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WO2011011675A1 - Formulations/compositions pharmaceutiquement acceptables pour des médicaments à base de peptidyle - Google Patents

Formulations/compositions pharmaceutiquement acceptables pour des médicaments à base de peptidyle Download PDF

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Publication number
WO2011011675A1
WO2011011675A1 PCT/US2010/043038 US2010043038W WO2011011675A1 WO 2011011675 A1 WO2011011675 A1 WO 2011011675A1 US 2010043038 W US2010043038 W US 2010043038W WO 2011011675 A1 WO2011011675 A1 WO 2011011675A1
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WIPO (PCT)
Prior art keywords
pth
diol
composition
formulation
teriparatide
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PCT/US2010/043038
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English (en)
Inventor
Martin Stogniew
Gene Scott Merutka
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Zelos Therapeutics Inc
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Zelos Therapeutics Inc
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Publication of WO2011011675A1 publication Critical patent/WO2011011675A1/fr
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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
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • excipients and cosolvents in parenteral pharmaceuticals is often necessary to overcome challenges in drug solubility of insoluble compounds, typically small molecules.
  • solvents to aid in solubility such as propylene glycol, polyethylene glycol, and glycerol have potential to cause irritation and hemolysis when delivered in large amounts, so their use in parenteral products has been limited.
  • Protein and peptide pharmaceuticals typically have good aqueous solubility, so use of cosolvents in these types of drugs is also limited as the need for solubility enhancers is typically not necessary. What has been unexpectedly observed is that certain cosolvent aqueous mixtures have the potential to increase the relative bioavailability of peptide and protein formulations.
  • the present invention provides for pharmaceutically acceptable formulations/ compositions for peptidyl drugs, method of making thereof, and methods of use thereof.
  • a pharmaceutically acceptable parenteral composition comprising: a pharmaceutically effective amount of a peptidyl drug and a bioavailability enhancer in an amount sufficient to increase the bioavailability of the peptidyl drug.
  • a pharmaceutically acceptable subcutaneous composition comprising: a pharmaceutically effective amount of a peptidyl drug and a bioavailability enhancer in an amount sufficient to increase the bioavailability of the peptidyl drug.
  • compositions are useful in methods of administering peptidyl drugs and may be used where it is desirable to increase the blood levels of the peptidyl drug or drugs.
  • the compositions of the present embodiments may assist the user in increasing blood levels of a peptidyl drug by greater than 10% AUC when administered to a subject as compared to a composition that is absent the bioavailability enhancer.
  • the compositions of the present embodiments may assist the user in increasing blood levels of a peptidyl drug by greater than 20% AUC when administered to a subject as compared to a composition that is absent the bioavailability enhancer.
  • the bioavailability enhancer may be present at concentration from about 10% to about 60%. In some embodiments, the bioavailability enhancer is a diol or diol ether. In some embodiments, the diol or diol ether may be between 2 to 20 carbons. In some embodiments, the diol or diol ether is straight-chain or branched, linear or cyclic, aliphatic or aromatic. In some embodiments, the diol or diol ether has a molecular weight of less than 400 MW. In some embodiments, the diol or diol ether has a molecular weight of less than 350 MW.
  • the diol or diol ether has a molecular weight of less than 300MW. In some embodiments, the diol or diol ether has a molecular weight of less than 250 MW. In some embodiments, the diol or diol ether has a molecular weight of less than 200 MW. In some embodiments, the diol or diol ether is propylene glycol.
  • the composition further comprises a buffer to maintain the composition at a physiological acceptable pH.
  • the buffer may be present in a concentration of from about 1 mM to about 100 mM.
  • the composition further comprises an antioxidant. In some embodiments, the composition further comprises a preservative. In some embodiments, the composition further comprises m-cresol, benzalkonium chloride, parabens, benzyl alcohol, chloroethanol, and mixtures or combinations thereof. In some embodiments, the composition further comprises a bulking/stabilizing agent.
  • the composition is formulated for parenteral administration. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the composition is in a sealed sterile glass vial.
  • a pharmaceutically acceptable subcutaneous composition comprising: a pharmaceutically effective amount of a peptide or peptide mimetic, wherein the peptide or peptide mimetic is less than or equal to 50 amino acids in length; a bioavailability enhancer in an amount sufficient to increase the relative bioavailability of the peptide or peptide mimetic.
  • the bioavailability enhancer may be a diol or diol ether as described herein.
  • the peptide or peptide mimetic is 2 to 10 amino acids in length. In some embodiments, the peptide or peptide mimetic is 10 to 50 amino acids in length.
