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WO2009126132A1 - Formulations et procédés de modulation de la satiété - Google Patents

Formulations et procédés de modulation de la satiété Download PDF

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Publication number
WO2009126132A1
WO2009126132A1 PCT/US2008/058958 US2008058958W WO2009126132A1 WO 2009126132 A1 WO2009126132 A1 WO 2009126132A1 US 2008058958 W US2008058958 W US 2008058958W WO 2009126132 A1 WO2009126132 A1 WO 2009126132A1
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WIPO (PCT)
Prior art keywords
cck
pharmaceutical
acid
peptide
agonist
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PCT/US2008/058958
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Inventor
Mark Rosenberg
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Individual
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Priority to PCT/US2008/058958 priority Critical patent/WO2009126132A1/fr
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Anticipated expiration legal-status Critical
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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
    • A61K38/2207—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms

Definitions

  • the invention relates to the field of appetite management and suppression. More specifically, the invention relates to methods, compositions for modulating satiety and thus, to approaches useful to control weight, especially to manage excess weight and obesity.
  • Overweight and obesity are diseases of excess energy stores in the form of fat.
  • Overweight individuals have a Body Mass Index (BMI) of between 26 kg/m 2 and 30 kg/m 2 and obese individuals have a BMI of between 30 kg/m 2 and 40 kg/m 2 .
  • morbid obesity (this term is synonymous with "clinically severe obesity") correlates with a Body Mass Index (BMI) of at least 40 kg/m 2 or with being 100 pounds overweight.
  • the morbidly obese patient is at risk for affective, anxiety and substance abuse disorders.
  • the obese often consider their condition as a greater handicap than deafness, dyslexia or blindness (Rand et ah, 1990, South Med. J. 83: 1390; Rand et ah, 1991, Int. J. Obes. 15: 577).
  • Surgical treatments have met some measure of success but are invasive and in some cases can be fatal. Assessing the risks of surgical treatment of obesity involves operative, perioperative, and long term complications. Morbidity in the early postoperative period (e.g. wound infections, dehiscence, leaks from staple breakdown, stomal stenosis, marginal ulcers, various pulmonary problems, and deep thrombophlebitis), may be as high as 10% or more. Splenectomy is necessary in 0.3% of patients to control operative bleeding. In the late postoperative period, other problems may arise and may require additional rounds of surgery.
  • Morbidity in the early postoperative period e.g. wound infections, dehiscence, leaks from staple breakdown, stomal stenosis, marginal ulcers, various pulmonary problems, and deep thrombophlebitis
  • Splenectomy is necessary in 0.3% of patients to control operative bleeding. In the late postoperative period, other problems may arise and may require additional rounds of surgery.
  • Combination therapies have also been employed with some success but often with serious consequences.
  • the appetite suppression cocktail fenfluramine and phentermine (“fen/phen”) was withdrawn from the market due to fatalities attributed to fenfluramine, as a result of an adverse effect on heart valves.
  • many of these medications are controlled substances and may have other serious side-effects that include the potential for dependence and the development of tolerance to the medication.
  • fen/phen phentermine
  • CCK peripherally administered cholecystokinin
  • caerulein a decapeptide closely related to CCK
  • CCK peripherally administered cholecystokinin
  • caerulein a decapeptide closely related to CCK
  • a pharmaceutical formulation for oral administration to a patient effective to reduce feeding in a patient comprising: an appetite- suppressing peptide and at least one chelating agent; wherein at least one of the appetite- suppressing peptide and the at least one chelating agent is encased in an enteric protectant; and wherein the combination of the chelating agent and enteric protectant is effective to increase the bioavailability of the appetite-suppressing peptide.
  • the pharmaceutical formulation is effective to increase satiety.
  • the pharmaceutical formulation further comprises one or more acceptable carriers.
  • the enteric protectant is an enteric coating or capsule.
  • the appetite-suppressing peptide is either a CCK or caerulein.
  • the CCK is provided at a dosage of between about 0.1 ug and 40 ug per day. In some embodiments, the CCK is provided at a dosage effective to result in blood circulating levels of CCK of at least about 3 pmol/L within 20 minutes after administration. In some embodiments, the CCK is provided at a dosage effective to results in blood circulating levels of CCK in a range of between about 4 pmol/L and 8 pmol/L, within 20 minutes after administration. In some embodiments, the caerulein is provided at a dosage of between about 0.05 and 20 ug per day.
  • the CCK is selected from the group consisting of cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N-pyroglutamic-CCK-8, C- terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine-CCK-7, N-pyroglutamic- CCK-7, t-BOCK-CCK-7 and cholecystokinin-4 (CCK-4).
  • CCK-8 cholecystokinin-8
  • N-sarkosyl-CCK-8 N-taurine-CCK-8
  • N-pyroglutamic-CCK-8 C- terminal heptapeptide of CCK
  • CCK-7 C- terminal heptapeptide of CCK
  • N-sarkosyl-CCK-7 N-taurine-CCK-7
  • N-pyroglutamic- CCK-7 t
  • the chelating agent is selected from the group consisting of: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassiura, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans- 1,2- diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane-N,N,N',N'-te- traacetic acid; l,3-diaminopropane-N,
  • EDTA ethylened
  • the chelating agent is citric acid.
  • the citric acid is present in an amount effective to bring the pH of the formulation within a range from about 1.5 to about 3.0.
  • the formulation further comprises a lipid-based delivery system.
  • the lipid-based drug delivery system is in the form of liposomes.
  • the formulation is provided in the form of nanoparticles.
  • the formulation further comprises a permeation enhancer, effective to increase transport of the appetite-suppressing peptide across the intestinal epithelium.
  • the permeation enhancer comprises at least one of oleate, palmitate, stearate, caprate, a conjugated linoleic acid, bile salts, or sterylglucoside.
  • the pharmaceutical formulation further comprises a bioactive substance, effective to enhance the therapeutic effect of the appetite-suppressing peptide.
  • the bioactive substance is at least one of: an epinephrine antagonist, an opiate antagonist, a pancreatic polypeptide blocker, a GABA agonist, a serotonin agonist, a calcitonin agonist, a corticotrophin-releasing factor agonist, a neurotensin agonist, a dopamine agonist, an anaesthetic, a glucagons agonist, pro-opiomelanocortin, cocaine- and amphetamine- regulated transcript (CART), urotcortin, thyrotropin-releasing hormone, galanin- like peptide- 1, peptide YY, ciliary neurotrophic factor, brain-derived neural factor, insulin, insulin-like growth factor- 1 , insulin-like growth factor-2, leptin, neuropeptide K,
  • the pharmaceutical composition further comprises a estrogenic hormone therapy composition.
  • the estrogenic hormone therapy composition comprises a birth control composition.
  • the estrogenic hormone therapy composition comprises an estrogen replacement composition.
