[go: up one dir, main page]

WO2017079611A1 - Formulations stables de peptide de glucagon - Google Patents

Formulations stables de peptide de glucagon Download PDF

Info

Publication number
WO2017079611A1
WO2017079611A1 PCT/US2016/060601 US2016060601W WO2017079611A1 WO 2017079611 A1 WO2017079611 A1 WO 2017079611A1 US 2016060601 W US2016060601 W US 2016060601W WO 2017079611 A1 WO2017079611 A1 WO 2017079611A1
Authority
WO
WIPO (PCT)
Prior art keywords
glucagon
patient
skin
formulation
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/060601
Other languages
English (en)
Inventor
Mahmoud Ameri
Peter E. Daddona
Yi Ao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZP OPCO Inc
Original Assignee
ZP OPCO Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/930,041 external-priority patent/US9782344B2/en
Application filed by ZP OPCO Inc filed Critical ZP OPCO Inc
Priority to EP16863067.1A priority Critical patent/EP3397269A4/fr
Publication of WO2017079611A1 publication Critical patent/WO2017079611A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles

Definitions

  • the present invention relates to drug delivery, and more particularly to
  • Glucagon is produced in humans by the pancreas. Glucagon binds to specific receptors on liver cells and increases the release of glucose in the blood stream. Thus, it is used in the treatment of diabetes as a rescue medication when the blood sugar level drops too low.
  • Glucagon is a short peptide having 29 amino acids and a molecular weight of 3,483 kilodaltons (kDa).
  • the sequence of amino acid in glucagon is :
  • Glucagon has a highly helical conformation in the crystalline state, but forms a random coil in dilute solution with about 15% alpha helix at the C-terminus. At higher concentrations it generally precipitates and forms fibrils. Glucagon readily dissolved in aqueous solution at pH below 3 or above 9, but precipitates readily at pH between 4 and 8. Liquid formulations of glucagon are highly unstable, and undergo hydrolysis and deamidation at several positions (amino acid at position 3, 9, 15, 20, 21, and 24) and thus pharmaceutical preparations are generally provided in dual containers: powders of glucagon in one side and a liquid diluent in another. A solution of glucagon is then prepared just prior to use. Procedures generally undertaken to mitigate the instability of glucagon in liquid formulations include the use of solid dispersions, aprotic solvents, surfactants, processes conducted at low temperature, and packaging in dried form.
  • Dilute formulations have been prepared that are stable for up to 6 days and are useful for delivery with a pump (US2011/0097386).
  • the concentration of glucagon in these formulations is between 0.8 mg/mL to 5 mg/mL and the pH is between 4 and 7.
  • Stabilizing agents are a combination of both low concentrations of a surfactant such as 1 mg/ml lyso- myristoyl phosphatidylcholine (LMPC) and high concentrations of saccharide such as 45 mg/mL of glucose.
  • LMPC lyso- myristoyl phosphatidylcholine
  • Applicant describes herein a highly concentrated liquid glucagon formulation that is stable for at least 4 days with the utilization of Sodium Carboxymethyl Cellulose (NaCMC) to prevent fibril and /or gelation of glucagon.
  • NaCMC Sodium Carboxymethyl Cellulose
  • the invention comprises new formulations of glucagon suitable for transdermal delivery.
  • Stable liquid formulations are described at high concentration of glucagon. These formulations do not form gels or fibrils and can be readily deposited onto substrates to form a uniform coating. Once deposited onto a substrate and dried, the glucagon in the coatings has improved stability over time. The glucagon can be readily reconstituted (such as with bodily fluids) without forming a gel. These formulations are thus suited for use as coatings on substrates such as microneedle patches for the transdermal delivery of glucagon for the treatment of low blood sugar.
  • a liquid pharmaceutical formulation comprising 15-20% (w/w) of glucagon, 7.5-10% (w/w) of a stabilizing agent selected from either a cationic or neutral surfactant, 3.75-5% (w/w) of an amino acid, 3.75-5% (w/w) of an organic acid, and a pharmaceutically acceptable diluent; the formulation having a pH between 2 and 3.
  • the surfactant is a phospholipid.
  • the phospholipid is lyso -myristoyl phosphatidylcholine.
  • the surfactant is decanoyl sucrose.
  • the amino acid is selected from the group consisting of glutamine and glycine.
  • the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, citric acid, caproic acid, benzoic acid, lactic acid, propionic acid, and sorbic acid.
  • the pharmaceutical formulation has a viscosity in the range of 20-200 centipoise (cP).
  • the pharmaceutical formulation the surfactant is decanoyl sucrose, the amino acid is glutamine and the organic acid is tartaric acid.
  • the surfactant is decanoyl sucrose, the amino acid is glycine and the organic acid is tartaric acid.
  • the surfactant is lyso-myristoyl phosphatidylcholine, the amino acid is glutamine and the organic acid is tartaric acid.
  • the surfactant is lyso-myristoyl phosphatidylcholine, the amino acid is glycine and the organic acid is tartaric acid.
  • a lyophilized glucagon formulation that has the following composition, 44.5 %w/w glucagon, 22.2 %w/w lyso-myristoyl
  • the liquid formulation upon reconstitution with de-ionized water, the liquid formulation comprises 0.5 mg/mL Sodium Carboxymethylcellulose (NaCMC), to make a high concentration glucagon formulation that is suitable for microneedle coating.
  • the liquid glucagon formulation has the following composition; 200 mg/mL glucagon, 100 mg/mL LMPC, 50 mg/mL trehalose, 50 mg/mL tartaric acid, 50 mg/mL glycine and 0.5 mg/mL NaCMC.