  • the peptide or peptide mimetic has a molecular weight of less than 8,000 Da. In some embodiments, the peptide or peptide mimetic has a molecular weight of less than 6,000 Da. In some embodiments, the peptide or peptide mimetic has a molecular weight of less than 4,000 Da. In some embodiments, the peptide or peptide mimetic has a molecular weight of less than 2,000 Da.
  • the peptidyl drug may be human parathyroid hormone (hPTH), therapeutic fragment thereof, or peptide mimetic thereof.
  • the peptidyl drug may be a PTH variant, including, but not limited to, the following PTH( 1-31), PTH( 1 - 34), PTH(l-37), PTH(l-38), PTH(1-41) and PTH(l-84).
  • the PTH variant is cyclic.
  • parenteral compositions comprising a pharmaceutically effective amount of a therapeutic protein and a bioavailability enhancer in an amount sufficient to increase the relative bioavailability of said therapeutic protein.
  • the parenteral compositions are suitable for subcutaneous administration.
  • the bioavailability enhancer may be a diol or diol ether as described herein.
  • the one or more therapeutic proteins may be between 8,000 Da and 200,000 Da. In some embodiments, the one or more therapeutic proteins may be between 10,000 Da and 150,000 Da. In some embodiments, the one or more therapeutic proteins may be between 20,000 Da and 150,000 Da. In some embodiments, the protein is an antibody. In some embodiments, the one or more therapeutic proteins may have molecular weight of between 10,000 Da and 20,000 Da. In some embodiments, the one or more therapeutic proteins may have molecular weight of between 20,000 Da and 50,000 Da. In some embodiments, the one or more therapeutic proteins may be 50 to 100 amino acids in length. In some embodiments, the one or more therapeutic proteins may be 100 to 250 amino acids in length.
  • kits comprising a pharmaceutically effective amount of a peptidyl drug in lyophilized form, and a solution for a reconstituting the lyophilized peptidyl drug comprising a bioavailability enhancer in an amount sufficient to increase the bioavailability of the peptidyl drug.
  • the bioavailability enhancer may be a diol or diol ether as described herein.
  • kits comprising a pharmaceutically effective amount of a peptide or peptide mimetic in lyophilized form, wherein the peptide or peptide mimetic is less than or equal to 50 amino acids in length; and a solution for a reconstituting the lyophilized peptide or peptide mimetic comprising a bioavailability enhancer in an amount sufficient to increase the bioavailability of the peptide or peptide mimetic.
  • the bioavailability enhancer may be a diol or diol ether as described herein.
  • kits comprising a pharmaceutically effective amount of a therapeutic protein and a solution for a reconstituting the lyophilized therapeutic protein comprising a bioavailability enhancer in an amount sufficient to increase the bioavailability of the therapeutic protein.
  • the bioavailability enhancer may be a diol or diol ether as described herein.
  • the present invention provides for methods of preparing the pharmaceutically acceptable formulations/compositions of the present invention.
  • the present invention provides for methods of treating a subject comprising administering to a subject in need thereof a formulation/composition of the present invention.
  • the composition is administered subcutaneously.
  • methods of treating a subject in need thereof comprising administering to the subject the peptidyl drug compositions of the present invention, wherein the amount of bioavailability enhancer is sufficient to reduce the dose given to achieve the same (e.g., within approx. within 10%) pharmacological activity of the peptidyl drug when administered to a subject as compared to a composition that is absent the bioavailability enhancer.
  • methods of reducing the side effects associated with treating a subject with peptidyl drugs comprising administering to the subject the peptidyl drug compositions of the present invention, wherein the amount of bioavailability enhancer is sufficient to reduce the dose given to achieve the same pharmacological activity of said drug when administered to a subject as compared to a composition that is absent the bioavailability enhancer.
  • the present invention provides pharmaceutical compositions and formulations containing suitable PTH peptides or analogs thereof for use in methods directed to treating subjects suffering from various bone degenerative, bone deficit, or hematopoietic, or hematological disorders.
  • the invention provides a method for the treatment of osteoporosis, for treating a bone fracture, for inducing bone formation in trabecular and cortical bones, for treating or preventing renal osteodystrophy (ROD) and related disorders, comprising administering to a subject in need thereof a pharmaceutically acceptable formulation comprising a parathyroid hormone (PTH) peptide or analog, wherein the dosage administered results in an effective pharmacokinetic profile and effective bioactivity.