  • the estrogenic hormone therapy composition comprises a selective estrogen receptor modulator.
  • the selective estrogen receptor modulator is at least one of raloxifene, lasofoxifene, apeledoxifene, clomifene, tamoxifen, toremifene, or ormeloxifene.
  • a method of reducing feeding in a patient comprising: providing a pharmaceutical formulation, comprising; an appetite-suppressing peptide and at least one chelating agent; wherein the pharmaceutical formulation is encased in an enteric protectant, and wherein the combination of the chelating agent and enteric protecting is effective to increase the bioavailability of the appetite-suppressing peptide; and administering the pharmaceutical formulation to the patient.
  • the administration of the pharmaceutical formulation increases satiety.
  • the pharmaceutical formulation further comprises one or more acceptable carriers.
  • the appetite-suppressing peptide is either a CCK or caerulein.
  • the CCK is provided at a dosage of between about 0.1 ug and 40 ug per day.
  • the dosage of the pharmaceutical formulation administered is effective to result in blood circulating levels of CCK of at least 3 pmol/L within 20 minutes after administration.
  • the dosage of the pharmaceutical formulation administered is effective to result in blood circulating levels of CCK in a range of between about 4 pmol/L and about 20 pmol/L within 20 minutes after administration.
  • caerulein is provided at a dosage of between about 0.05 and 20 ug per day.
  • the CCK is selected from the group consisting of: cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N- pyroglutamic-CCK-8, C-terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine- CCK-7, N-pyroglutamic-CCK-7, t-BOCK-CCK-7 or cholecystokinin-4 (CCK-4).
  • the chelating agent is selected from the group consisting of: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans- 1,2- diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l ,3-diamino-2-hydroxypropane-N,N,N',N'-te- triacetic acid; l,3-diaminopropane
  • EDTA ethylenediamine-
  • the bioactive substance is at least one of: an epinephrine antagonist, an opiate antagonist, a pancreatic polypeptide blocker, a GABA agonist, a serotonin agonist, a calcitonin agonist, a corticotrophin-releasing factor agonist, a neurotensin agonist, a dopamine agonist, an anaesthetic, a glucagons agonist, proopiomelanocortin, cocaine- and amphetamine- regulated transcript (CART), urotcortin, thyrotropin-releasing hormone, galanin-like peptide- 1, peptide YY, ciliary neurotrophic factor, brain-derived neural factor, insulin, insulin-like growth factor- 1, insulin-like growth factor-2, leptin, neuropeptide K, calcitonin-gene-related peptide, prolactin-releasing peptide, neuromedin, neuropeptide B, s
  • the method further comprises administering a volume of liquid prior to the pharmaceutical formulation in order to improve the effectiveness of the pharmaceutical formulation.
  • the volume of liquid is administered up to about 60 minutes prior to administration of the pharmaceutical formulation.
  • the volume of liquid is administered from about 10 minutes to about 20 minutes prior to administration of the pharmaceutical formulation.
  • the pharmaceutical formulation is administered to an individual who is also engaged in an estrogenic hormone therapy.
  • the pharmaceutical formulation is administered simultaneously with the estrogenic hormone therapy.
  • the pharmaceutical formulation is administered sequentially with the estrogenic hormone therapy.
  • the estrogenic hormone therapy comprises administration of estrogen in the form of a birth control pill. [0053] In some embodiments of the method, the estrogenic hormone therapy comprises an estrogen replacement therapy.
  • the estrogenic hormone therapy comprises administration of a selective estrogen receptor modulator.
  • the selective estrogen receptor modulator is at least one of raloxifene, lasofoxifene, apeledoxifene, clomifene, tamoxifen, toremifene, or ormeloxifene.
  • a pharmaceutical for oral administration to a patient, comprising a formulation comprising: an appetite-suppressing peptide; and a chelating agent comprising citric acid; wherein the citric acid is present in an amount that results in a pH of the formulation of from about 1 to about 3; and an enteric protectant encasing the formulation; wherein the combination of the chelating agent and the enteric protectant increases the bioavailability of the appetite-suppressing peptide in the patient; and wherein oral administration of the pharmaceutical reduces feeding in the patient.
  • the pharmaceutical is effective to increase satiety.
  • the pharmaceutical comprises one or more acceptable carriers.
  • the enteric protectant comprises an enteric coating or capsule.
  • the appetite-suppressing peptide comprises at least one of a CCK and caerulein.
  • the CCK is provided at a dosage of between about 0.1 ⁇ g and 40 ⁇ g per day. In some embodiments, the CCK is provided at a dosage effective to result in blood circulating levels of CCK of at least about 3 pmol/L within 20 minutes after administration. In some embodiments, the pharmaceutical the CCK is provided at a dosage effective to result in blood circulating levels of CCK in a range of between about 4 pmol/L and 8 pmol/L, within 20 minutes after administration. In some embodiments, the caerulein is provided at a dosage of between about 0.05 and 20 ⁇ g per day.
  • the CCK is selected from the group consisting of cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N-pyroglutamic-CCK-8, C- terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine-CCK-7, N-pyroglutamic- CCK-7, t-BOCK-CCK-7 and cholecystokinin-4 (CCK-4).
  • CCK-8 cholecystokinin-8
  • N-sarkosyl-CCK-8 N-taurine-CCK-8
  • N-pyroglutamic-CCK-8 C- terminal heptapeptide of CCK
  • CCK-7 C- terminal heptapeptide of CCK
  • N-sarkosyl-CCK-7 N-taurine-CCK-7
  • N-pyroglutamic- CCK-7 t
  • the pharmaceutical further comprises at least one additional chelating agent selected from the group consisting of: ethylenediamine-N,N,N',N'- tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans- l,2-diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane-N,N,N',N'-te- traacetic acid; l ,3-
  • EDTA ethylened
  • the pharmaceutical further comprises a lipid-based delivery system that delivers the formulation in the patient.
  • the lipid- based delivery system comprises liposomes.
  • the pharmaceutical is provided in the form of nanoparticles.
  • the pharmaceutical further comprises a permeation enhancer, effective to increase transport of the appetite-suppressing peptide across an intestinal epithelium.
  • the permeation enhancer comprises at least one of oleate, palmitate, stearate, caprate, a conjugated linoleic acid, a bile salt, and sterylglucoside.
  • the pharmaceutical further comprises a bioactive substance, effective to enhance a therapeutic effect of the appetite-suppressing peptide.