  • the pH of the liquid formulation is between 2.8 - 3.2.
  • the lyophilized glucagon formulation is reconstitution with reconstituting media comprising de-ionized water and an amount of NaCMC preferably less than 0.1 mg/mL and/or less than or equal to 1 mg/mL.
  • a liquid pharmaceutical formulation comprising glucagon and lyso-myristoyl phosphatidylcholine (LMPC), wherein the amount of LMPC is between 2 and 8 fold less than the amount of glucagon and further comprises 50 mg/mL trehalose, 50 mg/mL tartaric acid, 50 mg/mL glycine and Sodium Carboxymethyl Cellulose (NaCMC), wherein the concentration of NaCMC is greater than 0.1 mg/ml and less than 1 mg/ml, and wherein the pH of said liquid pharmaceutical formulation is between 2.8 and 3.2.
  • LMPC lyso-myristoyl phosphatidylcholine
  • glucagon is at a concentration of 200 mg/mL, and wherein LMPC is at a concentration of 100 mg/mL.
  • the liquid pharmaceutical formulation comprises NaCMC is at a concentration of 0.5 mg/mL.
  • a solid pharmaceutical formulation comprising glucagon and lyso-myristoyl phosphatidylcholine (LMPC), wherein the amount of LMPC is between 2 and 8 fold less than the amount of glucagon and further comprises 11.1 %w/w trehalose, 11.1 %w/w tartaric acid and 11.1 %w/w glycine.
  • the formulation comprises comprising 44.5 %w/w glucagon, 22.2 %w/w LMPC, 11.1 %w/w trehalose, 11.1 %w/w tartaric acid and 11.1 %w/w glycine.
  • Another aspect described herein is a medical device for the delivery of a pharmaceutical agent through the skin, the device comprising an array of microneedles having coated thereon a liquid composition described herein.
  • the medical device carries a therapeutic dose of glucagon ranging from of 0.5 mg to 1.0 mg.
  • a solid pharmaceutical formulation comprising 40-50% (w/w) of glucagon or a glucagon-like peptide, 20-25% (w/w) of a stabilizing agent selected from either a cationic or neutral surfactant, 10-12.5% (w/w) of an amino acid, 10-12.5% (w/w) of an organic acid; the formulation having a pH between 2 and 3.
  • the surfactant is a phospholipid.
  • the phospholipid is lyso-myristoyl phosphatidylcholine.
  • the surfactant is selected from the group consisting of glucose, sucrose, trehalose, and dextrose substituted with a C8-C12 alkyl chain. In other embodiments, the surfactant is decanoyl sucrose.
  • the amino acid is selected from the group consisting of glutamine and glycine.
  • the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, and citric acid.
  • the surfactant is decanoyl sucrose, the amino acid is glutamine and the organic acid is tartaric acid. In other embodiments, the surfactant is decanoyl sucrose, the amino acid is glycine and the organic acid is tartaric acid. In other embodiments, the surfactant is lyso-myristoyl phosphatidylcholine, the amino acid is glutamine and the organic acid is tartaric acid. In other embodiments, the surfactant is lyso-myristoyl phosphatidylcholine, the amino acid is glycine and the organic acid is tartaric acid.
  • a medical device for the delivery of a pharmaceutical agent through the skin, the device comprising an array of microneedles having coated thereon a liquid composition comprising 15-20% (w/w) of glucagon, 7.5-10% (w/w) of a stabilizing agent selected from either a cationic or neutral surfactant, 3.75-5%) (w/w) of an amino acid, 3.75-5%) (w/w) of an organic acid, and a pharmaceutically acceptable diluent; the formulation having a pH between 2 and 3.
  • the medical device carries a therapeutic dose of glucagon of either 1 mg for an adult dose, or 0.5 mg for a pediatric dose.
  • the surfactant is a phospholipid.
  • the phospholipid is lyso-myristoyl phosphatidylcholine.
  • the surfactant is selected from the group consisting of glucose, sucrose, trehalose, dextrose substituted with a C8-C12 alkyl chain.
  • the surfactant is decanoyl sucrose.
  • the amino acid is selected from the group consisting of glutamine and glycine.
  • the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, and citric acid.
  • a medical device for the delivery of a pharmaceutical agent through the skin comprising an array of microneedles having coated thereon a solid composition comprising 40-50%> (w/w) of glucagon or a glucagon-like peptide, 20-25% (w/w) of a stabilizing agent selected from either a cationic or neutral surfactant, 10-12.5%) (w/w) of an amino acid, 10-12.5%) (w/w) of an organic acid; the formulation having a pH between 2 and 3.
  • the medical device carries a therapeutic dose of glucagon of either 1 mg for an adult dose, or 0.5 mg for a pediatric dose.
  • the surfactant is a phospholipid.
  • the phospholipid is lyso-myristoyl phosphatidylcholine.
  • the surfactant is selected from the group consisting of glucose, sucrose, trehalose, dextrose substituted with a C8-C12 alkyl chain.
  • the surfactant is decanoyl sucrose.
  • the amino acid is selected from the group consisting of glutamine and glycine.
  • the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, and citric acid.
  • the solid formulation is such that once applied to the skin of a patient the coating is dissolved by the body fluids of the patient in less than 30 minutes. In other embodiments, the coating is dissolved by the body fluids of the patient in less than 20 minutes. In other embodiments, the coating is dissolved by the body fluids of the patient in less than 10 minutes.
  • a process for coating a medical device comprising coating a liquid pharmaceutical composition according to the invention described herein onto a medical device and drying the pharmaceutical composition.