  • PTH parathyroid hormone
  • PTH peptides of the present invention include full-length 1-84, or fragments thereof, including PTH 1-34 and PTH 1-31. Additional PTH peptide analogues can optionally include less than the first 34 amino acids at the N-terminal end.
  • PTH peptide analogues of the present invention include the following: PTH-(I -31)NH 2 , Ostabolin; PTH-(I -3O)NH 2 ; PTH-(I -29)NH 2 ; PTH-(I -28)NH 2 ; LeU 27 PTH-(I -31)NH 2 ; Leu 27 PTH-(l -3O)NH 2 ; Leu 27 PTH-(l-29)NH 2 ; Leu 27 cyclo(22-26)PTH- (1-3I)NH 2 Ostabolin-CTM; Leu 27 cyclo(22-26)PTH-(1-34)NH 2 ; Leu 27 cyclo(Lys 26 -Asp 30 )PTH- (1-34)NH 2 ; Cyclo(Lys 27 -Asp 30 )PTH-(l-34)NH 2 ; Leu 27 cyclo(22-26)PTH-( 1-31)NH 2 ; Ala 27 or NIe 27
  • inventions include any dosage with any route of administration which results in an effective pharmacokinetic profile and effective bioactivity.
  • Administration of the peptidyl or protein formulations of the present invention includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • a variety of administration routes can be used in accordance with the present invention, including oral, topical, transdermal, nasal, pulmonary, transpercutaneous (wherein the skin has been broken either by mechanical or energy means), rectal, buccal, vaginal, via an implanted reservoir, or parenteral.
  • Parenteral includes subcutaneous, intravenous, intramuscular, intraperitoneal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques, as well as injectable materials (including polymers) for localized therapy. More preferably, the route of administration is subcutaneous..
  • peptidyl drugs of the present invention can also be administered at a variety of doses. Effective dosages can vary according to the type of formulation of peptidyl drug administered as well as the route of administration. One skilled in the art can adjust the dosage by changing the route of administration or formulation, so that the dosage
  • Fig. 1 Mean PTH(I -34) (Teraparatide) Plasma Concentration vs. Time Profiles in Female Sprague Dawley Rats Following Single Subcutaneous 20 ⁇ g Fixed Doses
  • Fig. 2 Mean PTH(I -34) (Teriparatide) Plasma Concentration vs. Time Profiles in Female Sprague Dawley Rats Following a Single Intravenous 5 ⁇ g Fixed Dose of
  • the present invention provides for pharmaceutically acceptable formulations/ compositions of peptidyl drugs. According to some embodiments, the present invention provides for pharmaceutically acceptable formulations/ compositions of therapeutic peptides or peptide mimetics. According to some embodiments, the present invention provides for pharmaceutically acceptable formulations/ compositions of therapeutic proteins.
  • pharmaceutically acceptable or “therapeutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and more particularly in humans.
  • a “peptidyl drug” as used herein is an active agent, drug or pharmacologically active agent that comprises a peptide, polypeptide or protein. Pharmacologically active derivatives, variants, mimetics, and fragments of peptidyl drugs are included as well. For ease of discussion, a “peptidyl drug” will also include a single amino acid and derivatives thereof.
  • a “peptide” refers to a polymer in which the monomers are amino acids linked together through amide bonds.
  • “Peptides” are generally smaller than proteins, i.e., about two to about fifty amino acids in length.
  • the term “peptide” includes “dipeptides” comprised of two amino acids and “tripeptides” comprised of three consecutively linked amino acids, and so forth.
  • polypeptide is used synonymously with the term “peptide”.
  • a “protein” as used herein refers to a polymer of amino acids conventionally comprised of over fifty amino acids.
  • the proteins that may be used as peptidyl drugs in the present invention may be naturally occurring proteins, modified naturally occurring proteins, or chemically synthesized proteins that may or may not be identical to naturally occurring proteins.
  • the formulations/compositions of the present invention comprise a pharmaceutically effective amount of one or more peptidyl drugs and a bioavailability enhancer in an amount sufficient to increase the bioavailability of the peptide or peptide mimetic, wherein the bioavailability enhancer is a diol or diol ether.
  • the diol or diol ether is present in an amount in sufficient to increase the
  • the diol or diol ether is present in an amount in sufficient to increase the blood levels of the one or more peptidyl drugs to greater than about 10% (e.g., about 12%, about 15%, about 18%, about
  • AUC when administered to a subject as compared to a formulation without the bioavailability enhancer.
  • the comparison is made with an identical formulation but where glycerol is used instead of the diol or diol ether.