  • the bioactive substance comprises at least one of: an epinephrine antagonist, epinephrine agonist, an opiate antagonist, a pancreatic polypeptide blocker, a GABA agonist, a serotonin agonist, a calcitonin agonist, a corticotrophin-releasing factor agonist, a neurotensin agonist, a dopamine agonist, an anaesthetic, a glucagons agonist, pro-opiomelanocortin, cocaine- and amphetamine- regulated transcript (CART), urotcortin, thyrotropin-releasing hormone, galanin-like peptide- 1, peptide YY, ciliary neurotrophic factor, brain-derived neural factor, insulin, insulin-like growth factor- 1, insulin-like growth factor-2, leptin, neuropeptide K, calcitonin-gene-related peptide, prolactin-releasing peptide, neuromedin, neuropeptide
  • the pharmaceutical further comprises an estrogenic hormone therapy composition.
  • the estrogenic hormone therapy composition comprises a birth control composition.
  • the estrogenic hormone therapy composition comprises an estrogen replacement composition.
  • the estrogenic hormone therapy composition comprises a selective estrogen receptor modulator.
  • the selective estrogen receptor modulator is at least one of raloxifene, lasofoxifene, apeledoxifene, clomifene, tamoxifen, toremifene, and ormeloxifene.
  • a pharmaceutical for oral administration to a patient, comprising: a formulation comprising: an appetite- suppressing peptide; and a chelating agent comprising citric acid; wherein the citric acid is present in an amount that results in a pH of the formulation of from about 1 to about 3; and an enteric protectant encasing the formulation; and an estrogenic hormone therapy composition; wherein the combination of the chelating agent and the enteric protectant increases the bioavailability of the appetite-suppressing peptide in the patient; and wherein oral administration of the pharmaceutical reduces feeding in the patient.
  • the pharmaceutical is effective to increase satiety.
  • the pharmaceutical further comprises one or more acceptable carriers.
  • the enteric protectant comprises an enteric coating or capsule.
  • the appetite-suppressing peptide comprises at least one of a CCK and caerulein.
  • the CCK is provided at a dosage of between about 0.1 ⁇ g and 40 ⁇ g per day. In some embodiments, the the CCK is provided at a dosage effective to result in blood circulating levels of CCK of at least about 3 pmol/L within 20 minutes after administration. In some embodiments, the CCK is provided at a dosage effective to results in blood circulating levels of CCK in a range of between about 4 pmol/L and 8 pmol/L, within 20 minutes after administration. In some embodiments, the caerulein is provided at a dosage of between about 0.05 and 20 ⁇ g per day.
  • the CCK is selected from the group consisting of cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N-pyroglutamic-CCK-8, C- terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine-CCK-7, N-pyroglutamic- CCK-7, t-BOCK-CCK-7, and cholecystokinin-4 (CCK-4).
  • CCK-8 cholecystokinin-8
  • N-sarkosyl-CCK-8 N-taurine-CCK-8
  • N-pyroglutamic-CCK-8 C- terminal heptapeptide of CCK
  • CCK-7 C- terminal heptapeptide of CCK
  • N-sarkosyl-CCK-7 N-taurine-CCK-7
  • N-pyroglutamic- CCK-7 t
  • the chelating agent is selected from the group consisting of: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans- 1,2- diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane-N,N,N',N'-te- traacetic acid; l,3-diaminopropane-N,
  • EDTA ethylened
  • the chelating agent comprises citric acid.
  • the citric acid is present in an amount effective to bring the pH of the formulation within a range from about 1.5 to about 3.0.
  • the pharmaceutical further comprises a lipid-based delivery system that delivers the formulation in the patient.
  • the lipid- based drug delivery system comprises liposomes.
  • the formulation is provided in the form of nanoparticles.
  • the pharmaceutical comprises a permeation enhancer, effective to increase transport of the appetite-suppressing peptide across an intestinal epithelium.
  • the permeation enhancer comprises at least one of oleate, palmitate, stearate, caprate, a conjugated linoleic acid, a bile salt, and sterylglucoside.
  • the pharmaceutical further comprising a bioactive substance, effective to enhance a therapeutic effect of the appetite-suppressing peptide.
  • the bioactive substance comprises at least one of: an epinephrine antagonist, an epinephrine agonist, an opiate antagonist, a pancreatic polypeptide blocker, a GABA agonist, a serotonin agonist, a calcitonin agonist, a corticotrophin-releasing factor agonist, a neurotensin agonist, a dopamine agonist, an anaesthetic, a glucagons agonist, pro-opiomelanocortin, cocaine- and amphetamine- regulated transcript (CART), urotcortin, thyrotropin-releasing hormone, galanin-like peptide- 1, peptide YY, ciliary neurotrophic factor, brain-derived neural factor, insulin, insulin-like growth factor- 1, insulin-like growth factor-2, levothyrotropin-releasing hormone, gal
  • the estrogenic hormone therapy composition comprises a birth control composition. In some embodiments, the estrogenic hormone therapy composition comprises an estrogen replacement composition. In some embodiments, the estrogenic hormone therapy composition comprises a selective estrogen receptor modulator. In some embodiments, the selective estrogen receptor modulator is at least one of raloxifene, lasofoxifene, apeledoxifene, clomifene, tamoxifen, toremifene, and ormeloxifene.
  • the term “reducing feeding” means to reduce the average caloric intake in a patient over a period of time.
  • enteric protectant refers to an enteric coating applied to a pharmaceutical composition, or to any capsule or like device which functions to protect a pharmaceutical composition from release in the stomach.
  • variable can be equal to any integer value of the numerical range, including the end-points of the range.
  • variable can be equal to any real value of the numerical range, including the end-points of the range.
  • a variable which is described as having values between 0 and 2 can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • compositions of appetite suppressing (satiety) moieties may play an important role in weight- control. Specifically, it is shown that oral administration of appetite-suppressing peptides and related moieties increases appetite suppression, thereby leading to increased feelings of satiety, which, in turn lower food consumption and ultimately results in weight-loss. [0095] Accordingly, in some embodiments the disclosure sets forth formulations and methods suitable for oral administration of appetite suppressing (satiety) moieties previously believed to be poorly available, if not unavailable, upon oral administration.
  • the formulations of the disclosure are useful to modulate/induce satiety and reduce feeding as attested and measured by a body-weight reduction in treated patients as compared with untreated patients.
  • the expressions "reduce caloric intake,” “reduce food intake” or “reduce feeding” are used interchangeably to denote a reduction in caloric intake regardless as to whether solid or liquid food or other form of nutrition is involved.
  • compositions and methods of the present invention are intended for use with any patient, preferably a mammal, which may experience the benefits of the disclosure.
  • mammals preferably humans, although the disclosure is not intended to be so limited, and is applicable to veterinary uses.
  • "patient”, “mammals” or “mammal in need” include humans as well as non-human mammals, particularly domesticated animals including, without limitation, cats, dogs, and horses.
  • An aspect of the disclosure provides a pharmaceutical formulation for oral administration to a patient to modulate/induce satiety and reduce feeding comprising an appetite- suppressing peptide, and a chelating agent, wherein the formulation is encased in an enteric coating or capsule.