  • a blood serum C max of glucagon is reached in less than 30 minutes. In other embodiments, a blood serum C max of glucagon is reached in about 10 min. In yet other embodiments, a blood serum C max of glucagon reaches at least 5 ng/mL. In other embodiments, a blood serum C max of glucagon reaches at least 10 ng/mL. In still other embodiments, a blood serum C max of glucagon reaches about 20 ng/mL.
  • a blood serum C max of glucagon of at least 5 ng/mL is reached in less than 20 minutes following application of the device to the skin of the patient. In yet other embodiments, a blood serum C max of glucagon of at least 5 ng/mL is reached in about 10 minutes following application of the device to the skin of the patient. In yet other
  • a blood serum C max of glucagon of about 10 ng/mL is reached in about 10 minutes following application of the device to the skin of the patient.
  • a blood serum concentration of glucagon is less than 10 ng/mL at about 60 minutes following application of the device to the skin of the patient.
  • a blood serum C max of glucagon of at least 5 ng/mL is reached in less than 20 minutes and blood serum concentration of glucagon less than 10 ng/mL at about 40 minutes following application of the device to the skin of the patient.
  • a blood serum C max of glucagon of at least 10 ng/mL is reached in less than 20 minutes and blood serum concentration of glucagon less than 10 ng/mL at about 30 minutes following application of the device to the skin of the patient.
  • Figure 1 is a perspective view of a portion of one example of a microneedle patch, according to the invention.
  • Figure 2 is a perspective view of the microneedle patch shown in Figure 1 having a coating deposited on the microneedles, according to the invention.
  • Figure 3 is a side sectional view of a microneedle patch having an adhesive backing, according to the invention.
  • Figure 4 is a side sectional view of a retainer ring having a microneedle patch disposed therein, according to the invention.
  • Figure 5 is a perspective view of the retainer shown in Figure 4.
  • Figure 6 is an exploded perspective view of an applicator and retainer, according to the invention.
  • Figure 7 is an SEM photograph of microneedle patch coated with glucagon according to embodiments of the invention.
  • Figures 8A and 8B are schematic representations of the process of coating glucagon formulations onto microneedle patches according to an embodiment of the invention.
  • Figure 9 is a plot of time versus viscosity comparing time to gelation of formulations of glucagon using various stabilizing agents prepared according to Example 1.
  • Figure 10 is a plot of time versus viscosity comparing time to gelation of formulations of glucagon using various concentrations of the stabilizing agents lyso-myristoyl phosphatidylcholine (LMPC) prepared according to Example 2.
  • LMPC lyso-myristoyl phosphatidylcholine
  • Figure 11 is a plot of time versus viscosity comparing time to gelation of formulations of glucagon with and without glutamine prepared according to Example 3.
  • Figure 12 is a plot of time versus viscosity comparing time to gelation of formulations of glucagon with methanoic or tartaric acid prepared according to Example 4.
  • Figure 13 is a plot of time versus purity comparing stability of formulations of glucagon with glutamine, LMPC and methanoic or tartaric acid prepared according to example 5 at 25°C and 40°C.
  • Figure 14 is a plot of time versus purity comparing stability of formulations of glucagon with glutamine, decanoyl sucrose and methanoic or tartaric acid prepared according to Example 6 at 25°C and 40°C.
  • Figure 15 is a plot comparing the pharmacokinetics of formulations of glucagon on the microneedle patch prepared according to an embodiment of the invention versus subcutaneous injection in the hairless guinea pig, detailed at Example 7.
  • Figure 16 is a plot comparing purity over time for Formulation 1. The plot shows the stability of glucagon systems where the titanium array was coated Formulation 1 with 0.5 mg of glucagon, assembled with a polycarbonate retainer ring with a co-molded desiccant and a 5 cm 2 adhesive patch, and heat sealed in a nitrogen-purged foil pouch.
  • Figure 17 is a plot comparing purity over time for Formulation 2.
  • the plot shows the stability of glucagon systems where the titanium array was coated Formulation 1 with 0.5 mg of glucagon, assembled with a polycarbonate retainer ring with a co-molded desiccant and a 5 cm 2 adhesive patch, and heat sealed in a nitrogen-purged foil pouch.
  • Figure 18 shows the Far UV (FUV) circular dichroism (CD) spectra for glucagon extracted from Patch C and Patch D.
  • ZP-Glucagon patches were evaluated for glucagon fibrillation by CD after glucagon dissolution.
  • CD spectra are consistent with a glucagon peptide in a predominantly a-helical conformation as a soluble trimer or soluble helical monomer, as opposed to the ⁇ -sheet rich structure in glucagon fibrils. As there is still a significant amount of random coil structure, this is also consistent with monomeric glucagon.
  • Figure 19 is a plot of time versus viscosity comparing time to gelation of formulations of lyophilized glucagon reconstituted with NaCMC (0.5 mg/mL) ( ⁇ ) and de- ionized water ( ⁇ ).
  • Figure 20 is a plot of fluorescence against wavelength. An increase in the intensity of fluorescence with time at wavelength of 480 nm suggests fibril formation.
  • Figure 21 is a plot of time versus viscosity comparing time to gelation of formulations of lyophilized glucagon reconstituted with NaCMC at concentrations of 0.5 mg/mL ( ⁇ ), 0.2 mg/mL ( ⁇ ) and 0.1 mg/mL ( ⁇ ).
