⁇ g, is administered to the subject, and twice-a-week administration is repeated on a weekly basis at a total weekly dose of 4000 ⁇ g of insulinotropic peptide conjugate per week.
  • a weekly dose of 5000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 2500 ⁇ g is administered to the subject, and twice-a-week administration is repeated on a weekly basis at a total weekly dose of 5000 ⁇ g of insulinotropic peptide conjugate per week.
  • the dose of insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation, administered to the subject is increased over the course of repeated administrations.
  • an initial total weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to a subject for a first period of time, followed by administration of a total weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate for a second period of time.
  • the first period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the first period of time is four weeks, i.e., the increase in dose begins at the outset of the fifth week of dosing.
  • the second period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the weekly dose is chronically administered (i.e., the second period of time is chronic administration as described herein).
  • an initial total weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to a subject for four weeks, immediately followed by administration (starting at the fifth week) of a total weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate chronically.
  • the dose of insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the dose of insulinotropic peptide conjugate is administered to the subject in the following steps in the order stated: (a) administering 1.5 mg of the insulinotropic peptide conjugate to the subject once a week for a first duration of time; and (b) administering 2.0 mg of the insulinotropic peptide conjugate to the subject once a week for a second duration of time.
  • the first duration of time is 4 weeks. In some embodiments, the second duration of time is 8 weeks.
  • an initial total weekly dose of 3000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 1500 ⁇ g, is administered to a subject for a first period of time, followed by administration of a total weekly dose of 4000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 2000 ⁇ g, for a second period of time.
  • the first period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the first period of time is four weeks, i.e., the increase in dose begins at the outset of the fifth week of dosing.
  • the second period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the weekly dose is chronically administered (i.e., the second period of time is chronic administration as described herein).
  • an initial total weekly dose of 3000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 1500 ⁇ g is administered to a subject for four weeks, immediately followed by administration (starting at the fifth week) of a total weekly dose of 4000 ⁇ g of insulinotropic peptide conjugate, delivered in two doses of 2000 ⁇ g, chronically.
  • the dose of insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • the dose of insulinotropic peptide conjugate is administered to the subject in the following steps in the order stated: (a) administering 1.5 mg of the insulinotropic peptide conjugate to the subject twice a week for a first duration of time; and (b) administering 2.0 mg of the insulinotropic peptide conjugate to the subject twice a week for a second duration of time.
  • the first duration of time is 4 weeks. In some embodiments, the second duration of time is 8 weeks.
  • insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation
  • an initial total weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to a subject for a first period of time, followed by
  • the first period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks and the second period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the first period of time is four weeks and the second period of time is four weeks, i.e., the increase in dose begins at the outset of the fifth and ninth week of dosing.
  • the first period of time is two weeks and the second period of time is two weeks, i.e., the increase in dose begins at the outset of the third and fifth week of dosing.
  • the third period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the weekly dose is chronically administered (i.e, the third period of time is chronic administration as described herein).
  • an initial total weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to a subject for four weeks, immediately followed by administration (starting at the fifth week) of a total weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate for four weeks, immediately followed by administration (starting at the ninth week) of a total weekly dose of 3000 ⁇ g chronically.
  • an initial total weekly dose of 1500 ⁇ g of insulinotropic peptide conjugate is administered to a subject for two weeks, immediately followed by administration (starting at the third week) of a total weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate for two weeks, immediately followed by administration (starting at the fifth week) of a total weekly dose of 3000 ⁇ g chronically.
  • the dose of insulinotropic peptide conjugate is administered to the subject in the following steps in the order stated: (a) administering 1.5 mg of the insulinotropic peptide conjugate to the subject once a week for a first duration of time; (b) administering 2.0 mg of the insulinotropic peptide conjugate to the subject once a week for a second duration of time; and (c) administering 3.0 mg of the insulinotropic peptide conjugate to the subject once a week for a third duration of time.
  • the first and second durations of time are 1 week.
  • the first and second durations of time are 2 weeks.
  • the third duration of time is 10 weeks.
  • the third duration of time is 8 weeks.
  • the dose of insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation, administered to the subject is decreased over the course of repeated administrations. For instance, in a particular embodiment, 1500 ⁇ g of insulinotropic peptide conjugate is administered twice a week for a total weekly dose of 3000 ⁇ g to a subject for a first period of time, followed by administration of a total weekly dose of 2000 ⁇ g of insulinotropic peptide conjugate for a second period of time.
  • 1500 ⁇ g of insulinotropic peptide conjugate is administered twice a week for a total weekly dose of 3000 ⁇ g to a subject for a first period of time, followed by administration of a 1000 ⁇ g of insulinotropic peptide conjugate twice a week for a total weekly dose of 2000 ⁇ g to the subject for a second period of time.
  • the first period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the first period of time is four weeks.
  • the second period of time is 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.
  • the weekly dose is chronically administered (i.e, the second period of time is chronic administration as described herein).
  • an effective amount of an insulinotropic peptide conjugate described herein will provide therapeutic benefit without causing unacceptable or substantial toxicity.
  • Toxicity of an insulinotropic peptide conjugate can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD5 0 (the dose lethal to 50% of the population) or the LD1 00 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index.
  • the dosage of the compounds described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the subject's condition. (See, e.g., Fingl et al., 1996, In: The Pharmacological Basis of Therapeutics, 9th ed., Chapter 2, p. 29, Elliot M. Ross).
  • the insulinotropic peptide conjugate e.g., insulinotropic peptide conjugate formulation described herein and the one or more second therapeutic agents can be administered at essentially the same time, i.e., concurrently, e.g., within the same hour or same day, etc., or at separately staggered times, i.e. sequentially prior to or subsequent to the administration of the other antidiabetic agent, e.g., on separate days, weeks, etc.
  • the instant methods are therefore to be understood to include all such regimes of simultaneous or non-simultaneous treatment.
  • the insulinotropic peptide conjugate formulation is administered within 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18 or more than 18 hours of administration of the other second therapeutic agents. In some embodiments, the insulinotropic peptide conjugate formulation is administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14 or more than 14 days of administration of the other second therapeutic agents. In some embodiments, the insulinotropic peptide conjugate formulation is administered within 1, 2, 3, 4, 5 or more than 5 weeks of administration of the second therapeutic agents.
  • the insulinotropic peptide conjugate formulation will be administered to the subject by subcutaneous injection in accordance with a dosing regime provided herein, e.g., at intervals of between 5, 6, 7, 8 or 9 days or at intervals of between 12, 13, 14, 15 or 16 days.
  • the particular one or more second therapeutic agents can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebral ventricular (ICV), intracisternal injection or infusion, subcutaneous injection, or implant), inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non toxic agents, e.g., intramuscular, intraperitoneal, intravenous, intracerebral ventricular (ICV), intracisternal injection or infusion, subcutaneous injection, or implant), inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non toxic
  • the formulation can be administered at any injection site deemed suitable by the practitioner of skill. In certain embodiments, the formulation is administered in the abdomen, thigh or arm.
  • the formulation can be administered at any time deemed suitable by the practitioner of skill. In certain embodiments, the formulation is administered in the morning, before a meal or in the evening prior to sleep, or a combination thereof.
  • the subject should experience adverse events in response to one or more agents of the combination therapy provided herein, for example, nausea, vomiting, injection-related skin reaction, hypoglycemia, i.e., blood glucose level , 60 mg/dL (3.3 mmol/L) with clinical signs of hypoglycemia, or any other constitutional symptoms or signs, such as extreme and rapid weight loss
  • hypoglycemia i.e., blood glucose level , 60 mg/dL (3.3 mmol/L) with clinical signs of hypoglycemia, or any other constitutional symptoms or signs, such as extreme and rapid weight loss
  • the specific dose level and frequency of dosage for one or more of the agents can be reduced or adjusted according to the judgment of the practitioner of skill in the art.