  • composition may be administered subcutaneously, parenterally, intranasally, buccally, intravenously, or trans-mucosally.
  • the diol is a diol with 2 to 20 carbons.
  • the diol is a diol with 2 to 12 carbons (i.e., 2, 3, 4, 5, 6,
  • the diols may be straight-chain or branched.
  • the diols may be linear or cyclic.
  • the diols may be aliphatic or aromatic.
  • the diol has a molecular weight of less than about 400 MW (e.g. , less than about 350, less than about 300, less than about 250, less than about
  • the diol has a molecular weight of less than 200 MW.
  • a representative list of diols useful in the present invention include one or more of following: 1,2-ethanediol; 1,2-propanediol; 1,3-propanediol; 1,2-butanediol; 1,3-butanediol; 2,3-butanediol; 1,4-butanediol; but-2-ene-l,4-diol; 1 ,2-pentanediol; 1 ,4-pentanediol , 2,4-
  • Pentanediol 1,5-pentanediol; 1,2-hexanediol, 1,5-hexanediol , 2,5-hexanediol ;1,6- hexanediol; 1,2-heptanediol; 1,7-heptanediol; 1,2-octanediol; 1,8-octanediol; 1,2-Nonanediol;
  • 1,9-nonanediol 1,2-decanediol ;l,10-decanediol; 1,2-dodecanediol; 1,12-dodecanediol; 3- methylpentane- 1,5 -diol; 2,5-dimethyl-l,3-hexanediol; 1,2 -cyclopentanediol , 2,2,4-trimethyl- 1,3-pentanediol; 1,2-cyclohexanediol; 1,4-cyclohexanediol; 1,4- bis(hydroxymethyl)cyclohexane; neopentyl glycol hydroxypivalate; 2,2-bis(4- hydroxyphenyl)propane; 2,2-bis[4-(2-hydroxypropyl)phenyl]propane; diethylene glycol; triethylene glycol; tetraethylene glycol; dipropylene glycol; tripropylene glycol
  • 1,3 -propanediol and mixtures and combinations thereof.
  • the diol is propylene glycol.
  • diol ethers for use with the present embodiments may have the following structure:
  • diol ethers for use with the present embodiments may have the following structure:
  • a representative list of diol ethers useful in the present invention include one or more of following: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether, propylene glycol methel ether, propylene glycol n-propyl ether, propylene glycol n- butyl ether, propylene glycol phenyl ether, dipropylene glycol methyl ether, dipropylene glycol n-propyl ether, dipropylene glycol n-butyl ether, dipropylene glycol phenyl ether, tripropylene glycol methyl ether, tripropy
  • the diol or diol ether may be present in the formulations/compositions of the present invention in a concentration of from about 10% to about 60% (e.g., about 12%, about 14%, about 16%, about 18%, about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, about 32%, about 34%, about 36%, about 38%, about 40%, about 42%, about 44%, about 46%, about 48%, about 50%, about 60%).
  • the peptide or peptide mimetic to be used in the formulations/compositions of the present invention include any peptide or peptide mimetic known in the art to have therapeutic qualities.
  • the peptide is less than or 50 amino acids (e.g., 10, 15, 20, 22, 25, 30, 32, 34, 38, 40, 45, 50). This includes, but is not limited to, less than 50 amino acids, less than 45 amino acids, less than 40 amino acids, less than 35 amino acids, less than 30 amino acids, less than 25 amino acids, less than 20 amino acids, and less than 15 amino acids.
  • the peptide or peptide mimetic may comprise from about 10 to about 50 amino acids; from about 15 to about 50 amino acids; from about 20 to about 50 amino acids; from about 25 to about 50 amino acids; from about 30 to about 50 amino acids; from about 40 to about 50 amino acids; from about 10 to about 40 amino acids; from about 20 to about 40 amino acids; from about 30 to about 40 amino acids; from about 10 to about 35 amino acids; from about 10 to about 30 amino acids; from about 10 to about 25 amino acids; from about 10 to about 20 amino acids; from about 10 to about 15 amino acids; from about 15 to about 35 amino acids; from about 15 to about 55 amino acids; about 20 to about 55 amino acids; about 20 to about 35 amino acids; about 25 to about 35 amino acids; about 2 to about 7 amino acids; about 2 to about 10 amino acids; about 2 to about 15 amino acids; about 2 to about 20 amino acids; about 7 to about 10 amino acids; about 7 to about 15 amino acids; or about 7 to about 20 amino acids.
  • the peptide or peptide mimetic is less than 35 amino acids in length.