  • Figure 22 Plot of time versus viscosity comparing time to gelation of formulations of lyophilized glucagon reconstituted with lmg/mL NaCMC ( ⁇ ) and 2 mg/mL HEC ( ⁇ ).
  • An alkyl saccharide according to the invention means a compound comprising a carbohydrate moiety of the type R-C x H 2 y +z Oy, wherein x and y are integers ranging from 3-12, z is a numeral ranging from -1 to 1,
  • R may be an hydrogen or a linear or branched C1-C22 alkyl or alkyl groups saturated or partially unsaturated, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, octadecyl-, nondecyl-, eicosanyl-, heneicosanyl-,
  • a cationic surfactant according to the invention means a compound selected from a phosphatidylcholine and lyso phosphatidylcholine, including lyso -myristoyl phosphocholine (LMPC).
  • LMPC lyso -myristoyl phosphocholine
  • An organic acid means naturally occurring acids including methanoic (formic), acetic, caproic, tartaric, citric, benzoic, lactic, propionic, sorbic, malonic, malic, glycolic, and gluconic acids.
  • Pharmaceutically acceptable diluent means water with or without buffers, salts and the like.
  • transdermal means the delivery of an agent into and/or through the skin for local or systemic therapy.
  • transdermal flux means the rate of transdermal delivery.
  • co-delivering means that a supplemental agent(s) is administered transdermally either before the agent is delivered, before and during transdermal flux of the agent, during transdermal flux of the agent, during and after transdermal flux of the agent, and/or after transdermal flux of the agent. Additionally, two or more agents may be coated onto the microprojections resulting in co-delivery of the agents.
  • biologically active agent or “active agent” as used herein, refers to a composition of matter or mixture containing a drug which is pharmacologically effective when administered in a therapeutically effective amount.
  • biologically effective amount or “biologically effective rate” shall be used when the biologically active agent is a pharmaceutically active agent and refers to the amount or rate of the pharmacologically active agent needed to effect the desired therapeutic, often beneficial, result.
  • the amount of agent employed in the coatings will be that amount necessary to deliver a therapeutically effective amount of the agent to achieve the desired therapeutic result. In practice, this will vary widely depending upon the particular
  • pharmacologically active agent being delivered, the site of delivery, the severity of the condition being treated, the desired therapeutic effect and the dissolution and release kinetics for delivery of the agent from the coating into skin tissues. It is not practical to define a precise range for the therapeutically effective amount of the pharmacologically active agent incorporated into the microneedles and delivered transdermally according to the methods described herein.
  • the term "stability” shall refer to the property of a formulation to retain its purity level (% (w/w)), within 3% of its starting purity level after a period of time, preferably 0-24 months, 0-12 months, or 0-6 months; at a temperature of 0-50°C, preferably 4-42 °C, more preferably 25-40°C; and at a relative humidity (RH) of 0-100%, preferably 25-85%, more preferably 60-75%.
  • microneedles refers to piercing elements which are adapted to pierce or cut through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a human.
  • the piercing elements have a blade length of less than 500 Dm, and preferably less than 400 Dm.
  • the microprojections typically have a width of about 50 to 200 Dm and thickness of about 5 to 50 ⁇ m.
  • the microprojections may be formed in different shapes, such as needles, hollow needles, blades, pins, punches, and combinations thereof.
  • microneedle array or "microneedle patch” as used herein, refers to a substrate carrying a plurality of microneedles arranged in an array for piercing the stratum corneum.
  • the microneedle patch may be formed by etching or punching a plurality of microneedles from a thin sheet and folding or bending the microneedles out of the plane of the sheet to form a configuration such as that shown in Figure 1.
  • the microneedle patch may also be formed in other known manners, such as by forming one or more strips having microneedle along an edge of each of the strip(s) as disclosed in U.S. Pat. No. 6,050,988 of the ALZA
  • microneedle patch may also include hollow needles which hold a dry pharmacologically active agent.
  • Liquid and solid dry formulations according to the invention for application to microneedle patches are prepared according to the general procedures of publication Pharm. Res. 27, 303-313 (2010).
  • a liquid glucagon formulation containing a surfactant, an amino acid and an organic acid are prepared according to the following exemplary procedure. Three hundred mg of glucagon is added to 1.5 mL of stock solution containing 50 mg/mL of tartaric acid, 50 mg/rnL of glutamine and 100 mg/mL of surfactant. The resultant slurry is then mixed for 2-3 hours or until a clear solution of the liquid formulation is obtained.
  • a liquid pharmaceutical formulation according to the invention may contain 15- 20% (w/w) of glucagon, 7.5-10%) (w/w) of a stabilizing agent selected from the group consisting of a cationic or alkyl saccharide surfactant, 3.75-5%) (w/w) of an amino acid; 3.75-5%) (w/w) of an organic acid, and a pharmaceutically acceptable diluent.
  • the pH of the formulation is adjusted to between 2 and 3.
  • the dried pharmaceutical formulation on the coated, ready for packaging, patches according to the invention may contain 40-50%> (w/w) of glucagon, 20-25%> (w/w) of a stabilizing agent selected from either a cationic surfactant or an alkyl saccharide, 10-12.5% (w/w) of an amino acid, 10-12.5% (w/w) of an organic acid.