  • the subject receives the insulinotropic peptide conjugate and an OAD, e.g., a biguanide, e.g., metformin.
  • OAD e.g., a biguanide
  • metformin e.g., metformin
  • the subject receives the insulinotropic peptide conjugate, and two OADs, e.g., a biguanide, e.g., metformin,, sulfonylurea or a thiazolidinedione, and a second OAD.
  • kits comprising an
  • kits for the treatment of type II diabetes mellitus in a subject in need thereof comprise an insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation, in a package for distribution to a practitioner of skill in the art.
  • kits can comprise a label or labeling with instructions for use of the insulinotropic conjugate as described herein, e.g, instructions for administering the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation, for the treatment of subjects with (or who are or are undergoing), e.g.
  • pre-diabetes e.g., impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)
  • diabetes e.g., type I diabetes or type II diabetes, late autoimmune diabetes in adults (“LADA") also known as late onset autoimmune diabetes of adulthood, slow onset type I diabetes and type 1.5 diabetes, steroid induced diabetes, Human Immunodeficiency Virus (HIV) Treatment-Induced Diabetes, diabetes development in subjects with congenital or HIV-Associated Lipodystrophy ("Fat Redistribution Syndrome"), obesity (i.e., BMI of 30 kg/m 2 or greater), overweight (i.e., BMI between 25 kg/m 2 and 30 kg/m 2 ), metabolic syndrome (Syndrome X), nervous system disorders, surgery, insulin resistance, hypoglycemia unawareness, restrictive lung disease, gastrointestinal disorders, e.g., irritable bowel syndrome (IBS), functional dyspepsia, pain associated with gastrointestinal disorders, e.g., pain associated with IBS and functional
  • kits can comprise a label or labeling with instructions for use of the insulinotropic conjugate as described herein, e.g., instructions for administering the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation, to promote weight loss, stimulate insulin synthesis and release, to enhance adipose, muscle or liver tissue sensitivity toward insulin uptake, to stimulate glucose uptake, to slow (e.g., decrease the rate of) digestive processes, e.g., gastric emptying, to block or inhibit secretion of glucagon, to promote beta cell function, proliferation, and/or activity, to restore first phase insulin release in subjects with diabetes, to reduce food intake, to reduce appetite, to prevent or protect against liver disease, e.g., liver disease associated with obesity, diabetes, or hyperglycemia (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH)).
  • liver disease e.g., liver disease associated with obesity, diabetes, or hyper
  • the instructions on the label can further include instructions for storage conditions of the insulinotropic peptide conjugates as described herein.
  • the kit can comprise one or more containers, e.g., bottles, vials, ampoules, cartridge, pre-filled containers, e.g., pre-filled syringes or prefilled injection pens, microchip (e.g., a microchip for controlled release of its contents) or test tubes which contain a unit dosage or a multi-use dosage of the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation.
  • components of the insulinotropic peptide conjugate formulation are contained in more than one, i.e., in different containers.
  • components of the insulinotropic peptide conjugate formulation are contained in a single, multi-chamber container (e.g. a 2-chamber syringe or a 2-chamber cartridge).
  • the dosage forms can be contained as liquid or lyophilized formulations.
  • Kits comprising lyophilized dosage forms can further comprise one or more additional containers comprising a diluent for reconstituting the lyophilized formulation, such that the protein, insulinotropic peptide conjugate, concentration in the reconstituted formulation is at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50 mg/ml, for example from about 1 mg/ml to about 100 mg/ml, more preferably from about 1 mg/ml to about 50 mg/ml, and most preferably from about 1 mg/ml to about 15 mg/ml.
  • the diluent for reconstituting the lyophilized formulation is provided in a 2-chamber syringe also containing the lyophilized formulation, and reconstitution is performed in the syringe.
  • the diluent for reconstituting the lyophilized formulation is provided in a 2-chamber cartridge also containing the lyophilized formulation, and reconstitution is performed in the cartridge.
  • the kit can further comprise one or more additional components useful for carrying out the methods of treatment described herein, including, but not limited to, buffers, filters, needles, syringes, and package inserts with instructions for use.
  • the kit comprises a needle, e.g., a 25-gauge needle, a 26-gauge needle, a 27-gauge needle, a 28-gauge needle, a 29-gauge needle, a 30-gauge needle, a 31-gauge needle, a 32-gauge needle, or a 33- gauge needle, or a higher gauge needle, useful, e.g. for the subcutaneous administration of the insulinotropic peptide conjugate formulation to a subject.
  • the kits can comprise components useful for the safe disposal of means for administering the insulinotropic peptide conjugate formulation, e.g. a sharps container for used syringes and needles.
  • the kit comprises 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 syringes pre-loaded with a first dosage of the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation.
  • the kit comprises 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 syringes pre-loaded with a second higher dosage of the insulinotropic peptide conjugate, e.g., insulinotropic peptide conjugate formulation.
  • syringes pre-loaded with a first dosage comprise the
  • insulinotropic peptide conjugate in an amount of about 1000 ⁇ g.
  • syringes pre-loaded with a first dosage comprise the insulinotropic peptide conjugate in an amount of about 1500 ⁇ g.
  • syringes pre-loaded with a second higher dosage comprise the insulinotropic peptide conjugate in an amount of about 2000 ⁇ g.
  • the kit comprises one, two, three, four, five, six, seven, eight, nine, ten or more than ten empty syringes, and one, two, three, four, five, six, seven, eight, nine, ten or more than ten vials, wherein each vial contains 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses or more than 10 doses of the insulinotropic peptide conjugate formulation.
  • the kit comprises one, two, three, four, five, six, seven, eight, nine, ten or more than ten syringes pre-loaded with 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, or more than 10 doses of the insulinotropic peptide conjugate formulation.
  • the syringe comprises a luer-lock, luer- cone, or other needle fitting connector that facilitates attachment of a disposable needle.
  • the syringe comprises a staked, i.e., permanent, needle.
  • the kit comprises a pen-type delivery apparatus and one, two, three, four, five, six, seven, eight, nine, ten or more than ten replaceable cartridges, wherein the replaceable cartridge comprises, e.g., is pre-loaded with 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses or more than 10 doses of the insulinotropic peptide conjugate formulation.
  • the dose can be pre-set, i.e., fixed.
  • the dose can be a flexible dose, i.e., dialed-in by the user.
  • the kit comprises one, two, three, four, five, six, seven, eight, nine, ten or more than ten pen-type delivery apparatuses pre-loaded with one, two, three, four, five, six, seven, eight, nine, ten or more than ten doses of the insulinotropic peptide conjugate formulation.
  • the pen-type delivery apparatus comprises a luer-lock, luer-cone, or other needle fitting connector that facilitates attachment of a disposable needle.
  • the kit comprises a disposable pen-type delivery apparatus.
  • the pen-type delivery apparatus comprises a staked, i.e., permanent, needle.
  • the invention is directed to pharmaceutical formulations comprising an insulinotropic peptide conjugate.
  • Useful insulinotropic peptides include, but are not limited to, GLP-1, exendin- 3 and exendin-4, and their precursors, derivatives and fragments.
  • Such insulinotropic peptides include those disclosed in U.S. Patent Nos. 6,514,500; 6,821,949; 6,887,849; 6,849,714;
  • the insulinotropic peptide has a C-terminal amide (CO- NH 2 ).
  • the insulinotropic peptide is GLP-1. In some embodiments, the insulinotropic peptide is a GLP-1 derivative. In some embodiments, the insulinotropic peptide is exendin-3. In some embodiments, the insulinotropic peptide is an exendin-3 derivative. In some embodiments, the insulinotropic peptide is exendin-4. In some embodiments, the insulinotropic peptide is an exendin-4 derivative. In some embodiments, the insulinotropic peptide is exendin- 4(l-39)-NH 2 . In some embodiments, the insulinotropic peptide is exendin-4(l-39)Lys 40 -NI3 ⁇ 4.