  • the peptide or peptide mimetic may less than about 8 kDa.
  • the peptide may be PTH (e.g., human PTH) or peptide mimetic thereof.
  • the peptide mimetic is PTH(I -31), PTH(I- 34), PTH(l-37), PTH(l-38), PTH(1-41) and PTH(l-84).
  • a representative list of peptide drugs useful in the present invention include one or more of following: activin, amylin, angiotensin, atrial natriuretic peptide, calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, cholecystokinin, ciliary neurotrophic factor, corticotropin, corticotropin-releasing factor, epidermal growth factor, follicle-stimulating hormone, gastrin, gastrin inhibitory peptide, gastrin-releasing peptide, ghrelin, glucagon, gonadotropin-releasing factor, growth hormone releasing factor, human chorionic gonadotropin, inhibin A, inhibin B, insulin, leptin, lipotropin, luteinizing hormone, luteinizing hormone-releasing hormone, a-melanocyte-stimulating hormone, (3- melanocyte-stimulating hormone, y-melanocyte-stimulating hormone,
  • Cetrotide DDAVP (desmopressin acetate), and SANDOSTATIN.
  • the therapeutic proteins for use in the formulations/compositions of the present invention include any protein (e.g., antibody) known in the art to have therapeutic qualities.
  • the therapeutic proteins are between about 8,000 Da and about 200,000 Da, preferably between about 20,000 Da and about 160,000 Da.
  • proteins having a molecular weight between about 10 kDa and 150 kDa, between about 8 kDa and 20 kDa, between about 10 kDa and 20 kDa, between about 12 kDa and 20 kDa, between about 15 kDa and 20 kDa, between about 20 kDa and 150 kDa, between about 20 kDa and 140 kDa, between about 20 kDa and 120 kDa, between about 20 kDa and 100 kDa, between about 20 kDa and 90 kDa, between about 20 kDa and 80 kDa, between about 20 kDa and 70 kDa, between about 20 kDa and 60 kDa, between about 20 kDa and 50 kDa, between about 20 kDa and 40 kDa, between about 20 kDa and 30 kDa, between about 40 kDa and 150 kDa, between about 40 kDa and
  • a representative list of therapeutic protein or protein drugs useful in the present invention include one or more of following: antithrombin III, factor I, factor II, factor III, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, heparin cofactor II, kallikrein, plasmin, plasminogen, prekallikrein, protein C, protein S, thrombo-modulin ;colony stimulating factor 4, heparin binding neurotrophic factor, interferon-a, interferon a- 2a, interferon a-2b, interferon a-n3, interferon-(3, interferon-y, interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-11, interleukin-12, interleukin-13, interleukin-14, interleukin
  • the active peptidyl drug is at least "very slightly soluble” at 37 ⁇ 1° C in aqueous media in the pH range of approximately 4 - 8.0. According to some embodiments, the active peptidyl drug is at least "slightly soluble” at 37 ⁇ 1° C in aqueous media in the pH range of approximately 4 - 8.0. According to some embodiments, the active peptidyl drug is at least "sparingly soluble” at 37 ⁇ 1° C in aqueous media in the pH range of approximately 4 - 8.0. According to some embodiments, the active peptidyl drug is at least "soluble” at 37 ⁇ 1° C in aqueous media in the pH range of approximately 4 - 8.0.
  • the active peptidyl drug is at least "freely soluble” at 37 ⁇ 1° C in aqueous media in the pH range of approximately 4 - 8.0. In some embodiments, the active peptidyl drug is "very soluble" at 37 ⁇ 1° C in aqueous media in the pH range of
  • any pharmaceutically acceptable buffer may be used in the present formulations/ compositions.
  • the buffer is present in a concentration of from about 1 mM to about 100 mM ⁇ e.g., about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM).
  • the buffer to be included in the formulations may include, but is not limited to, the following: acetate ⁇ e.g., sodium acetate), sodium carbonate, citrate ⁇ e.g., sodium citrate), tartrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethan, or mixtures thereof.
  • acetate ⁇ e.g., sodium acetate
  • sodium carbonate citrate ⁇ e.g., sodium citrate
  • tartrate glycylglycine
  • histidine glycine
  • glysine arginine
  • sodium dihydrogen phosphate sodium dihydrogen phosphate
  • disodium hydrogen phosphate sodium phosphate
  • tris(hydroxymethyl)-aminomethan or mixtures thereof.