  • a stabilizing agent selected from either a cationic surfactant or an alkyl saccharide, 10-12.5% (w/w) of an amino acid, 10-12.5% (w/w) of an organic acid.
  • the pH of the formulation is 2 to 3.
  • the surfactant may be a cationic phospholipid such as lyso-myristoyl
  • the alkyl saccharide may be sucrose with a C8-C12 alkyl chain such as decanoyl sucrose.
  • the amino acid may be glutamine or glycine.
  • the organic acid may be methanoic acid or tartaric acid.
  • Embodiments of the present invention provide a formulation containing a biologically active agent, glucagon which when coated and dried upon one or more microneedles of a microneedle patch as shown in Figure 1, forms a stable coating with enhanced solubilization of the drug upon insertion into the skin for a fast release into the blood stream of the patient and quick treatment onset.
  • embodiments of the present invention include a device 22 having a plurality of stratum corneum-piercing microneedles 24 extending therefrom.
  • the microneedles are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, but do not penetrate so deep as to reach the capillary beds and cause significant bleeding.
  • the microneedles carry a coating 26 of the dry formulation of the biologically active agent, glucagon.
  • body fluids intracellular fluids and extracellular fluids such as interstitial fluid
  • the solid coating is obtained by drying a liquid formulation on the microneedles, as described in U.S. Patent No. 7,537,795 of the ALZA Corporation, the entire content of which is incorporated herein by reference herein.
  • the liquid formulation is usually an aqueous formulation.
  • the drug is typically present in an amount of 1-2 mg per unit dose. With the addition of formulating agents, the total mass of the solid coating is less than 4 mg per unit dose.
  • the microneedle array 22 is usually present on an adhesive 30 with a backing 40 as shown in Figure 3, which is attached to a disposable polymeric retainer ring 50 as shown in Figures 4 and 5. This assembly is packaged individually in a pouch or a polymeric housing.
  • the microneedle patch 22 is applied to the skin of a patient with the use of a deployment device 60, shown in Figure 6, on which is mounted the retainer ring 50 with the microneedle patch 22.
  • the deployment device is depressed, detaching the patch 22 from the retainer ring and pushing the microneedles 24 into the skin of the patient.
  • the patch can be mounted in a single use applicator ready for patient application, as described in US patent application, 61/864,857 filed August 12, 2013.
  • Coated microneedle patches for delivery of glucagon may be prepared as follows. Coatings on the microneedles can be formed by a variety of known methods such as dip-coating or spraying. Dip-coating consists of partially or totally immersing the microneedles into a formulation prepared according to the invention. Alternatively, the entire device can be immersed into the formulation. In many instances, it may be preferable to only coat the tips of the microneedles. Microneedles tip coating apparatus and methods are disclosed in U.S. Patent No. 6,855,372 of the ALZA Corporation, the content of which is incorporated herein by reference in its entirety.
  • FIG. 8A A sketch of the process is shown in Figure 8A.
  • the coating apparatus only applies coatings to the microneedles themselves and not upon the substrate that the microneedles project from.
  • a liquid formulation 10 prepared according to the invention is placed into a reservoir 12.
  • a rotating drum 14 is partially submerged into the liquid and is rotated.
  • the liquid 10 forms a thin film on the coating drum 16.
  • a blade 18 controls the thickness of the film to match the length of the microneedles or adjust the dosage on the patches.
  • a sled 20 carrying the substrate 22 with the microneedles 24 is positioned on the drum 14 so that the microneedles 24 are immersed or dipped into the film 16 (shown in the excerpt in Figure 8B).
  • the substrate 22 moves from one side to the other so as to coat the microneedles sequentially.
  • the process can be performed in a continuous manner feeding a series of substrates to the apparatus. The process may be repeated to increase the thickness of the coatings and thus vary the dosage of the patches.
  • This coating technique has the advantage of forming a smooth coating that is not easily dislodged from the microneedles during skin piercing.
  • Other coating techniques such as micro fluidic spray or printing techniques can be used to precisely deposit a coating on the microneedles 24.
  • Dosage of glucagon on the microneedle patches can be controlled by varying a variety of features, such as the size of the patch, the size of the microneedles, the thickness of the coating on the microneedles, and the surface area of the coatings on the microneedles. Patches may thus be prepared for the transdermal delivery of glucagon at the following dose ranges and doses: 0.25-2.0 mg/patch, preferably 0.5-1.0 mg/patch; patch size can be 5 cm 2 to 10 cm 2 with a microneedle array of 2.5 cm 2 to 8 cm 2 .
  • Treatment of low blood sugar in a patient may require the application of one patch per occurrence. It may also require the application of several patches simultaneously or sequentially until the sugar blood level has reached the normal range of glucose serum concentration.
  • Physical stabilization is an important step in assuring efficacy of the therapeutic agents, particularly when the mode of delivery of the therapeutic agent is via a transdermal delivery device having a plurality of microneedles coated with an agent containing biocompatible coating.