  • compositions according to the disclosure are prepared in a pharmaceutically acceptable vehicle with any of the well known pharmaceutically acceptable carriers, including diluents and excipients (see, Remington's Pharmaceutical Sciences, 18 th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995). While the type of pharmaceutically acceptable carrier/vehicle employed in generating the compositions of the disclosure will vary depending upon the mode of administration of the composition to a mammal, generally pharmaceutically acceptable carriers are physiologically inert and non-toxic. Formulations of compositions according to the disclosure may contain more than one type of compounds of the disclosure, N
  • permeation enhancers are contemplated. These substances can operate by increasing either paracellular or transcellular transport systems. An increase in paracellular transport can be achieved by opening the tight junctions of the cells; an increase in transcellular transport can be achieved by increasing the fluidity of the cell membrane.
  • Paracellular permeation enhancers include a variety of moiety known in the art (see e.g., (see, Remington's Pharmaceutical Sciences, 1990, supra, and Remington: The Science and Practice of Pharmacy, 1995, supra).
  • Representative, non-limiting examples of such permeation enhancers include for example calcium chelators, bile salts (such as sodium cholate), fatty acids, and sterylglucoside. Both short and medium chain fatty acids have shown to enhance the uptake of minerals (Fe and Ca), as well as other substances, via the augmentation of paracellular transport.
  • compositions of the disclosure may be delivered in conjunction with a fatty acid (e.g., oleate, palmitate, stearate, sodium caprate, or conjugated linoleic acid) in an enteric-coated capsule, with the goal of increasing bioavailability via increased paracellular transport.
  • a fatty acid e.g., oleate, palmitate, stearate, sodium caprate, or conjugated linoleic acid
  • enteric-coated capsule e.g., oleate, palmitate, stearate, sodium caprate, or conjugated linoleic acid
  • compositions may be further enhanced by coating liposomes with polyethylene glycol and related moieties known to interact with the mucus layer of the GI tract, to modulate transit rate.
  • bile salts and fatty acids are individually, permeation enhancers. Studies have been performed on both GI and nasal mucosa, revealing that the bile salt, "sodium glycocholate, (NaGC)" when added to a fatty acid such as linoleic acid, to form mixed micelles, enhances the absorption of a peptide greater than that seen with the use of the bile salt alone.
  • NaGC sodium glycocholate
  • compositions of the disclosure may be delivered orally in any of the carrier vehicles described herein, in conjunction with a bile salt, such as NAGC, and a fatty acid, such as linoleic acid, with the intent of improving bioavailability via permeation enhancement.
  • a bile salt such as NAGC
  • a fatty acid such as linoleic acid
  • the mucus layer barrier of the intestinal epithelium is often underestimated and can be a daunting obstacle to the absorption of peptide drugs.
  • Detergents, sulfhydryl compounds, and mucolytic enzymes are reported to display mucolytic activity, thereby improving peptide absorption. Sulfhydryl compounds display more potent hydrolytic activity than detergents by cleaving disulfide bonds which connect mucus glycoproteins with each other.
  • N-acetylcysteine A well-established sulfhydryl compound of high mucolytic activity is N-acetylcysteine, which is used as an expectorant in various pharmaceutical preparations.
  • N-acetylcysteine Another potent sulfhydryl compound is dithiothreitol. In ileum and proximal colon, this agent increased the absorption and biliary recovery of a tripeptide four-fold and 70-fold over control rats respectively.
  • compositions of the disclosure may be delivered to the small intestine in conjunction with a sulfhydryl compound, such as for example N-acetylcysteine or dithiothreitol.
  • a sulfhydryl compound such as for example N-acetylcysteine or dithiothreitol.
  • Permeation enhancers useful according to the disclosure include the high molecular mass polymers such as chitosan and polyacrylates. Their mucoadhesive properties allow them to remain concentrated at the area of drug absorption. In general, these polymers are divided into cationic and anionic polymers. Representative for cationic polymers is the widely used chitosan. The permeation enhancing effect of this polymer could be demonstrated via various studies on Caco-2 monolayers and in vivo rat models. The underlying mechanism of opening of tight junctions by chitosan was attributed to the interaction of the positively charged amino groups with the negatively charged sialic groups of membrane-bound glycoproteins.
  • anionic polymers such as polycarbophil or carboxymethylcellulose also demonstrated permeation-enhancing properties.
  • these two polymers were shown to express a high calcium-binding ability.
  • the depletion of calcium ions from the extracellular cell medium has been shown to increase the permeation of sodium-fluorescein, bacitracin, a vasopressin analogue, and insulin.
  • Parallel measurement of the transepithelial electrical resistance (TEER) demonstrated a decrease in TEER indicating the opening of the tight junctions.
  • Chitosan derivatives are not soluble at pH above 6.5.
  • N-trimethylation of chitosan chloride was tested and found to increase the solubility at higher pH.
  • the use of this new trimethylated chitosan in vivo on rats was shown to significantly improve the absorption of octreotide after intrajejunal administration.
  • Another chemical modification is the mono-N-carboxymethylation of chitosan. This resulted in an improved permeation of low molecular mass heparin in vitro and in vivo. Accordingly, such derivatives suitable at the pH of interest are contemplated.
  • thiomers thiolated polymers
  • hydrophilic compounds such as sodium fluoresceine, rhodamine 123, bacitracin, insulin, or FITC-labeled HGH
  • thiomers exhibit improved mucoadhesive properties, which allow it to remain concentrated at the area of drug absorption.
  • PTP protein tyrosine phosphatase
  • compositions of the disclosure may be delivered orally (e.g., in a tablet), based on a chitosan derivative as mentioned above, that is soluble above pH 6.5, such as a thiolated chitosan, with and without the addition of glutathione.
  • a chitosan derivative as mentioned above, that is soluble above pH 6.5, such as a thiolated chitosan, with and without the addition of glutathione.
  • the type of formulation itself influences the peptide drug absorption.
  • Formulations such as nanoparticles and liposomes are reported to improve mucosal peptide drug absorption.
  • Nanoparticles offer the advantage of protecting incorporated peptides from degradation. They can cross over the mucosal membrane either through Peyer's patch and/or the paracellular route. After having reached the systemic circulation, the particles are biodegraded releasing the incorporated peptide drug.
  • compositions of the disclosure may be delivered (e.g., orally) in a liposomal or nanoparticle carrier.
  • Mucoadhesive delivery systems are able to adhere on the mucus gel layer covering mucosal membranes, allowing for a prolonged stay of the peptide at the absorption site.
  • Mucoadhesive strength of polymers is based on non-covalent bonds such as hydrogen bonding and ionic interactions or covalent bonds such as the formation of disulfide bonds with the mucus layer. These polymers adhere on mucosal surfaces.
  • Polymers displaying high mucoadhesive properties are polyacrylates and chitosans.
  • Particles and liposomes can be coated with mucoadhesive polymers, or the mucoadhesive polymer can directly be used in the form of matrix tablets, microparticles, or nanoparticles.