  • the buffer is glycylglycine, sodium di
  • the buffers are added to maintain the pH of the formulation to between about 3 to about 8 ⁇ e.g., about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 6.8, about 7, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0).
  • the pH of the formulation may be between about 3 to about 6, between about 3 to about 5.5, between about 3 to about 5.2, between about 3 to about 4.5, between about 3 to about 4, between about 4 to about 5.5, between about 4.5 to about 5.5, between about 4 to about 6, between about 4 to about 7, between about 3 to about 7, between about 4 to about 7.5, between about 5 to about 7.5, between about 5 to about 6.5, between about 5 to about 8, between about 6 to about 8, between about 6.5 to about 7.5, or between about 7.5 to about 8.0).
  • the value of pH assumes normal procedures taken to obtain a pH measurement of 100% aqueous solutions.
  • the preservative is selected from the group consisting of phenol, m-cresol, benzalkonium chloride, chloroethanol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, parabens, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof.
  • the preservative is benzyl alcohol, a phenol, or m-cresol.
  • the preservative is present in a concentration from about 0.1 mg/ml to about 50 mg/ml, more preferably in a concentration from about 0.1 mg/ml to about 25 mg/ml, and most preferably in a concentration from about 0.1 mg/ml to about 10 mg/ml.
  • compositions of the present invention may be administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers.
  • the peptidyl drugs may be prepared as compositions/formulations according to the present invention for parenteral administration by injection, for example, by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, or sterile cosolvent formulation, before use.
  • the compound(s) for administration by injection, it is preferred to use the compound(s) in solution in a sterile vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.
  • the pharmaceutical compositions of the present invention may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, trehalose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • the compositions are in a sealed sterile glass vial.
  • compositions are in liquid form. In some embodiments, the compositions are in lyophilized form.
  • compositions comprising one or more of proteins, peptides, and mimetics thereof of the present invention may be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.”
  • the dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.
  • Exemplary dosages within the scope of the present invention include administering a peptidyl drug in a daily dose selected from about 0.1 mg to about 10 mg ⁇ e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg), or fractions thereof, for example 2.5, 4.7, etc.
  • Exemplary dosages for subcutaneous delivery include a daily dose of 2 ⁇ g to 10 mg of a formulation stabilized with propylene glycol and/or ethanol, and weekly doses at 3-7 times the daily doses.
  • Other suitable dosages include any dosage with any route of administration that results in a bioavailability or pharmacokinetic profile similar to those yielded by the above-described dosage ranges.
  • Highly specific peptidyl drugs may be administered at a dose in a daily dose selected from about 1 ⁇ g to 200 ⁇ g (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,
  • Exemplary dosages for subcutaneous delivery include a daily dose of 1 ⁇ g to 200 ⁇ g of a formulation stabilized with propylene glycol and/or ethanol, and weekly doses at 3-7 times the daily doses.
  • Other suitable dosages include any dosage with any route of administration that results in a bioavailability or pharmacokinetic profile similar to those yielded by the above-described dosage ranges.
  • Dosages for subcutaneous delivery of an aqueous formulation of peptidyl drugs include dosages between about 0.1 to about 9 mg, about 0.1 to about 8 mg, about 0.1 to about 7 mg, about 0.1 to about 6 mg, about 0.1 to about 5 mg, about 0.1 to about 4 mg, about 0.1 to about 3 mg, about 0.1 to about 2 mg, about 0.1 to about 1 mg, about 0.1 to about 0.5 mg, about 0.1 to about 0.2 mg, 0.2 to about 9 mg, about 0.2 to about 8 mg, about 0.2 to about 7 mg, about 0.2 to about 6 mg, about 0.2 to about 5 mg, about 0.2 to about 4 mg, about 0.2 to about 3 mg, about 0.2 to about 2 mg, about 0.2 to about 1 mg, about 0.2 to about 0.5 mg, 0.5 to about 9 mg, about 0.5 to about 8 mg, about 0.5 to about 7 mg, about 0.5 to about 6 mg, about 0.5 to about 5 mg, about 0.5 to about 4 mg, about 0.5 to about 3 mg, about 0.5 to about
  • Dosages for subcutaneous delivery of an aqueous formulation of highly specific peptidyl drugs include dosages between 1-9 ⁇ g, 10-19 ⁇ g, 20-30 ⁇ g, 31-40 ⁇ g, 42-45 ⁇ g, 46-50 ⁇ g, and more specifically at 5 ⁇ g, 7.5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, or 50 ⁇ g.