  • the formulations of the present invention display superior stability and are shown to retain substantial purity after storage of up to six months when stored under various temperature and relative humidity conditions.
  • the formulations of the present invention are shown to remain in predominantly a- helical conformation as a soluble trimer or soluble or soluble helical monomer, as opposed to the ⁇ -sheet rich structures found in glucagon fibrils.
  • the superior stability and limited fibril formation of the formulations presented herein offer a significant improvement over currently available glucagon therapeutics.
  • compositions of, and methods for formulating and delivering, biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is manufactured and/or packaged in a dry inert atmosphere, preferably nitrogen or argon.
  • compositions of, and methods for formulating and delivering, biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is coated on at least one stratumcorneum piercing microneedle, preferably a plurality of stratumcorneum piercing microneedles of a microneedle delivery device, and manufactured and/or packaged in a dry inert atmosphere, preferably nitrogen or argon.
  • compositions of, and methods for formulating and delivering, biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is manufactured and/or packaged in a dry inert atmosphere, preferably nitrogen or argon, and in the presence of a desiccant.
  • compositions of, and methods for formulating and delivering, biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a biocompatible coating that is manufactured and/or packaged in a foil lined chamber having a dry inert atmosphere, preferably nitrogen and a desiccant.
  • compositions of, and methods for formulating and delivering, biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is manufactured and/or packaged in a partial vacuum.
  • compositions of and methods for formulating and delivering biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is manufactured and/or packaged in a dry inert atmosphere, preferably nitrogen or a partial vacuum.
  • compositions of and methods for formulating and delivering biologically active agents are particularly suitable for transdermal delivery using a microneedle delivery device, wherein the biologically active agents are included in a
  • biocompatible coating that is manufactured and/or packaged in a foil lined chamber having a dry inert atmosphere, preferably nitrogen and a desiccant.
  • Glucagon was acquired from BACHEM and was produced by chemical synthesis at a purity of 98.8% (w/w). Formulations of glucagon are prepared following the procedures of publication Pharm. Res. 27, 303-313 (2010). A liquid formulation containing a surfactant, an amino acid and an organic acid was prepared. Three hundred mg of glucagon was added to 1.5 mL of stock solution containing 50 mg/mL tartaric acid, 50 mg/mL glutamine and 100 mg/mL surfactant. The resultant slurry was then mixed for 2-3 hours or until a clear solution of the liquid formulation was obtained.
  • Example 1 Study of the effect of surfactants on the physical stability of glucagon liquid formulations.
  • Example 2 Study of the effect of the concentration of the surfactant on the physical stability of glucagon liquid formulations. [0081] A summary of the various formulations is shown in Table 2 below. A comparison of the gelation profiles between the formulations is shown in Figure 10 and gelation point results are shown in Table 2 below.
  • Example 3 Study of the effect of glutamine on the physical stability of glucagon liquid formulations.
  • Example 4 Study of the effect of the organic acid on the physical stability of glucagon liquid formulations.
  • Example 5 Stability of glucagon coatings on microneedle patches, effect of the organic acid with LMPC.
  • Example 6 Stability of glucagon coatings on microneedle patches, effect of the org with decanoyl sucrose.
  • Example 7 PK Study of glucagon coated microneedle patches compared to subcutaneous injection.
  • IACUC Institutional Animal Care and Use Committee
  • Formulations C and D were coated on microneedle patches at 0.5 mg/3 cm 2 . Patches were applied to the skin and removed after 1 hour. Subcutaneous (SC) glucagon injection was prepared according to manufacturer's instructions (Lilly- Glucagon Rescue kit ® -*. Both the patch and injection were administered at a dose of 1 mg/kg.
  • coatings of the formulation C and D provide the fast and high release of glucagon as measured in the serum levels.
  • Table 11 shows that the
  • bioavailability of glucagon delivery with formulation C or D coated microneedle patch is 83% and 86%, respectively of that observed with SC injection. This indicates that the glucagon formulations can be efficiently re-solubilized in the skin and glucagon delivered comparable to the commercially available glucagon injection.
  • Example 8 Stability of glucagon coatings on microneedle patch
  • Formulation 1 comprises 200 mg/mL glucagon, 100 mg/mL LMPC (l-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine), 50 mg/mL glutamine, and 50 mg/mL tartaric acid;
  • Formulation 2 comprises 200 mg/mL glucagon, 100 mg/mL decanoyl sucrose (DS), 50 mg/mL glutamine, and 50 mg/mL tartaric acid.
  • DS decanoyl sucrose
  • Each glucagon liquid formulation was coated on a microneedle array using a dip coating method.
  • glucagon systems were manufactured for stability studies, using patch components involving a polycarbonate retainer ring with co-molded desiccant and a 5cm 2 adhesive patch.
  • the coated patch was heat sealed in a nitrogen-purged foil pouch.