  • appetite suppressing moieties are compounds known in the literature to reduce feeding through modulation of an individual's appetite. Reduced food consumption results in a reduced caloric intake and ultimately quantifiable by a detectable body-weight loss.
  • Appetite suppressing moieties include naturally occurring peptides as well as synthetic peptides (see e.g. EP226217 and EP268297), peptidomimetics or other moiety containing a peptide bond.
  • One such appetite suppressing moiety is cholecystokinin and its derivatives, analogs, variants, as well as fragments thereof preserving appetite suppressing properties, pseudopeptides and peptidomimetics.
  • Fragments and derivatives of a CCK of particular interest include without limitation cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N- pyroglutamic-CCK-8, C-terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine- CCK-7, N-pyroglutamic-CCK-7, t-BOCK-CCK-7, and cholecystokinin-4 (CCK-4).
  • the sulfated form of CCK-8 has a high affinity for the CCK A receptors, while the non-sulfated form of CCK- 8, as well as CCK-4, gastrin, and pentagastrin (CCK-5) have a 10,000 fold lower affinity for these receptors (see, de Montigny, 1989, Arch. Gen. Psychiatry 46(6): 511).
  • the CCK B receptors exhibit a high affinity and selectivity for CCK-4, gastrin, pentagastrin (CCK-5), and the non- sulfated CCK-8.
  • Sulfated CCK-8 has a slightly lower or same affinity for CCK B receptors (see, de Montigny, 1989, Arch. Gen.
  • CCK-8 is preferred in certain embodiments.
  • Other appetite suppressing moieties contemplated include any CCK A agonist having appetite suppressing properties, caerulein, Bombesin, and all other fragments of CCK containing at least the four C- terminal amino acids (Trp-Met-Asp-Phe-NH 2 ) (see, Abhiram, 2004, Endocrinology 145 : 2613).
  • CCK was first identified in 1928 from preparations of intestinal extracts by its ability to stimulate gallbladder contraction. Other biological actions of CCK have since been reported, including stimulation of pancreatic secretion, delayed gastric emptying, stimulation of intestinal motility and stimulation of insulin secretion (see, Lieverse et al., 1994, Ann. N. Y. Acad. ScL, 713: 268). The actions of CCK, also reportedly include effects on cardiovascular function, respiratory function, neurotoxicity and seizures, cancer cell proliferation, analgesia, sleep, sexual and reproductive behaviors, memory, anxiety and dopamine-mediated behaviors (Crawley and Corwin, 1994, Peptides 15: 731).
  • CCK cardiac acid secretion
  • pancreatic polypeptide release a contractile component of peristalsis
  • Additional reported effects of CCK include vasodilation (Walsh, "Gastrointestinal Hormones,” In Physiology of the Gastrointestinal Tract (3d ed. 1994; Raven Press, New York)).
  • estradiol and CCK can have a synergistic effect on satiety (Dulawa et ah, 1994, Peptides Jj) : 913; Smith and Gibbs, supra).
  • Experimental manipulations of exogenous and endogenous CCK and estradiol have produced converging evidence that estradiol cyclically increases the activity of the CCK satiation-signaling pathway so that meal size and food intake decrease during the ovulatory or estrous phase in animals (Geary, 2001, Peptides 22(8): 1251). It is common-place for women who begin oral administration of estrogen (hormone replacement therapy or birth control) to gain weight.
  • CCK induces satiety in several species. For example, it has been reported that feeding depression was caused by CCK injected intra- peritoneally in rats, intra-arterially in pigs, intravenously in cats and pigs, into the cerebral ventricles in monkeys, rats, dogs and sheep, and intravenously in obese and nonobese humans (see e.g., Lieverse et at., supra).
  • CCK was characterized in 1966 as a 33 -amino acid peptide (Crawley and Corwin, supra). Species-specific molecular variants of the amino acid sequence of CCK have been identified. The 33 -amino acid sequence and a truncated peptide, its 8-amino acid C- terminal sequence (CCK-8) have been reportedly identified in pig, rat, chicken, chinchilla, dog and humans. A 39-amino acid sequence was reportedly found in pig, dog and guinea pig. A 58- amino acid sequence was reported to have been found in cat, dog and humans. Frog and turtle reportedly show 47-amino acid sequences homologous to both CCK and gastrin.
  • CCK-83 Very fresh human intestine has been reported to contain small amounts of an even larger molecule, termed CCK-83.
  • CCK-22 Physiology of the Gastrointestinal Tract 3d Ed., Walsh, 1994; Raven Press, New York, NY 1994.
  • CCK-4 CCK30-33
  • CCK-4 CCK 29-33
  • the C-terminal sulfated octapeptide sequence, CCK-8, Asp-Tyr(SO 3 H)-Met-Gly-Trp-Met-Asp-Phe- NH 2 is reportedly relatively conserved across species.
  • CCK is said to be distributed throughout the central nervous system and in endocrine cells and enteric nerves of the upper small intestine.
  • CCK agonists include CCK itself (also referred to as CCK-33), CCK-8 (CCK26-33), non-sulfated CCK-8, pentagastrin (CCK-5 or CCK(29-33)), and the tetrapeptide, CCK-4 (CCK30-33).
  • CCK- 8 reportedly displaced binding with a 1000-5000 greater potency than unsulfated CCK-8 or CCK-4, and CCK-8 has been reported to be approximately 1000-fold more potent than unsulfated CCK-8 or CCK-4 in stimulating pancreatic amylase secretion (see, Crawley and Corwin, supra).
  • CCK receptor binding was said to be displaced by unsulfated CCK-8 and by CCK-4 at concentrations that were equimolar, 10-fold or 100-fold greater than sulfated CCK-8.
  • CCK A Receptors for CCK have been reportedly identified in a variety of tissues, and two primary subtypes have been described: type A receptors and type B receptors. Type A receptors have been reported in peripheral tissues including pancreas, gallbladder, pyloric sphincter and afferent vagal fibers, and in discrete areas of the brain. The type A receptor subtype (CCK A ) has been reported to be selective for the sulfated octapeptide. Accordingly, in certain embodiments of the disclosure, the CCK fragment includes at least one sulfation group. CCK A agonists also include A-71623 and A-708874, which were developed based on the structure of CCK-4.
  • CCK A agonists which includes JMV- 180, are reportedly active in stimulating pancreatic amylase release and inhibiting feeding (Crawley and Corwin, supra).
  • non-peptide CCK A agonists are L-364718 and FPL 15849KF (Crawley and Corwin, supra and Morley et ah, 1994, Am. J. Physiol. 267: Rl 78). Accordingly, substances which function as Type-A receptor-selective CCK agonists which may serve as anorectic agents are contemplated appetite suppressing moieties.