  • the pharmaceutically acceptable composition or solution described herein may incorporate full-length PTH (1-84), 1-31 and 1-34 fragments, and other fragments, or variants of fragments, including substitutions, deletions, or insertions, of human PTH, or of rat, porcine or bovine PTH that have human PTH activity as determined in the ovarectomized rat model of osteoporosis reported by Kimmel et al., Endocrinology, 1993, 32(4): 1577.
  • the PTH analogues used in the present invention are naturally or non-naturally occurring and may optionally incorporate less than the first 34 N-terminal residues of PTH.
  • the native PTH sequence, and its truncated 1-34 form, has been shown to have all of these activities.
  • the hPTH-(l-34) sequence is:
  • PTH peptide analogues of the present invention include the following: PTH-(l-34), PTH-(I -34)NH 2 , PTH-(I -31)NH 2 , Ostabolin; PTH-(I -3 O)NH 2 ; PTH- (1-29)NH 2 ; PTH-(I -28)NH 2 ; Leu 27 PTH-(l-31)NH 2 ; LeU 27 PTH-(I -3O)NH 2 ; LeU 27 PTH-(I- 29)NH 2 ; Leu 27 cyclo(22-26)PTH-(1-31)NH 2 Ostabolin-CTM; Leu 27 cyclo(22-26)PTH-(1- 34)NH 2 ; Leu 27 cyclo(Lys26-Asp30)PTH-(l-34)NH 2 ; Cyclo(Lys27-Asp30)PTH-(l-34)NH 2 ; Leu 27 cyclo(22-26)PTH-(1-34)NH 2
  • Exemplary dosages within the scope of the present invention include administering a PTH peptidyl drug in a daily dose selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 ⁇ g, or fractions thereof, for example 12.5, 14.7, etc.
  • PTH 1-34 may be administered in a daily dose selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 ⁇ g, or fractions thereof, for example 12.5, 14.7, etc.
  • PTH 1- 84 may be administered in a daily dose selected from 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 ⁇ g, or fractions thereof, for example 12.5, 14.7, etc.
  • the PTH peptidyl drugs of the present invention can also be administered at a variety of doses. Effective dosages can vary according to the type of formulation of PTH peptidyl drug administered as well as the route of administration. One skilled in the art can adjust the dosage by changing the route of administration or formulation, so that the dosage
  • Exemplary dosages include a daily dose of 2 ⁇ g to 50 ⁇ g for subcutaneous delivery of a formulation stabilized with propylene glycol and/or ethanol, and weekly doses at 3-7 times the daily doses.
  • Other suitable dosages include any dosage with any route of administration that results in a bioavailability or pharmacokinetic profile similar to those yielded by the above-described dosage ranges.
  • Preferred dosages for subcutaneous delivery of an aqueous formulation for a PTH peptiyl drug include dosages between 5-9 ⁇ g, 10-19 ⁇ g, 20-30 ⁇ g, 31-40 ⁇ g, 42-45 ⁇ g, 46-50 ⁇ g, and more specifically at 5 ⁇ g, 7.5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, or 50 ⁇ g.
  • the methods provided by this invention are generally practiced by administering to an animal in need thereof a daily or weekly dose of a PTH compound in an amount effective to induce bone formation and inhibit or reduce bone loss or resorption.
  • One aspect of the present invention provides a method for treating osteoporosis by administering to a subject in need thereof a pharmaceutically acceptable formulation comprising a PTH peptide analogue in a daily subcutaneous dose of an aqueous formulation of 2 ⁇ g to 100 ⁇ g or a weekly dose of from 14 ⁇ g to 700 ⁇ g ,
  • Exemplary dosages include a daily dose of 0.5 to 50 ⁇ g for subcutaneous delivery of a formulation stabilized with propylene glycol.
  • Exemplary dosages within the scope of the present invention include administering PTH 1-34 in a daily dose selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 ⁇ g, or fractions thereof, for example 12.5, 14.7, etc., and administering PTH 1-84 in a daily dose selected from 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,
  • suitable dosages include any dosage with any route of administration that results in a bioavailability or pharmacokinetic profile similar to those yielded by the above- described dosage ranges.
  • the subject is a human man or woman.
  • the woman is post-menopausal.
  • the osteoporosis can be selected from the group consisting of advanced-stage osteoporosis, hypogonadal osteoporosis, spinal osteoporosis, transplant- induced osteoporosis, and steroid-induced osteoporosis.
  • Administration of the PTH peptide analogues of the present invention includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • a variety of administration routes can be used in accordance with the present invention, including oral, topical, transdermal, nasal, pulmonary, transpercutaneous (wherein the skin has been broken either by mechanical or energy means), rectal, buccal, vaginal, via an implanted reservoir, or parenteral.