  • the final systems were stored under two conditions, 25°C/60% relative humidity (RH) and 40°C/75% RH.
  • the coated patches were assessed for purity at initial, 1-, 3-, and 6-month time points.
  • RP-HPLC was used to quantify purity of glucagon.
  • Glucagon related impurities were separated from native glucagon using an ACE CI 8 column (3.0 mm ID x 150 mm, 3 ⁇ ) maintained at 45 °C.
  • the eluted glucagon was detected by UV at 214 nm.
  • the mobile phase involved a gradient elution.
  • mobile phase B comprised of 60% water and 40% acetonitrile.
  • Table 12 Summary of stability data of glucagon coated systems
  • Patch C coated with formulation 1, and Patch D coated with Formulation 2 were each placed into a separate extraction vessel and 1.0 mL of dissolution solution was added to each vessel. Each solution was then agitated for 2 minutes and a sample was taken for circular dichroism (CD) spectroscopy. Each sample was also scanned for OD280 (optical density at a wavelength of 280 nm) in a 1 mm quartz cuvette.
  • CD circular dichroism
  • An Aviv Model 202 with a peltier controlled temperature controlled cell was used to collect all CD spectra. All spectra were collected at 25°C in quartz cuvettes. The quartz cuvettes were tested using camphorsulfonic acid (CSA) to measure accurate path lengths for all cells used. The 0.1 mm cell was measured at 0.089 mm, and the 0.01 mm cell was measured at 0.0165 mm. All CD spectra are reported in units of mean residue ellipticity ( ⁇ ) using a molecular weight of 3482.8 kDa and 29 residues.
  • CSA camphorsulfonic acid
  • the Far UV (FUV) circular dichroism (CD) spectra for glucagon extracted from two patches (Patch C and Patch D), shown in Figure 18, are consistent with a glucagon peptide in a predominantly a-helical conformation as a soluble trimer or soluble helical monomer, as opposed to the ⁇ -sheet rich structure in glucagon fibrils.
  • the spectra are also consistent with a peptide in a soluble trimer or soluble helical monomer. As there is still a significant amount of random coil structure, this is also consistent with monomeric glucagon.
  • Example 10 The incorporation of sodium salt of carboxymethyl cellulose (NaCMC) to a liquid glucagon formulation to prevent fibril and /or gelation.
  • NaCMC carboxymethyl cellulose
  • a lyophilized glucagon formulation that has the following composition, 44.5 %w/w glucagon, 22.2 %w/w LMPC, 11.1 %w/w trehalose, 11.1 %w/w tartaric acid and 11.1 %w/w glycine was reconstituted with de-ionized water containing 0.5 mg/mL NaCMC, to make a high concentration glucagon formulation that is suitable for microneedle coating.
  • the liquid glucagon formulation had the following composition; 200 mg/mL glucagon, 100 mg/mL LMPC, 50 mg/mL trehalose, 50 mg/mL tartaric acid, 50 mg/mL glycine and 0.5 mg/mL NaCMC.
  • the pH of the liquid formulation is between 2.8 - 3.2.
  • Figure 19 shows that the lyophilized formulation that was reconstituted with NaCMC did not gel within the testing period, while the formulation that was reconstituted with de-ionized water gelled in approximately 1300 seconds. Gelation point was noted at the inflection of the viscosity versus time curve, i.e. at the point where a rapid increase in viscosity was observed.
  • Example 11 Comparison of coating formulation stability by Thio flavin fluorescence assay of Lyo formulations reconstituted w/ Na-CMC and water
  • a lyophilized glucagon formulation that has the following composition, 44.5 %w/w glucagon, 22.2 %w/w LMPC, 11.1 %w/w trehalose, 11.1 %w/w tartaric acid and 11.1 %w/w glycine was reconstituted with de-ionized water containing 0.5 mg/mL NaCMC or de-ionized water.
  • the liquid glucagon formulations had the following compositions: • 200 mg/mL glucagon, 100 mg/mL LMPC, 50 mg/mL trehalose, 50 mg/mL tartaric acid, 50 mg/mL glycine and 0.5 mg/mL NaCMC.
  • the two solutions were then stored at 2-8 °C. At each day an aliquot of the two formulations were taken and thioflavin a dye that specifically binds to amyloid fibrils was added. If fibrils are detected there is an enhanced fluorescence or maxima around wavelength 480 nm. The fluorescence was measured by SpectraMax M2e.
  • a lyophilized glucagon formulation that has the following composition, 44.5 %w/w glucagon, 22.2 %w/w LMPC, 11.1 %w/w trehalose, 11.1 %w/w tartaric acid and 11.1 %w/w glycine was reconstituted with 0.5 mg/mL NaCMC, 0.2 mg/mL NaCMC and 0.1 mg/mL NaCMC.
  • the liquid glucagon formulations had the following compositions:
  • Figure 21 is a plot of time versus viscosity comparing time to gelation of formulations of lyophilized glucagon reconstituted with NaCMC at concentrations of 0.5 mg/mL, 0.2 mg/mL and 0.1 mg/mL.
  • the lyophilized formulations that were reconstituted with NaCMC at 0.5 mg/mL and 0.2 mg/mL did not gel within the testing period, while the formulation that was reconstituted with 0.1 mg/mL NaCMC gelled in approximately 2200 seconds.
  • the concentration of the NaCMC in the reconstituting media is preferably >0.1 mg/mL and less than or equal to 1 mg/mL.
  • Example 13 Determining if other cellulose based polymers prevent gelation of glucagon
  • a lyophilized glucagon formulation that has the following composition, 57.1 %w/w glucagon, 14.3 %w/w LMPC, 14.3 %w/w sucrose, 14.3 %w/w tartaric acid and 14.3 %w/w glycine was reconstituted with 1 mg/mL NaCMC or 2 mg/mL hydroxyethylcellulose (HEC).
  • the liquid glucagon formulations had the following compositions:
  • Figure 22 is a plot of time versus viscosity comparing time to gelation of formulations of lyophilized glucagon reconstituted with 1 mg/mL NaCMC and 2 mg/mL HEC. Figure 22 shows that the lyophilized formulations that were reconstituted with NaCMC at