  • the insulinotropic peptide conjugate is exendin-4(l-39) Lys 40 ( ⁇ - ⁇ - ⁇ )- ⁇ 2 albumin conjugate.
  • the insulinotropic peptide of the insulinotropic peptide conjugate described herein is GLP-1 or a derivative thereof.
  • the hormone glucagon is known to be synthesized as a high molecular weight precursor molecule which is subsequently
  • GLP-1 glucagon-like peptide 1
  • GLP-2 glucagon-like peptide 2
  • GLP-1 has 37 amino acids in its unprocessed form as shown in SEQ ID NO: 1 (HDEFERHAEG TFTSDVSSYL EGQAAKEFIA WLVKGRG). Unprocessed GLP-1 is essentially unable to mediate the induction of insulin biosynthesis.
  • GLP-1 (7-37) The unprocessed GLP-1 peptide is, however, naturally converted to a 31-amino acid long peptide (7-37 peptide) having amino acids 7-37 of GLP-1 ("GLP-1 (7-37)") SEQ ID NO:2 (HAEG TFTSDVSSYL EGQAAKEFIA WLVKGRG).
  • GLP-1 (7-37) can also undergo additional processing by proteolytic removal of the C-terminal glycine to produce GLP-l(7-36) which also exists predominantly with the C-terminal residue, arginine, in amidated form as arginineamide, GLP- 1(7-36) amide.
  • GLP-1 peptides useful in the formulations and methods described herein include, but are not limited to, GLP-1Q-37), GLP-l(7-37), GLP-l(7-36), and derivatives thereof.
  • a compound is said to have an "insulinotropic activity" if it is able to stimulate, or cause the stimulation of, the synthesis or expression of the hormone insulin.
  • the hormonal activity of GLP- 1(7-37) and GLP-l(7-36) appear to be specific for the pancreatic beta cells where it appears to induce the biosynthesis of insulin.
  • Glucagon-like-peptide hormones are useful in the study of the pathogenesis of maturity onset diabetes mellitus, a condition characterized by hyperglycemia in which the dynamics of insulin secretion are abnormal. Moreover, glucagon-like peptides are useful in the therapy and treatment of this disease, and in the therapy and treatment of hyperglycemia.
  • Peptide moieties can be chosen from the determined amino acid sequence of human GLP- 1.
  • the interchangeable terms "peptide fragment” and “peptide moiety” are meant to include both synthetic and naturally occurring amino acid sequences derivable from a naturally occurring amino acid sequence.
  • the amino acid sequence for GLP-1 has been reported by several researchers. See Lopez, L. C. et al., 1983, Proc. Natl. Acad. Sci., USA 80:5485-5489; Bell, G. I. et al, 1983, Nature 302:716-718; Heinrich, G. et al., 1984, Endocrinol. 115:2176-2181.
  • GLP- 1(1-37) refers to a GLP-1 polypeptide having all amino acids from 1 (N-terminus) through 37 (C-terminus).
  • GLP- 1(7-37) refers to a GLP-1 polypeptide having all amino acids from 7 (N- terminus) through 37 (C-terminus).
  • GLP-l(7-36) refers to a GLP-1 polypeptide having all amino acids from number 7 (N-terminus) through number 36 (C-terminus).
  • GLP- 1(7-36) and its peptide fragments are synthesized by conventional means as detailed below, such as by the well-known solid-phase peptide synthesis described by Merrifield, J. M., 1962, Chem. Soc. 85:2149, and Stewart and Young, Solid Phase Peptide Synthesis, Freeman, San Francisco, 1969, pp. 27-66), the contents of each of which are incorporated by reference herein in their entireties.
  • Useful GLP-1 derivatives for use in the formulations and methods described herein include peptides which are derivable from GLP-1 such as GLP-l(l-37) and GLP-l(7-36).
  • a peptide is said to be "derivable from a naturally occurring amino acid sequence” if it can be obtained by fragmenting a naturally occurring sequence, or if it can be synthesized based upon a knowledge of the sequence of the naturally occurring amino acid sequence or of the genetic material (DNA or RNA) which encodes this sequence.
  • a useful derivative which finds use in the formulations and methods described herein comprises a GLP- 1 sequence.
  • a "GLP-1 derivative” has the following characteristics: (1) it shares substantial homology with GLP-1 or a similarly sized fragment of GLP-1; (2) it is capable of functioning as an insulinotropic hormone; and (3) using at least one of the assays provided herein, the derivative has an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of GLP-1
  • a derivative of GLP- 1 is said to share "substantial homology" with GLP- 1 if the amino acid sequence of the derivative shares at least 80%, and more preferably at least 90%, and most preferably at least 95% identity to GLP-l(l-37).
  • Percent identity in this context means the percentage of amino acid residues in the candidate sequence that are identical (i.e., the amino acid residues at a given position in the alignment are the same residue) or similar (i.e., the amino acid substitution at a given position in the alignment is a conservative substitution, as discussed above), to the corresponding amino acid residue in the peptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence homology.
  • a GLP- 1 derivative is characterized by its percent sequence identity or percent sequence similarity with the naturally occurring GLP-1 sequence. Sequence homology, including percentages of sequence identity and similarity, are determined using sequence alignment techniques well-known in the art, preferably computer algorithms designed for this purpose, using the default parameters of said computer algorithms or the software packages containing them.
  • Useful derivatives also include GLP- 1 fragments which, in addition to containing a sequence that is substantially homologous to that of a naturally occurring GLP- 1 peptide may contain one or more additional amino acids at their amino and/or their carboxy termini, or internally within said sequence.
  • useful derivatives include polypeptide fragments of GLP-1 that may contain one or more amino acids that may not be present in a naturally occurring GLP-1 sequence provided that such polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of GLP-1.
  • the additional amino acids may be D-amino acids or L-amino acids or combinations thereof.
  • Useful GLP-1 fragments also include those which, although containing a sequence that is substantially homologous to that of a naturally occurring GLP-1 peptide, lack one or more additional amino acids at their amino and/or their carboxy termini that are naturally found on a GLP-1 peptide.
  • useful polypeptide fragments of GLP-1 may lack one or more amino acids that are normally present in a naturally occurring GLP- 1 sequence provided that such
  • polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of GLP-1.
  • Useful derivatives further include GLP- 1 fragments which are otherwise identical in sequence to that of a naturally occurring GLP-1 peptide but for the addition, deletion or substitution of no more than 5, 4, 3, 2 or 1 amino acids.
  • the derivative contains no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 amino addition, deletion, or substitution relative to a naturally occurring GLP-1 sequence.
  • useful derivatives include polypeptide fragments of a naturally occurring GLP- 1 sequence that are identical but for no more than 5, 4, 3, 2, or 1 amino acid additions, deletions or substitutions relative to the naturally occurring GLP-1 sequence, provided that such polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of the naturally occurring GLP-1 sequence.
  • the polypeptide fragments lack one amino acid normally present in a naturally occurring GLP- 1 sequence.
  • the polypeptide fragments lack two amino acids normally present in a naturally occurring GLP-1 sequence.
  • the polypeptide fragments lack three amino acids normally present in a naturally occurring GLP- 1 sequence.
  • the polypeptide fragments lack four amino acids normally present in a naturally occurring GLP-1 sequence.
  • Useful derivatives also include conservative variants of the above-described fragments which have conservative amino acid substitutions (and thus have amino acid sequences which differ from that of the natural sequence) provided that such variants still have an insulinotropic activity.
  • conservative substitutions include the substitution of one basic residue for another (i.e. Arg for Lys), the substitution of one hydrophobic residue for another (i.e. Leu for He), or the substitution of one aromatic residue for another (i.e. Phe for Tyr), etc.
  • the following six groups each contain amino acids that are conservative substitutions for one another:
  • I Isoleucine
  • L Leucine
  • M Methionine
  • V Valine
  • GLP- 1 derivatives which stimulate glucose uptake by cells but do not stimulate insulin expression or secretion are useful for the methods and formulations described herein.