  • cholecystokinin-8 (CCK-8), N-sarkosyl-CCK-8, N-taurine-CCK-8, N- pyroglutamic-CCK-8, C-terminal heptapeptide of CCK (CCK-7), N-sarkosyl-CCK-7, N-taurine- CCK-7, N-pyroglutamic-CCK-7, t-BOCK-CCK-7, cholecystokinin-4 (CCK-4), caerulein, Bombesin, and all other fragments of CCK containing at least the four C-terminal amino acids (Trp-Met-Asp-Phe-NH 2 ).
  • Caerulein refers to a specific decapeptide obtained from the skin of hila caerulea, an Australian amphibian. Caerulein is similar in action and composition to cholecystokinin. It stimulates gastric, biliary, and pancreatic secretion and certain smooth muscle (for a comprehensive review see e.g., Stacher et ah, 1982, Peptides 3: 607; Reidelberger et al, 1989, Am. J. Physiol. Regul. Integr. Comp. Physiol. 256: Rl 148; Anika, 1982, European J. Pharm. 85: 195-199).
  • a wide variety of medicaments, bioactive active substances and pharmaceutical compositions may be included in the formulations/dosage forms of the present invention to further enhance their therapeutic effects or to otherwise increase their benefit.
  • useful active drugs include agents that act as agonists or antagonists to transmitters acting in the brain to increase satiety, including e.g., epinephrine antagonists, opiate antagonists, pancreatic polypeptide blockers, GABA agonists, serotonin agonists, calcitonin agonists, corticotropin-releasing factor agonists, neurotensin agonists; or to decrease hunger, including e.g., dopamine agonists, pancreatic polypeptide blockers, norepinephrine agonists, anesthetics, glucagon agonists, POMC, CART, urocortin, thyrotropin-releasing hormone, GLP-I, Galanin- like peptide- 1, peptide Y- Y, cili
  • the formulations according to the disclosure include, in addition to at least an appetite suppressing moiety (e.g., CCK or caerulein), a chelating agent.
  • chelating agents are moieties capable of sequestering ions (which are co factors participating in a variety of biochemical reactions) and thus, may impair the activity of many enzymes.
  • Chemically chelators are organic chemicals that form two or more bonds with a metal ion forming a heterocyclic ring (e.g., porphyrin ring) with the metal atom as part of the ring.
  • Chelating agents are well known in the art.
  • Non-limiting representative examples of chelating agents within the scope of the disclosure include ethylenediamine- N,N,N',N'-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans-l,2-diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; 1 ,3-diamino-2-hydroxypropane-N,N,N',N'-te- traacetic acid; l ,3
  • the calcium salt of EDTA is exemplified herein.
  • the amount of chelating agent included in the formulations according to the disclosure is significant to the stability of the formulation and ultimately to the overall bioavailability of the appetite suppressing moieties of the disclosure.
  • the chelating agent is present in an amount from about 25 mg to about 400 mg, or from about 100 mg to about 300 mg.
  • 200 mg of calcium EDTA were included.
  • citric acid is used as a chelating agent.
  • Citric acid is a weak inorganic carboxylic acid, effective as a buffer, antioxidant and as a chelator.
  • citric acid in amount effective to bring the pH of the formulation to between about 1.5 and 3.5 provides the additional advantage of buffering the local environment of the appetite-suppressing peptide, such that degradation of the peptide, for example a CCK, by digestive enzymes in the small intestine is retarded.
  • formulations according to the disclosure may include specific enzyme inhibitors (e.g., any substrate that blocks the natural activity of a given enzyme) such as known peptidases inhibitors (e.g., thiorphan, a metalloendopeptidease inhibitor, amastatin, a competitive inhibitor of aminopeptidases, kelatophan, and neuropeptidases (e.g., endopeptidases (such as for example neurolysin and nephrilysin), aminopeptidases (e.g., proglutamyl aminopeptidase II, aminopeptidases N, A, B, and P), dipeptidases (e.g., NAALA dipeptidase), or carboxypeptidases (e.g., angiotensin converting enzyme homolog (ACEH), carboxypeptidases H, N, or P)).
  • peptidases inhibitors e.g., thiorphan, a metalloendopeptidease inhibitor, amastatin, a competitive inhibitor of aminopeptida
  • the formulations according to the disclosure are in the form of a tablet coated with a conventional enteric coating.
  • the formulations according to the disclosure may be presented in the form of a variety of oral dosage forms such as a capsule, the shell of which is made from enteric material or is coated with an enteric material.
  • enteric coating or material refers to a coating or material that will pass through the stomach essentially intact but will rapidly disintegrate in the small intestine to release the active drug substance.
  • the enteric coating solution used comprises cellulose acetate phthalate ("CAP"), ammonium hydroxide (27-31%), triacetin USP, ethyl alcohol (190 proof USP), methylene blue 1% solution, and purified water.
  • USP CAP is a polymer that has been extensively used in the pharmaceutical industry for enterically coating individual dosage forms (e.g., tablets and capsules). CAP is not soluble in water at a pH of less than 5.8.
  • the enteric coating provides protection against the acidic environment of the stomach, but begins to dissolve in environment of the duodenum (pH of about 6-6.5), and is completely dissolved by the time the capsule has reached the ileum (pH 7-8).
  • An enteric coating according the disclosure is one which promotes dissolution of the dosage form primarily at a site outside the stomach.
  • the enteric coating of the disclosure promotes dissolution/breakdown of the dosage form to occur at a pH of approximately at least 6.0.
  • the coating is selected to promote dissolution at a pH of from about 6.0 to about 8.0 preferably favoring dissolution in the proximity of the ileum, where the pH is approximately 7-8).
  • the oral dosage forms may also contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycolate) or wetting agents, such as sodium lauryl sulphate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol
  • lubricants for example, magnesium ste
  • the capsule may be prepared in an oxygen free environment, such as in an enclosure having a nitrogen atmosphere.
  • the enteric coatings may be applied to the tablets and/or capsules according to methods well-known in the art.
  • the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof.
  • physiologically acceptable salts of the appetite suppressant moieties of the disclosure include conventional salts formed from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts.
  • Suitable salts include hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulphonic, methanesulphonic, naphthalene-2-sulphonic, benzenesulphonic and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the disclosure and their pharmaceutically acceptable salts.
  • References hereinafter to an appetite suppressing moiety for use in the disclosure include pharmaceutically acceptable salts and solvates.
  • Suitable enteric coatings for use in embodiments described in the disclosure will be these coatings known to those skilled in the art.
  • Such coatings include without limitation, cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, styrene maleic acid copolymers, methyacrylic acid copolymers (e.g., those marketed under the trademark EUDRAGIT®) and hydroxypropyl methyl cellulose phthalate.
  • the said coatings may also contain art known plasticizers and/or dye(s).