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formulations de glucagon convenant pour la préparation de revêtements sur des timbres à micro-aiguilles destinés à l'administration transdermique de glucagon. Les timbres revêtus peuvent être utilisés pour le traitement de l'hypoglycémie chez les patients diabétiques. L'invention concerne également des timbres chargés de glucagon, des procédés pour les préparer et des méthodes d'utilisation de ces timbres.
PCT/US2016/060601 2015-11-02 2016-11-04 Formulations stables de peptide de glucagon Ceased WO2017079611A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP16863067.1A EP3397269A4 (fr) 2015-11-02 2016-11-04 Formulations stables de peptide de glucagon

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/930,041 US9782344B2 (en) 2013-08-22 2015-11-02 Stable glucagon peptide formulations
US14/930,041 2015-11-02

Publications (1)

Publication Number Publication Date
WO2017079611A1 true WO2017079611A1 (fr) 2017-05-11

Family

ID=58662794

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/060601 Ceased WO2017079611A1 (fr) 2015-11-02 2016-11-04 Formulations stables de peptide de glucagon

Country Status (2)

Country Link
EP (1) EP3397269A4 (fr)
WO (1) WO2017079611A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11058630B2 (en) 2016-02-19 2021-07-13 Zosano Pharma Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11660264B2 (en) 2017-08-23 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
US11660265B2 (en) 2018-06-28 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6050988A (en) 1997-12-11 2000-04-18 Alza Corporation Device for enhancing transdermal agent flux
US6855131B2 (en) 2000-10-13 2005-02-15 Alza Corporation Microprotrusion member retainer for impact applicator
US6855372B2 (en) 2001-03-16 2005-02-15 Alza Corporation Method and apparatus for coating skin piercing microprojections
US20080207514A1 (en) * 2005-07-15 2008-08-28 Emisphere Technologies, Inc. Intraoral Dosage Forms of Glucagon
US7537795B2 (en) 2000-10-26 2009-05-26 Alza Corporation Transdermal drug delivery devices having coated microprotrusions
US20110097386A1 (en) 2009-10-22 2011-04-28 Biodel, Inc. Stabilized glucagon solutions
US20130281368A1 (en) * 2010-06-24 2013-10-24 Biousian Biosystems, Inc. Glucagon-Like Peptide-1 Glycopeptides
US20150057605A1 (en) * 2013-08-22 2015-02-26 Zosano Pharma, Inc. Stable Glucagon Peptide Formulations
US20160051467A1 (en) * 2013-08-22 2016-02-25 Zp Opco, Inc. Stable Glucagon Peptide Formulations

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09241295A (ja) * 1996-03-06 1997-09-16 Shiseido Co Ltd 皮膚外用剤

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6050988A (en) 1997-12-11 2000-04-18 Alza Corporation Device for enhancing transdermal agent flux
US6855131B2 (en) 2000-10-13 2005-02-15 Alza Corporation Microprotrusion member retainer for impact applicator
US7537795B2 (en) 2000-10-26 2009-05-26 Alza Corporation Transdermal drug delivery devices having coated microprotrusions
US6855372B2 (en) 2001-03-16 2005-02-15 Alza Corporation Method and apparatus for coating skin piercing microprojections
US20080207514A1 (en) * 2005-07-15 2008-08-28 Emisphere Technologies, Inc. Intraoral Dosage Forms of Glucagon
US20110097386A1 (en) 2009-10-22 2011-04-28 Biodel, Inc. Stabilized glucagon solutions
US20130281368A1 (en) * 2010-06-24 2013-10-24 Biousian Biosystems, Inc. Glucagon-Like Peptide-1 Glycopeptides
US20150057605A1 (en) * 2013-08-22 2015-02-26 Zosano Pharma, Inc. Stable Glucagon Peptide Formulations
US20160051467A1 (en) * 2013-08-22 2016-02-25 Zp Opco, Inc. Stable Glucagon Peptide Formulations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PHARM. RES., vol. 27, 2010, pages 303 - 313
See also references of EP3397269A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11058630B2 (en) 2016-02-19 2021-07-13 Zosano Pharma Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11839683B2 (en) 2016-02-19 2023-12-12 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11660264B2 (en) 2017-08-23 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
US11660265B2 (en) 2018-06-28 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

Also Published As

Publication number Publication date
EP3397269A4 (fr) 2019-09-04
EP3397269A1 (fr) 2018-11-07

Similar Documents

Publication Publication Date Title
US9173924B2 (en) Stable glucagon peptide formulations
EP1744683B1 (fr) Appareil et procédé pour la délivrance transdermique d'agents à base d'hormone parathyroïde
AU2003279641B2 (en) Transdermal drug delivery devices having coated microprotrusions
AU2006206272A1 (en) Therapeutic peptide formulations for coating microneedles with improved stabitity containing at least one counterion
AU2007225056A1 (en) Apparatus and method for transdermal delivery of parathyroid hormone agents to prevent or treat osteopenia
AU2004292954A1 (en) Composition and apparatus for transdermal delivery
US20180153798A1 (en) Stable Glucagon Peptide Formulations
HK1209657A1 (en) Microneedle array coated with drug composition
US20100226966A1 (en) Method for transdermal controlled release drug delivery
WO2017079611A1 (fr) Formulations stables de peptide de glucagon
ZA200610412B (en) Apparatus and method for transdermal delivery of parathyroid hormone agents
KR20070017197A (ko) 부갑상샘 호르몬 약제의 경피전달용 장치 및 방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16863067

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016863067

Country of ref document: EP