  • GLP- 1 derivatives are described in U.S. Pat. No. 5,574,008, which is hereby incorporated by reference herein in its entirety.
  • GLP-1 derivatives which stimulate glucose uptake by cells but do not stimulate insulin expression or secretion which find use in the methods described herein include:
  • peptides are C-terminal GLP- 1 fragments which do not have insulinotropic activity but which are nonetheless useful for treating diabetes and hyperglycemic conditions as described in U.S. Pat. No. 5,574,008, which is hereby incorporated by reference herein in its entirety.
  • GLP- 1 derivative which finds use in the formulations and methods described herein includes a GLP-1 /exendin-4 hybrid peptide comprising GLP-l(7-36) fused to the nine C-terminal amino acids of exendin-4, having the sequence: HAEG TFTSDVSSYL EGQAAKEFIA WLVKGRPSSGAPPPS (SEQ ID NO:28).
  • insulinotropic peptide conjugate LY2189265 a long-acting GLP-1 analog consisting of a dipeptidyl peptidase- IV (DPP-IV)-protected GLP-1 analog covalently linked to a human IgG4-Fc heavy chain by a small peptide linker.
  • DPP-IV dipeptidyl peptidase- IV
  • insulinotropic peptide conjugate LY2428757 a long-acting GLP-1 analog consisting of a GLP-1 analog covalently linked to a polyethylene glycol (PEG) by a small peptide linker.
  • insulinotropic peptide conjugate CNTO-3649 a long-acting GLP-1 analog consisting of a GLP-1 analog covalently linked to a IgG-Fc fragment by a small linker.
  • insulinotropic peptide conjugate MODI-1001 a long-acting GLP-1 analog consisting of a GLP-1 analog fused to the carboxy terminal peptide (CTP) of human chorionic gonadotropin (hCG).
  • GLP-1 derivative comprising a fusion protein molecule as follows: [Gly 8 ]GLP-l(7-36)-[Gly 8 ]GLP-l(7-36)-human serum albumin (albiglutide), as described in U.S. Patent No. 7, 141,547, which is hereby incorporated by reference in its entirety.
  • the formulations described herein comprise the [Gly 8 ]GLP-l(7-36)-[Gly 8 ]GLP-l(7-36)-human serum albumin molecule without further modification to the molecule, e.g., without the addition of a reactive group and/or the coupling of albumin thereto, as described in Section V, C.
  • GLP-1 fusion protein molecules GLP-1 (7-36)-human serum albumin; human serum albumin-GLP-l(7-36); [Gly 8 ]GLP-l(7-36)-human serum albumin; human serum albumin- [Gly 8 ]GLP-l (7-36); GLP-l(7-36)-GLP-l(7-36)-human serum albumin; GLP- l(9-36)-human serum albumin; and [Gly 8 ]GLP-l(7-36)-GLP-l(7-36)-human serum albumin, as described in U.S. Patent No.
  • the formulations described herein comprise the GLP-l(7-36)- human serum albumin; human serum albumin-GLP-l(7-36); [Gly 8 ]GLP-l(7-36)-human serum albumin; human serum albumin-[Gly 8 ]GLP-l(7-36); GLP-l(7-36)-GLP-l(7-36)-human serum albumin; GLP-1 (9-36)-human serum albumin; or the [Gly 8 ]GLP-l(7-36)-GLP-l(7-36)-human serum albumin molecule without further modification to the molecule, e.g., without the addition of a reactive group and/or the coupling of albumin thereto, as described in Section V, C.
  • GLP-l/exendin-4 human serum albumin hybrid polypeptide comprising [Gly 8 ][Glu 22 ]GLP-l(7-36) fused to the eight C-terminal amino acids of exendin-4(l- 39), fused to a linker sequence, fused to human serum albumin, having the sequence:
  • HGEGTFTSDV SSYLEEQAAK EFIAWLVKGR GSSGAPPPSG GGGGSGGGGS GGGGSDAHKS EVAHRFKDLG EENFKALVLI AFAQYLQQCP FEDHVKLVNE VTEFAKTCVA DESAENCDKS LHTLFGDKLC TVATLRETYG EMADCCAKQE PERNECFLQH KDDNPNLPRL VRPEVDVMCT AFHDNEETFL KKYLYEIARR HPYFYAPELL FFAKRYKAAF TECCQAADKA ACLLPKLDEL RDEGKASSAK QRLKCASLQK FGERAFKAWA VARLSQRFPK AEFAEVSKLV TDLTKVHTEC CHGDLLECAD DRADLAKYIC ENQDSISSKL KECCEKPLLE KSHCIAEVEN DEMPADLPSL AADFVESKDV CKNYAEAKDV FLGMFLYEYA RRHPDYSVVL LLRLAKTYET TLEKCCAAAD
  • the formulations described herein comprise the GLP-l/exendin-4 human serum albumin hybrid polypeptide without further modification to the polypeptide, e.g., without the addition of a reactive group and/or the coupling of albumin thereto, as described in Section V, C.
  • Exendin-3 and exendin-4 are 39 amino acid peptides (differing at residues 2 and 3) which are approximately 53% homologous to GLP-1 and find use as insulinotropic agents.
  • peptides useful in the formulations and methods described herein include, but are not limited to, exendin-3, exendin-4, and derivatives thereof
  • HSDGTFTSDLSKQMEEEAVRLFIEWLKNGG PSSGAPPPS (SEQ ID NO: 16)
  • amino acid sequence of exendin-4 is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 17).
  • exendin-4 comprising the amino acid sequences: exendin-4(l-31) desGlu 17 Tyr 32 (SEQ ID NO: 18) HGEGTFTSDLSKQMEEAVRLFIEWLKNGGPY and exendin-4(l-30) Tyr 31 (SEQ ID NO: 19) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGY.
  • inhibitory fragment of native exendin-4 comprising the amino acid sequence: exendin-4(9-39) (SEQ ID NO:20) DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS.
  • HSDGTFTSDLS KQMEEE A VRLFIEWLKNGGPS S GAPPPSK SEQ ID NO: 24
  • Useful exendin-3 and exendin-4 derivatives for use in the formulations and methods described herein also include peptides which are derivable from the naturally occurring exendin-3 and exendin-4 peptides.
  • a peptide is said to be "derivable from a naturally occurring amino acid sequence” if it can be obtained by fragmenting a naturally occurring sequence, or if it can be synthesized based upon a knowledge of the sequence of the naturally occurring amino acid sequence or of the genetic material (DNA or RNA) which encodes this sequence.
  • a useful derivative comprises an exendin-3 or exendin-4 sequence.
  • an "exendin-3 or exendin-4 derivative” has the following characteristics: (1) it shares substantial homology with exendin-3 or exendin-4 or a similarly sized fragment of exendin-3 or exendin-4; (2) it is capable of functioning as an insulinotropic hormone and (3) using at least one of the assays provided herein, the derivative has an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of either exendin-3 or exendin-4.
  • a derivative of exendin-3 or exendin-4 is said to share "substantial homology" with exendin-3 and exendin-4 if the amino acid sequences of the derivative shares at least 80%, and more preferably at least 90%, and most preferably at least 95% identity to exendin-3 and exendin- 4.
  • Percent identity in this context means the percentage of amino acid residues in the candidate sequence that are identical (i.e., the amino acid residues at a given position in the alignment are the same residue) or similar (i.e., the amino acid substitution at a given position in the alignment is a conservative substitution, as discussed above), to the corresponding amino acid residue in the native peptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence homology.
  • a exendin-3 or exendin-4 derivative is characterized by its percent sequence identity or percent sequence similarity with the naturally occurring exendin-3 or exendin-4 sequence. Sequence homology, including percentages of sequence identity and similarity, are determined using sequence alignment techniques well- known in the art, preferably computer algorithms designed for this purpose, e.g., BLAST, using the default parameters of said computer algorithms or the software packages containing them.