  • Some embodiments provide a method to modulate/induce satiety and reduce feeding comprising the step of orally administrating to a patient a pharmaceutical formulation comprising an appetite-suppressing peptide, and a chelating agent, wherein the formulation is encased in an enteric coating or capsule.
  • compositions will be provided in unit dosage form containing an amount of a compound as described in the disclosure (with or without another feeding suppressing agent) which will be effective in one or multiple doses to control appetite at the selected level.
  • Therapeutically effective amounts of an appetite modulator according to the disclosure for use in reducing appetite and/or suppressing food intake and in conditions in which food intake is beneficially reduced are those treatments at dosages effective to achieve the therapeutic result sought.
  • the therapeutically effective amount of the compounds disclosed may be lowered or increased by fine tuning and/or by administering more than one compound, or by administering a compound as disclosed with another compound. Some embodiments therefore provide a method to tailor the administration/treatment to the particular exigencies specific to a given mammal. As illustrated in the following examples, therapeutically effective amounts may be easily determined for example empirically by starting at relatively low amounts and by step-wise increments with concurrent evaluation of beneficial effect.
  • Such dosages of each of CCK are between about 0.1 ⁇ g/day and about 10 ⁇ g/day, preferably between about 0.1 ⁇ g/day and about 5 ⁇ g/day, administered in a single dose or in multiple doses.
  • Such dosages of caerulein are between about 0.05 ⁇ g/day and about 5 ⁇ g/day, or between about 0.1 ⁇ g/day and about 4 ⁇ g/day, and between about 0.1 ⁇ g/day and 2.5 ⁇ g/day administered in a single dose or in multiple doses.
  • the compounds of this invention may be administered to patients in need of such treatment in dosage ranges similar to those given above, however, the compounds may be administered more frequently, for example, one, two, or three times a day.
  • the formulations as disclosed may be presented as discrete units such as capsules, caplets, gelcaps, cachets, pills, or tablets each containing a predetermined amount of the active ingredient as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
  • administration of a composition of all of the aspects of the present invention may be effected by liquid solutions, suspensions or elixirs, powders, lozenges, micronized particles and osmotic delivery systems.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein.
  • Dosage forms according to the disclosure may contain from about 0.1 to 10 ⁇ g of a appetite-suppressing peptide and from about 0.1 to 500 mg of a chelating agent.
  • Non- limiting example formulations include at least 2.4 ⁇ g of a appetite-suppressing peptide such as for example CCK, from about 25mg to about 400 mg of a chelating agent, such as for example calcium EDTA.
  • An exemplified dosage form according to the disclosure includes, 4 ⁇ g of CCK, and 200 mg of calcium EDTA.
  • compositions such as, for example, carboxymethylcellulose sodium or ethylcellulose, may incorporated into the dosage forms, if desired (see, Remington's Pharmaceutical Sciences, 18 th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 1995).
  • a dose of the pharmaceutical formulation effective to result in blood circulating levels of CCK of at least 3 pmol/L, and preferably between 4 and 20 pmol/L, within 20 minutes after administration.
  • Administration methods using the formulations described herein are within the scope of the disclosure. It is recommended that the person seeking appetite suppression follow the proceeding protocol to obtain maximal satiety.
  • the capsule should be taken on an empty stomach (no solid food for 2 hours) to ensure rapid release of the capsule from the stomach. It has been discovered that consuming 8 ounces of liquid, for example water, up to 20 minutes prior to administration of the pharmaceutical composition increases the effectiveness of the composition. In particular, consuming the liquid at about 10 minutes prior to ingesting the pharmaceutical composition appears to be most effective.
  • controlling weight is meant reducing, preventing, and/or reversing the weight gain of the individual to which a compound as disclosed has been administered, as compared to the weight gain of an individual receiving no such administration.
  • the composition can be effective in controlling weight gain due to estrogenic effects.
  • estrogen is involved in regulating the activity of CCK and opioid peptide systems through regulation of expression and interaction with specific receptors (Micevych, P. and Sinchak, K., 2001, Peptides, 22(8): 1235-44).
  • studies in rats show that estrogen regulates the expression of prepro-CCK in cells of the medial preoptic nucleus (Simmerly, R.B. et al, 1989, Proc. Natl. Acad. Sci. 86: 4766-4770).
  • embodiments of the composition will be useful in regulating appetite and satiety, and in turn controlling weight in individuals who are prone to estrogenic weight gain, or who are otherwise already engaged in a course of estrogenic hormone therapy. These may include, but are not limited to females taking estrogen containing birth control compositions, as well as those receiving estrogen replacement therapy.
  • the weight gain associated with administration of compounds known to have partial agonist activity with respect to the estrogen receptor may be treatable with embodiments of the present pharmaceutical composition.
  • an estrogenic hormone therapy can also be taken to include, but is not limited to, persons taking selective estrogen receptor modulators (SERMs), for example, raloxifene, lasofoxifene, apeledoxifene, clomifene, tamoxifen, toremifene, and ormeloxifene, and like compounds.
  • SERMs selective estrogen receptor modulators
  • Mean weight loss was 0.671b. Percentage (mean) of the initial body weight lost was 0.29%. Median weight loss was 1.25 Ib. Percentage (mean) of the initial body weight lost 0.0 1b.
  • Mean weight loss was 1.1 Ib. Percentage (mean) of the initial body weight lost was 0.74%. Median weight loss was 2 Ib. Percentage (mean) of the initial body weight lost was 1.05%.
  • CCK-8 levels in the fasting state are typically less than 1 pm/L. Following a meal containing fat, CCK-8 levels rise above 5.8 pm/L, and often are measured between 7 and 8 pm/L. As mentioned earlier, CCK-8 has never before been prepared in an orally bio-available fashion. Because oral bio-availability has been less than 1 %, elevated CCK-8 levels had never been detected in response to an oral CCK-8 challenge.
  • the elevated CCK-8 levels measured above may be associated with some feelings of fullness but are not in the range of the levels seen after ingestion of a fatty meal. Individual #3 had the highest level; this most likely occurred because this individual had the lowest BMI (24), and therefore the ingested CCK-8 would have a smaller volume of distribution.
  • the appetite suppressing moiety was sulfated CCK-8 (Bachem AG, Bubendorf, Switzerland), the chelating agent Calcium EDTA, and the carrier was microcrystalline cellulose.
  • the active ingredient, microcrystalline cellulose, and chelator were sieved through a 500 micron sieve and blended in a suitable mixer to form the active mix.
  • Number 1 gelatin capsules (Hawkins Chemicals, Minneapolis, MN) were then filled with the active mix. Additional microcrystalline cellulose was added to the capsule to remove any remaining air space to inhibit oxidation of the active ingredient. Alternatively, the capsule may be filled under flowing nitrogen to remove any remaining free air from the capsule.