  • Useful derivatives also include exendin-3 or exendin-4 fragments which, in addition to containing a sequence that is the same or that is substantially homologous to that of a naturally occurring exendin-3 or exendin-4 peptide may contain one or more additional amino acids at their amino and/or their carboxy termini, or internally within said sequence.
  • useful derivatives include polypeptide fragments of exendin-3 or exendin-4 that may contain one or more amino acids that may not be present in a naturally occurring exendin-3 or exendin-4 sequences provided that such polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of either exendin-3 or exendin-4.
  • useful derivatives include exendin-3 or exendin-4 fragments which, although containing a sequence that is substantially homologous to that of a naturally occurring exendin-3 or exendin-4 peptide may lack one or more additional amino acids at their amino and/or their carboxy termini that are naturally found on a exendin-3 or exendin-4 peptide.
  • useful derivatives include polypeptide fragments of exendin-3 or exendin-4 that may lack one or more amino acids that are normally present in a naturally occurring exendin-3 or exendin-4 sequence provided that such polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of either exendin-3 or exendin-4.
  • Useful derivatives further include exendin-3 or exendin-4 fragments which are otherwise identical in sequence to that of the naturally occurring exendin-3 or exendin-4 peptide but for the addition, deletion or substitution of no more than 5, 4, 3, 2 or 1 amino acids.
  • the derivative contains no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 amino addition, deletion, or substitution relative to the native exendin-3 or exendin-4 sequence.
  • useful derivatives include polypeptide fragments of exendin-3 or exendin-4 that are identical but for no more than 5, 4, 3, 2, or 1 amino acid additions, deletions or substitutions relative to the native exendin-3 or exendin-4 sequence, provided that such polypeptides have an insulinotropic activity of at least 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the insulinotropic activity of either exendin-3 or exendin-4.
  • Useful derivatives also include conservative variants of the above-described fragments which have inconsequential amino acid substitutions (and thus have amino acid sequences which differ from that of the natural sequence) provided that such variants still have an insulinotropic activity.
  • conservative substitutions include the substitution of one basic residue for another (i.e. Arg for Lys), the substitution of one hydrophobic residue for another (i.e. Leu for He), or the substitution of one aromatic residue for another (i.e. Phe for Tyr), etc.
  • the following six groups each contain amino acids that are conservative substitutions for one another:
  • I Isoleucine
  • Leucine L
  • Methionine M
  • Valine V
  • Phenylalanine F
  • Tyrosine Y
  • Tryptophan W
  • insulinotropic peptide conjugate PF-4856883/ CVX-096 a long-acting exendin-4 analog consisting of an exendin-4 analog covalently linked to an antibody scaffold by a small linker.
  • insulinotropic peptide conjugate LAPS-exendin (HM11260) a long-acting exendin-4 analog consisting of an exendin-4 analog covalently linked to an antibody scaffold by a small linker.
  • insulinotropic peptide conjugate exenatide-XTEN VRS859
  • a long-acting exendin-4 analog consisting of an exendin-4 analog covalently linked to a pseudo-PEG protein.
  • exendin-4 derivatives comprising a fusion protein molecule as follows: exendin-4(l-39)-human serum albumin, and human serum albumin-exendin-4(l-39), as described in U.S. Patent No. 7, 141,547 or 7,271, 149, the contents of each of which are incorporated by reference herein in their entireties.
  • the formulations described herein comprise the exendin-4(l- 39)-human serum albumin or human serum albumin-exendin-4(l-39) molecule without further modification to the molecule, e.g., without the addition of a reactive group and/or the coupling of albumin thereto, as described in Section V, C
  • Useful insulinotropic peptide conjugates of the pharmaceutical formulation described herein include insulinotropic peptides and their derivatives conjugated to albumin. Several methods can be used to link an insulinotropic peptide to albumin. In certain embodiments, the insulinotropic peptide is linked to albumin according to any technique known to those of skill in the art. In some embodiments, the insulinotropic peptide is modified to include a reactive group which can react with available reactive functionalities on albumin to form covalent linkages.
  • the reactive group is chosen for its ability to form a stable covalent bond with albumin, for example, by reacting with one or more amino groups, hydroxyl groups, or thiol groups on the serum protein or peptide.
  • a reactive group reacts with only one amino group, hydroxyl group, or thiol group on albumin.
  • a reactive group reacts with a specific amino group, hydroxyl group, or thiol group on albumin.
  • a useful conjugate of the methods described herein comprises a modified peptide, or a modified derivative thereof, which is covalently attached to albumin via a reaction of the reactive group with an amino group, hydroxyl group, or thiol group on albumin.
  • a useful conjugate can comprise a modified peptide, or a modified derivative thereof, in which the reactive group has formed a covalent bond to albumin.
  • the functional group on albumin is the single free thiol group located at amino acid residue 34 (Cys34) and the chemically reactive group is a maleimido- containing group such as (GMBA or MPA).
  • GMBA stands for gamma-maleimide-butrylamide.
  • Such maleimide containing groups are referred to herein as maleimido groups.
  • albumin is covalently linked to a succinimidyl or maleimido group on the insulinotropic peptide.
  • an albumin amino, hydroxyl or thiol group is covalently linked to a succinimidyl or maleimido group on the insulinitropic peptide.
  • albumin cysteine 34 thiol is covalently linked to a [2-[2-[2- maleimidopropionamido(ethoxy)ethoxy] acetic acid linker on the epsilon amino of a lysine of the insulinotropic peptide.
  • the reactive group is a single MPA reactive group attached to the peptide, optionally through a linking group, at a single defined amino acid and the MPA is covalently attached to albumin at substantially a single amino acid residue of albumin, preferably cysteine 34.
  • the albumin is recombinant human albumin.
  • the reactive group, preferably MPA is attached to the peptide through one or more linking groups, preferably AEEA, AEA, or amino-octanoic acid, more particularly 8-amino- octanoic acid.
  • each linking group can be independently selected from the group consisting preferably of AEA ((2-amino) ethoxy acetic acid), AEEA ([2-(2-amino)ethoxy)]ethoxy acetic acid), and amino-octanoic acid, more particularly 8-amino-octanoic acid.
  • the reactive group, preferably MPA is attached to the peptide via 1, 2, 3, 4, 5 or 6 AEEA linking groups which are arranged in tandem.
  • the reactive group, preferably MPA is attached to the peptide via 1, 2, 3, 4, 5 or 6 8-amino-octanoic acid linking groups which are arranged in tandem.
  • the reactive group can be attached to any residue of the insulinotropic peptide suitable for attachment of such a reactive group.
  • the residue can be a terminal or internal residue of the peptide.
  • the reactive group can be attached to the carboxy-terminus or amino-terminus of the peptide.
  • the reactive group is attached to a single site of the peptide. This can be achieved using protecting groups known to those of skill in the art.
  • a derivative of the insulinotropic peptide can comprise a residue incorporated for attachment of the reactive group.
  • Useful residues for attachment include, but are not limited to, lysine, aspartate and glutamate residues. The residue can be incorporated internally or at a terminus of the peptide.
  • the reactive group is attached to an internal lysine residue.
  • the reactive group is attached to a terminal lysine residue.
  • the reactive group is attached to an amino-terminal lysine residue.
  • the reactive group is attached to a carboxy-terminal lysine residue, for instance, a lysine residue at the carboxy-terminus of GLP-1, GLP- 1(7-37) or exendin-4.
  • the manner of modifying insulinotropic peptides with a reactive group for conjugation to a macromolecule, e.g., albumin, will vary widely, depending upon the nature of the various elements comprising the insulinotropic peptide.
  • the synthetic procedures will be selected so as to be simple, provide for high yields, and allow for a highly purified product.
  • the chemically reactive group will be created at the last stage of insulinotropic peptide synthesis, for example, with a carboxyl group, esterification to form an active ester.
  • Specific methods for the production of modified insulinotropic peptides are described in U.S. Patent Nos. 6, 329,336, 6,849,714 or 6,887,849, the contents of each of which are incorporated by reference herein in their entireties.
  • the insulinotropic peptide can also be non-specifically conjugated to albumin. Bonds to amino groups will generally be employed, particularly with the formation of amide bonds for non-specific conjugation. To form such bonds, one can use as a chemically reactive group coupled to the insulinotropic peptide a wide variety of active carboxyl groups, particularly esters. While a number of different hydroxyl groups can be employed in these linking agents, the most convenient would be N-hydroxysuccinimide (NHS) and N-hydroxysulfosuccinimide (sulfo- NHS). Other linking agents which can be utilized are described in U.S. Pat. No. 5,612,034, which is hereby incorporated by reference herein in its entirety.
  • the insulinotropic peptide conjugates can comprise an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to an albumin
  • the albumin fusion protein can be generated by translation of a nucleic acid comprising a polynucleotide encoding all or a portion of a therapeutic protein joined to a polynucleotide encoding all or a portion of albumin.
  • the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to a glucagon-like peptide 1 as described in U.S. Patent No. 7, 141,547 or 7,271, 149, which are hereby incorporated by reference in their entireties.
  • the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to exendin-3, or a fragment or variant thereof.
  • the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to exendin-4, or a fragment or variant thereof.
  • the albumin fusion protein is [GIy 8 ]GLP-l(7-36)-[Gly 8 ]GLP-l(7-36)-human serum albumin (albiglutide) as described in U.S. Patent No. 7, 141,547 or 7,271, 149.
  • Insulinotropic peptides can be synthesized by standard methods of solid phase peptide chemistry known to those of ordinary skill in the art.
  • insulinotropic peptides fragments can be synthesized by solid phase chemistry techniques following the procedures described by Steward and Young (Steward, J. M. and Young, J. D., 1984, Solid Phase Peptide Synthesis, 2nd Ed. (Pierce Chemical Company, Rockford, 111.) using an Applied Biosystem synthesizer.
  • multiple fragments can be synthesized then linked together to form larger fragments.
  • These synthetic peptide fragments can also be made with amino acid substitutions at specific locations.
  • solid phase peptide synthesis a summary of the many techniques may be found in J. M.
  • the peptide and albumin are present in the conjugate in a 1 : 1 molar ratio, or an approximately 1 : 1 molar ratio.
  • the peptide and albumin are present in the conjugate in a 1 : 1 molar ratio, or an approximately 1 : 1 molar ratio, and the peptide is attached to the reactive group, optionally through a linking group, at substantially only one site on the peptide and the reactive group is attached to the albumin at substantially only one site on albumin.
  • the albumin in the peptide conjugates is human serum albumin.
  • the single site of attachment of the reactive group to albumin is preferably the thiol of cysteine 34 of albumin ⁇ e.g., via a maleimide linkage).
  • the reactive group is a single MPA reactive group attached to the peptide, optionally through a linking group, at a single defined amino acid and the MPA is covalently attached to albumin at substantially a single amino acid residue of albumin, preferably cysteine 34.
  • a conjugate is formed by contacting a modified peptide comprising a maleimido group with a thiol-containing serum protein, preferably albumin, under conditions comprising a pH of between 3.0 and 8.0, thereby preferably forming a stable thioether linkage which cannot be cleaved under physiological conditions.
  • serum protein is recombinant human albumin.
  • the modified peptide of the conjugate is amidated at its C-terminal end. In another embodiment, the modified peptide is not amidated at its C-terminal end.
  • a conjugate can also comprise such an amidated peptide.
  • a single reactive group is covalently attached at a defined site of the modified peptide.
  • a single reactive group is covalently attached at a defined site of the modified peptide and the reactive group is covalently attached to a single defined site of albumin, preferably to the thiol group of amino acid residue Cys34 of albumin.
  • the reactive group of a modified peptide or conjugate of the invention comprises a maleimide group and forms peptide: albumin conjugates of
  • a 1 : 1 molar ratio of peptide to serum protein is preferred over higher ratios because a 1 : 1 molar ratio provides better biological activity and less immunogenicity than higher ratios (see e.g., Stehle et al. 1997 Anti-Cancer Drugs 8:677- 685, incorporated by reference herein in its entirety).
  • the albumin is recombinant human albumin. Specific methods for the production of preformed peptide: albumin conjugates are described in U.S.
  • the conjugate is according to the following:
  • albumin of the conjugate can be any albumin as described above.
  • the conjugate is according to the following:
  • albumin (SEQ ID NO: 32) wherein X is S, O, or NH of an amino acid of said protein.
  • said protein is albumin.
  • said protein is albumin and X is S (sulfur) of Cys 34 of said albumin.
  • the albumin of the conjugate can be any albumin as described below.
  • albumin can be serum albumin isolated from a host species and purified for use in the formation of a conjugate.
  • the serum albumin can be any mammalian serum albumin known to those of skill in the art, including but not limited to mouse, rat, rabbit, guinea pig, dog, cat, sheep, bovine, ovine, equine, or human albumin.
  • the albumin is human serum albumin.
  • the albumin is bovine serum albumin.
  • HSA Human serum albumin
  • the albumin is recombinant albumin.
  • the recombinant albumin can be any mammalian albumin known to those of skill in the art, including but not limited to mouse, rat, rabbit, guinea pig, dog, cat, sheep, bovine, ovine, equine, or human albumin.
  • the recombinant albumin is recombinant human albumin (rHA).
  • the recombinant human albumin is recombinant human serum albumin.
  • rHA can be produced in a mammalian or non-mammalian organism. In one embodiment, the rHA is produced in a non-mammalian organism.
  • non-mammalian organisms that can be used for the production of rHA include, without limitation, yeast, bacteria, plants, fungi, and insects.
  • the rHA is produced in a whole plant or a whole fungus.
  • the rHA is produced in cultured plant cells, cultured fungus cells, or cultured insect cells.
  • the rHA is produced in a non-human mammal or in non-human mammalian cells.
  • the non-human mammal that is used for the production of rHA is selected from the group consisting of a cow, a dog, a pig, a sheep, a goat, a rat, a mouse, a rabbit, a chimpanzee, and a gorilla.
  • the non-human mammalian cells used for the production of rHA are, without limitation, bovine, canine, porcine, ovine, caprine, rodent, rabbit, or non-human primate cells.
  • the main advantage of rHA produced in a non-human organism compared with albumin purified from human blood or serous fluids is the absence of human-derived products in the manufacturing process of rHA.
  • the use of such controlled production methods leads to a purer product with less structural heterogeneity.
  • the insulinotropic peptide albumin conjugate can comprise an albumin precursor.
  • Human albumin is synthesized in liver hepatocytes and then secreted in the blood stream. This synthesis leads, in a first instance, to a precursor, prepro-HSA, which comprises a signal sequence of 18 amino acids directing the nascent polypeptide into the secretory pathway.
  • prepro-HSA which comprises a signal sequence of 18 amino acids directing the nascent polypeptide into the secretory pathway.
  • conjugates formed with an albumin precursor are within the scope of the conjugates described herein.
  • the insulinotropic peptide albumin conjugate can comprise molecular variants of albumin.
  • Variants of albumin can include natural variants resulting from the polymorphism of albumin in the human population. More than 30 apparently different genetic variants of human serum albumin have been identified by electrophoretic analysis under various conditions. See e.g., Weitkamp et al, Ann. Hum. Genet., 36(4):381-92 (1973); Weitkamp, Isr. J. Med. ScL, 9(9): 1238-48 (1973);.Fine et al, Biomedicine, 25(8):291-4 (1976); Fine et al, Rev. Fr. Transfus. ImmunohematoL, 25(2): 149-63. (1982); Rochu et al., Rev. Fr. Transfus.