  • cholecystokinin-8 were examined using a human model. Twenty overweight or obese men (BMI >26) were each orally administered (p.o.) an enterically coated appetite suppressing composition containing CCK-8 (4 ⁇ g) and calcium EDTA (200 mg) or an identical looking placebo. They were then monitored every week over a 4 week period for weight loss. After the 4 week period, a greater than 35 fold increase in weight loss was observed wherein the treatment group showed a mean weight loss of approximately 17.8 lbs whereas the control group displayed only a 0.5 Ib weight loss.
  • the appetite suppressing composition contains 4 ⁇ g of CCK-8, 200 mg of calcium EDTA, and an enteric coating.
  • Each subject participates for 25 days and is asked to keep a daily journal of their appetite and meal size. The participants are weighed 5 days prior to taking the appetite suppressing composition and every 5 days while taking the appetite suppressing composition. Subjects are asked to take one capsule approximately 35 minutes before the largest meal of the day and not to eat any food 90 minutes prior to taking the capsule.
  • Subjects are also asked to drink the capsule with a glass of water or seltzer water, and to drink another glass 30 minutes later.
  • subjects are asked to drink another glass of water or seltzer water with the meal.
  • water or seltzer water allows for faster distension after taking the capsule thus allowing subjects to receive the maximum benefit from the capsule.
  • After taking the capsule subjects are asked to write in their daily journals in 15 minute increments rating their satiety as follows:
  • Subjects are asked to keep a daily journal of their caloric intake beginning 4 weeks prior to the administration of the appetite suppressing composition and ending 4 weeks after administration begins.
  • the administration of the capsule is identical to Example 3.
  • a control group of twenty human male subjects is administered placebo.
  • the results should indicate a reduction in caloric intake after the administration of the capsule than compared to before its administration.
  • the results should show that the reduction in caloric intake is dose-dependent indicating that the appetite suppressing composition is not only useful to reduce caloric intake, but also to maintain a certain caloric intake. This result would be particularly useful in type II diabetes applications to control blood sugar and maintain lower weights than those associated with the adult onset of type II diabetes.
  • the bioavailability of orally administered CCK-8 composition can be examined using a human model. Using 30 healthy subjects, 10 are orally administered an enterically coated appetite suppressing composition containing CCK-8 (4 ⁇ g) and Calcium EDTA (200 mg). Another 10 subjects are orally administered an enterically coated composition containing CCK-8 (4 ⁇ g). The third group of 10 subjects are orally administered a non- enterically coated composition containing CCK-8 (4 ⁇ g). [0141] Bioavailability tests should demonstrate that those subjects taking the enterically coated appetite suppressing composition achieved a very high bioavailability, while those taking enterically coated cholecystokinin-8 alone had much lower bioavailability. In contrast, those taking non-enterically coated cholecystokinin-8 should have a bioavailability of about 0% because stomach peptidases should have destroyed most of the peptide before reaching the ileum.

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Abstract

L'invention concerne des formulations et des procédés pour supprimer l'appétit et induire la satiété chez les mammifères. Dans certaines formes de réalisation, l'administration orale d'une quantité efficace d'un peptide supprimant l'appétit, dans une composition qui augmente la biodisponibilité du peptide supprimant l'appétit, est efficace pour induire la satiété.
PCT/US2008/058958 2008-03-31 2008-03-31 Formulations et procédés de modulation de la satiété Ceased WO2009126132A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011116139A3 (fr) * 2010-03-16 2012-04-12 Chiasma Inc. Compositions pharmaceutiques améliorées et procédés d'administration
WO2014009808A3 (fr) * 2012-07-12 2014-03-06 Ustav Organicke Chemie A Biochemie Akademie Ved Cr, V.V.I Peptides lipidés en tant qu'agents anti-obésité
WO2015062158A1 (fr) * 2013-10-31 2015-05-07 上海现代药物制剂工程研究中心有限公司 Composition de type facteur neurotrophique ciliaire humain recombiné pour une administration par voie nasale et son procédé de préparation
WO2015073878A1 (fr) * 2013-11-15 2015-05-21 Ur Diet, Llc Rétroaction biologique de la satiété en temps réel
CN111838659A (zh) * 2020-07-24 2020-10-30 河南思迈尔健康科技有限公司 一种调控机体饱腹感激素的物质及其应用
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
US12285521B2 (en) 2016-11-15 2025-04-29 Klaria Pharma Holding Ab Pharmaceutical formulation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350741A (en) * 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
US5922680A (en) * 1996-10-23 1999-07-13 Ferring, B.V. Stabilized composition for oral administration of peptides
US20020156010A1 (en) * 2000-11-20 2002-10-24 Lustig Robert H. Method of treating obesity in adult patients exhibiting primary insulin hypersecretion
US20030149008A1 (en) * 2002-02-07 2003-08-07 Velayudhan Sahadevan Hormonal implants treatment of the breast cancer
WO2006023976A2 (fr) * 2004-08-23 2006-03-02 Mark Rosenberg Formulations et methodes de modulation de la satiete

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350741A (en) * 1988-07-30 1994-09-27 Kanji Takada Enteric formulations of physiologically active peptides and proteins
US5922680A (en) * 1996-10-23 1999-07-13 Ferring, B.V. Stabilized composition for oral administration of peptides
US20020156010A1 (en) * 2000-11-20 2002-10-24 Lustig Robert H. Method of treating obesity in adult patients exhibiting primary insulin hypersecretion
US20030149008A1 (en) * 2002-02-07 2003-08-07 Velayudhan Sahadevan Hormonal implants treatment of the breast cancer
WO2006023976A2 (fr) * 2004-08-23 2006-03-02 Mark Rosenberg Formulations et methodes de modulation de la satiete

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011116139A3 (fr) * 2010-03-16 2012-04-12 Chiasma Inc. Compositions pharmaceutiques améliorées et procédés d'administration
WO2014009808A3 (fr) * 2012-07-12 2014-03-06 Ustav Organicke Chemie A Biochemie Akademie Ved Cr, V.V.I Peptides lipidés en tant qu'agents anti-obésité
US9937235B2 (en) 2012-07-12 2018-04-10 USTAV ORGANICKE CHEMIE A BIOCHEMIE AKADEMIE VED CR, v.v.i. Lipidated peptides as anti-obesity agents
WO2015062158A1 (fr) * 2013-10-31 2015-05-07 上海现代药物制剂工程研究中心有限公司 Composition de type facteur neurotrophique ciliaire humain recombiné pour une administration par voie nasale et son procédé de préparation
WO2015073878A1 (fr) * 2013-11-15 2015-05-21 Ur Diet, Llc Rétroaction biologique de la satiété en temps réel
US12285521B2 (en) 2016-11-15 2025-04-29 Klaria Pharma Holding Ab Pharmaceutical formulation
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
CN111838659A (zh) * 2020-07-24 2020-10-30 河南思迈尔健康科技有限公司 一种调控机体饱腹感激素的物质及其应用

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