  • the insulinotropic peptide albumin conjugate can comprise mercaptalbumin enriched albumin. While not intending to be bound by any particular theory of operation, it is believed that oxidation, or "capping" of the cysteine 34 thiol of albumin by cysteine, glutathione, metal ions, or other adducts can reduce the specificity of conjugation to the reactive group of the compound. Accordingly, mercaptalbumin can be enriched from
  • the mercaptalbumin can be enriched by contacting the albumin with thioglycolic acid (TGA). In certain embodiments, the mercaptalbumin can be enriched by contacting the albumin with dithiothreitol (DTT). In some embodiments, mercaptalbumin may be enriched by subjecting the albumin to hydrophobic interaction chromatography, using phenyl or butyl sepharose, or a combination thereof. In other embodiments, mercaptalbumin may be enriched by contacting the albumin with TGA or DTT, followed by purification by hydrophobic interaction chromatography, using phenyl or butyl sepharose resin, or both.
  • TGA thioglycolic acid
  • DTT dithiothreitol
  • mercaptalbumin may be enriched by subjecting the albumin to hydrophobic interaction chromatography, using phenyl or butyl sepharose, or a combination thereof.
  • mercaptalbumin may be enriched
  • the albumin variant has not more than 5, 4, 3, 2 or 1 amino acid substitutions, deletions or additions relative to the sequence of mature native human serum albumin.
  • the insulinotropic peptide albumin conjugate can comprise derivatives of albumin which share substantial homology with albumin.
  • conjugates can be formed with an albumin homologue having an amino acid sequence which shares at least 75%, at least 80%, at least 85%, more preferably at least 90%, and most preferably at least 95% identity to native human serum albumin, i.e., SEQ ID NO. 30.
  • Percent identity in this context means the percentage of amino acid residues in the candidate sequence that are identical (i.e., the amino acid residues at a given position in the alignment are the same residue) or similar (i.e., the amino acid substitution at a given position in the alignment is a conservative substitution, as discussed above), to the corresponding amino acid residue in the peptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence homology.
  • an albumin derivative is characterized by its percent sequence identity or percent sequence similarity with the naturally occurring albumin sequence. Sequence homology, including percentages of sequence identity and similarity, are determined using sequence alignment techniques well-known in the art, preferably computer algorithms designed for this purpose, such as BLAST, using the default parameters of said computer algorithms or the software packages containing them.
  • the albumin homologue comprises a free cysteine. In certain embodiments, the albumin homologue comprises a single free cysteine. In some embodiments, the albumin homologue comprises a free cysteine 34.
  • the insulinotropic peptide albumin conjugate can comprise an N- terminal fragment of human serum albumin of at least 100, 200, 300, 400, 500 or more than 500 amino acids.
  • the insulinotropic peptide albumin conjugate can comprise a human serum albumin variant comprising a modification of the Asp-Ala-His-Lys N-terminal sequence.
  • the insulinotropic peptide albumin conjugate can comprise at least one deletion among the three N-terminal amino acid residues Asp-Ala-His.
  • the insulinotropic peptide albumin conjugate can comprise an N- terminal extension of albumin, such as Glu 3 , Ala "2 Glu 1 , Phe°-HSA (1-585 of SEQ ID NO. 30) or an N-terminal fragment thereof.
  • the human serum albumin (HSA) variant is selected from the group consisting of HSA (2-585 of SEQ ID NO. 30), HSA (3-585 of SEQ ID NO. 30), HSA (4-585 of SEQ ID NO. 30), Asp-Ala- HSA (4-585 of SEQ ID NO. 30), Xaa 3 -HSA (1-585 of SEQ ID NO. 30) where Xaa 3 is an amino acid residue which has substituted the His residue occupying position 3 in native HSA, and N-terminal fragments thereof.
  • the insulinotropic peptide albumin conjugate can comprise structural derivatives of albumin.
  • Structural derivatives of albumin can include proteins or peptides which possess an albumin-type activity, for example, a functional fragment of albumin.
  • the derivative is an antigenic determinant of albumin, i.e., a portion of a polypeptide that can be recognized by an anti-albumin antibody.
  • the recombinant albumin can be any protein with preferably a plasma half-life of 75% to 100% of the plasma half-life of human serum albumin in humans and which can be obtained by modification of a gene encoding human serum albumin.
  • the recombinant albumin can contain additions or deletions in the trace metal binding region of albumin, such that binding of trace metals, e.g., nickel and/or copper is reduced or eliminated, as described in U.S. Patent No. 6,787,636, which is incorporated by reference herein in its entirety.
  • the recombinant albumin can be modified in the N-terminal region or binding region VI, such as through a truncation of at least one amino acid at the N-terminal end, so that it exhibits reduced or eliminated binding of trace metals such as nickel and/or copper.
  • Structural derivatives of albumin can be generated using any method known to those of skill in the art, including but not limited to, oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and polymerase chain reaction (PCR) mutagenesis.
  • Site-directed mutagenesis see Carter, Biochem. J. 237: 1-7 (1986); Zoller and Smith, Methods Enzymol.
  • cassette mutagenesis cassette mutagenesis, restriction selection mutagenesis (Wells et al., Gene 34:315-323 (1985)) or other known techniques can be performed on cloned albumin-encoding DNA to produce albumin variant DNA or sequences which encode structural derivatives of albumin (Ausubel et al., Current Protocols In Molecular Biology, John Wiley and Sons, New York (current edition); Sambrook et al., Molecular Cloning, A Laboratory Manual, 3d. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (2001), the contents of each of which are incorporated by reference herein in their entireties.
  • albumin derivatives include any macromolecule with preferably a plasma half-life of 75% to 100% of the plasma half-life of human serum albumin in humans which can be obtained by in vitro modification of the albumin protein.
  • the albumin is modified with fatty acids.
  • the albumin is modified with metal ions.
  • the albumin is modified with small molecules having high affinity to albumin.
  • the albumin is modified with sugars, including but not limited to, glucose, lactose, mannose, and galactose.
  • the insulinotropic peptide albumin conjugate can comprise an albumin fusion protein, i.e., an albumin molecule, or a fragment or variant thereof, fused to a therapeutic protein, or a fragment or variant thereof.
  • the albumin fusion protein can be generated by translation of a nucleic acid comprising a polynucleotide encoding all or a portion of a therapeutic protein joined to a polynucleotide encoding all or a portion of albumin.
  • Any albumin fusion protein known to those of skill in the art can be used to form conjugates according to the processes of the invention. Exemplary albumin fusion proteins are described in U.S. Patent Nos.
  • the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to a glucagon-like peptide 1 as described in U.S. Patent No. 7, 141,547 or
  • the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to exendin-3, or a fragment or variant thereof. In some embodiments, the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to exendin-4, or a fragment or variant thereof. In some embodiments, the albumin fusion protein is comprised of albumin, or a fragment or variant thereof, fused to a multiyear of exendin-4, or a fragment or variant thereof.
  • Albumin used to form a conjugate described herein can be obtained using methods or materials known to those of skill in the art.
  • albumin can be obtained from a commercial source, e.g., Novozymes Biopharma UK Ltd. (Nottingham, UK; recombinant human albumin produced by Saccharomyces cerevisiae); Cortex-Biochem (San Leandro, Calif.; serum albumin), Talecris Biotherapeutics (Research Triangle Park, North Carolina; serum albumin), ZLB Behring (King of Prussia, PA), or New Century Pharmaceuticals (Huntsville, Ala.;
  • the albumin derivative is RECOMBUMIN ® (Novozymes Biopharma UK Ltd. (Nottingham, UK)).
  • Recombumin ® is a recombinant human albumin (rHA) that is produced in vitro using recombinant yeast technology, in which genetically modified yeast (Saccharomyces cerevisiae) secrete soluble rHA which is subsequently harvested, purified and formulated for use as an excipient for the manufacture of biologies or a coating for medical devices.
  • rHA human albumin
  • the main advantage of rHA over HSA is that it is expressed in yeast with no animal- or human-derived products used in the manufacturing process. The use of such controlled production methods leads to a purer product with less structural heterogeneity.
  • the albumin derivative is MED WAY® (ALBREC®, GB-1057, Mitsubishi Tanabe Pharma Corp., Osaka, Japan).
  • MEDWAY is a recombinant human albumin (rHA) that is produced in vitro using recombinant yeast technology, in which genetically modified yeast (Pichia pastoris) secrete soluble rHA which can be subsequently harvested, purified and formulated for the indicated treatment.
  • the albumin derivative is ALBAGEN (New Century Pharma, Huntsville, AL). ALBAGEN is HSA (2-585) and is hypoallergenic due to the modified metal binding properties caused by the single N-terminal deletion.
  • the albumin derivative is ALBUCULTTM (Novozymes
  • AlbucultTM is a yeast-derived recombinant human albumin solution designed specifically for cell culture applications. It is produced without the use of animal- or human-derived materials and is therefore free from risk of contaminating human or animal-derived viruses or prions.
  • a pharmaceutical formulation comprising:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and optionally a buffer, wherein when present, the buffer is at a concentration of no more than 0.05 M; wherein the formulation has a pH from about 4.0 to about 7.0.
  • a pharmaceutical formulation consisting of or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; and pluronic F68 at a concentration of 0.05 to 0.2% (w/v); wherein the formulation has a pH from about 4.0 to about 7.0.
  • a pharmaceutical formulation consisting of or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a preservative selected from the group consisting of methanol, ethanol, isopropanol, glycerol, resorcinol, benzoic acid and sodium benzoate, wherein the formulation has a pH from about 4.0 to about 7.0.
  • a pharmaceutical formulation comprising:
  • a conjugate of albumin and an insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a tonicity modifier; a stabilizer; a surfactant, and a buffer selected from the group consisting of maleate, citrate-phosphate and L-histidine, wherein said formulation has a pH from about 5.0 to about 7.0.
  • a pharmaceutical formulation consisting or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a tonicity modifier; a stabilizer; a surfactant, and a buffer selected from the group consisting of maleate, citrate-phosphate and L-histidine, wherein said formulation has a pH from about 5.0 to about 7.0.
  • a pharmaceutical formulation comprising:
  • a conjugate of albumin and an insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a succinate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 4.0 to about 7.0.
  • a pharmaceutical formulation consisting or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a succinate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 4.0 to about 7.0.
  • a pharmaceutical formulation comprising:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a sodium phosphate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 5.5 to about 7.0.
  • a pharmaceutical formulation consisting or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; sodium octanoate at a concentration of 1 to 20 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a sodium phosphate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 5.5 to about 7.0.
  • a pharmaceutical formulation comprising:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; myristic acid at a concentration of 0.1 to 5.0 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a sodium phosphate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 6.0 to about 8.0.
  • a pharmaceutical formulation consisting of or consisting essentially of:
  • a conjugate of albumin and an insulinotropic peptide said insulinotropic peptide comprising an amino acid sequence which has not more than 3 amino acid substitutions, deletions, or additions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; sodium chloride at a concentration of 100 to 200 mM; myristic acid at a concentration of 0.1 to 5.0 mM; pluronic F68 at a concentration of 0.05 to 0.2% (w/v); and a sodium phosphate buffer at a concentration of 5 mM to 30 mM; wherein the formulation has a pH from about 6.0 to about 8.0.
  • X is S of an amino acid of albumin.

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Abstract

La présente invention concerne des formulations pharmaceutiques comprenant des conjugués peptidiques insulinotropiques, en particulier un conjugué d'albumine à l'exendine-4, ou son dérivé, et leurs procédés d'administration. La présente invention concerne également des méthodes de traitement du diabète et de maladies ou états associés à des peptides insulinotropiques par l'administration des formulations pharmaceutiques décrites ici.
PCT/US2011/027311 2010-03-05 2011-03-04 Formulation de conjugués peptidiques insulinotropiques Ceased WO2011109784A1 (fr)

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WO2013192131A1 (fr) 2012-06-21 2013-12-27 Indiana University Research And Technology Corporation Polypeptides de fusion de région fc de polypeptide ligand du récepteur d'incrétine et conjugués à fonction effectrice fc modifiée
WO2014159813A1 (fr) 2013-03-13 2014-10-02 Moderna Therapeutics, Inc. Molécules polynucléotidiques à longue durée de vie
WO2015095684A1 (fr) 2013-12-20 2015-06-25 Indiana University Research And Technology Corporation Polypeptides de fusion ligand lipidé du récepteur de l'incrétine - région fc d'immunoglobuline humaine
JP2016526899A (ja) * 2013-08-01 2016-09-08 江蘇泰康生物医薬有限公司 Ｇｌｐ−１類似体融合タンパク質とその作製方法及び用途
EP3121194A1 (fr) * 2012-03-14 2017-01-25 Innovative Targeting Solutions Inc. Génération d'une diversité de séquence ciblée dans des protéines de fusion
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
WO2022157747A3 (fr) * 2021-01-25 2022-09-01 Mylan Ireland Limited Compositions peptidiques pharmaceutiques et leurs procédés de préparation
US11622996B2 (en) 2018-05-07 2023-04-11 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
US20240424072A1 (en) * 2023-06-26 2024-12-26 AlbuNext, LLC Albumin Bound Macromolecule Tri-Agonist Activating GLP 1/GIP/Glucagon Receptors And Methods Therefor

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WO2009075859A2 (fr) * 2007-12-11 2009-06-18 Conjuchem Biotechnologies Inc. Formulation de conjugués de peptides insulinotropes

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WO2007053946A1 (fr) * 2005-11-09 2007-05-18 Conjuchem Biotechnologies Inc. Procede de traitement du diabete et/ou de l'obesite en reduisant les effets secondaires nauseeux au moyen d'un peptide insulinotrope conjugue a de l'albumine
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Cited By (28)

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Publication number Priority date Publication date Assignee Title
EP3121194A1 (fr) * 2012-03-14 2017-01-25 Innovative Targeting Solutions Inc. Génération d'une diversité de séquence ciblée dans des protéines de fusion
US10563206B2 (en) 2012-03-14 2020-02-18 Innovative Targeting Solutions Inc. Generating targeted sequence diversity in fusion proteins
US9914929B2 (en) 2012-03-14 2018-03-13 Innovative Targeting Solutions Inc. Generating targeted sequence diversity in fusion proteins
WO2013192131A1 (fr) 2012-06-21 2013-12-27 Indiana University Research And Technology Corporation Polypeptides de fusion de région fc de polypeptide ligand du récepteur d'incrétine et conjugués à fonction effectrice fc modifiée
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
WO2014159813A1 (fr) 2013-03-13 2014-10-02 Moderna Therapeutics, Inc. Molécules polynucléotidiques à longue durée de vie
JP2016526899A (ja) * 2013-08-01 2016-09-08 江蘇泰康生物医薬有限公司 Ｇｌｐ−１類似体融合タンパク質とその作製方法及び用途
EP3029072A4 (fr) * 2013-08-01 2017-01-04 Jiangsu T-MAB Biopharma Co., Ltd. Protéine de fusion analogue glp-1 et son procédé de préparation et son utilisation
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
WO2015095684A1 (fr) 2013-12-20 2015-06-25 Indiana University Research And Technology Corporation Polypeptides de fusion ligand lipidé du récepteur de l'incrétine - région fc d'immunoglobuline humaine
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
US12214017B2 (en) 2017-08-24 2025-02-04 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11622996B2 (en) 2018-05-07 2023-04-11 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
WO2022157747A3 (fr) * 2021-01-25 2022-09-01 Mylan Ireland Limited Compositions peptidiques pharmaceutiques et leurs procédés de préparation
US20240424072A1 (en) * 2023-06-26 2024-12-26 AlbuNext, LLC Albumin Bound Macromolecule Tri-Agonist Activating GLP 1/GIP/Glucagon Receptors And Methods Therefor

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