  • Parenteral includes subcutaneous, intravenous, intramuscular, intraperitoneal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. More preferably, the route of administration is subcutaneous, transcutaneous, intranasal, transdermal, oral, or inhalation administration.
  • a stabilized solution of a parathyroid hormone can include a stabilizing agent, a buffering agent, a preservative, an antibacterial agent and the like.
  • the stabilizing agent incorporated into the solution or composition includes alcohols, ethanol or a polyol which includes a saccharide, preferably a monosaccharide or disaccharide, e.g., glucose, trehalose, raffinose, or sucrose; a sugar alcohol such as, for example, mannitol, sorbitol or inositol, and a polyhydric alcohol such as glycerine or propylene glycol or mixtures thereof.
  • a preferred polyol is propylene glycol.
  • the concentration of polyol may range from about 10 to about 40 wt-%, preferably about 10-30 wt-% of the total solution.
  • the buffering agent employed in the solution or composition of the present invention may be any acid or salt combination which is pharmaceutically acceptable.
  • Useful buffering systems are, for example, acetate, tartrate or citrate sources.
  • Preferred buffer systems are acetate or tartrate sources, most preferred is an acetate source.
  • the concentration of buffer may be in the range of about 2 mM to about 500 mM, preferably about 2 mM to 100 mM.
  • the stabilized solution or composition of the present invention may also include a parenterally acceptable preservative.
  • preservatives include, for example, cresols, benzyl alcohol, phenol, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal and phenylmercuric nitrate and acetate.
  • a preferred preservative is m-cresol or benzyl alcohol; most preferred is m-cresol.
  • the amount of preservative employed may range from about 0.1 to about 2 wt-%, preferably about 0.3 to about 1.0 wt-% of the total solution.
  • the parathyroid hormone compositions can, if desired, be provided in a powder form containing not more than 2% water by weight, that results from the freeze-drying of a sterile, aqueous hormone solution prepared by mixing the selected parathyroid hormone, a buffering agent and a stabilizing agent as above described.
  • a buffering agent when preparing lyophilized powders is a tartrate source.
  • Particularly useful stabilizing agents include glycine, sucrose, trehalose and raffinose.
  • PTH(I -34) (Forteo ® ), are not stable at room temperature and must be stored under refrigerated conditions (2-8 0 C). Since hPTH undergoes hydrolysis, oxidation and
  • the formulation is stable at 5 0 C, it is preferred that the formulation is stable at about pH 7.5, as the pH is closer to physiological pH.
  • Ostabolin-C or PTH(l-34) (Forteo ® ) solution is less stable at pH 7.5 compared to the ready-to-use formulation. Oxidation and deamidation both occur and takes place above pH 7.0. As such, a 100% aqueous formulation above pH 7 under refrigerated conditions may not be feasible.
  • mixtures of ethanol/water or propyl ene/water systems were used with the antioxidants methionine or lipoic acid to evaluate the stability of the formulations of this invention.
  • Methionine Another additive to help maintain the stability of an hPTH formulation is Methionine.
  • Methionine has been shown to be a potential antioxidant and improve hPTH stability.
  • polyols have the potential to stabilize peptide and protein formulations and sucrose concentrations up to IM at pH 5.5 have been found to reduce the rate of both deamidation and oxidation of hPTH.
  • the PTH peptide analogue may also be formulated into a composition suitable for administration by any convenient route, e.g., orally (including sublingually), topically, transdermally (including percutaneous absorption of the composition through the skin, such as by patches, ointments, creams, gels, salves and the like), or intranasally.
  • a convenient route e.g., orally (including sublingually), topically, transdermally (including percutaneous absorption of the composition through the skin, such as by patches, ointments, creams, gels, salves and the like), or intranasally.
  • compositions for parenteral administration may be formulated using an injectable liquid carrier such as sterile pyrogen-free water, sterile peroxide-free ethyl oleate, dehydrated alcohol or propylene glycol or a dehydrated alcohol/propylene glycol mixture, and may be injected intravenously, intraperitoneally, subcutaneously or intramuscularly.
  • injectable liquid carrier such as sterile pyrogen-free water, sterile peroxide-free ethyl oleate, dehydrated alcohol or propylene glycol or a dehydrated alcohol/propylene glycol mixture
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • Administration in this invention may consist of one or more cycles; during these cycles one or more periods of osteoclastic and osteoblastic activity will occur, as well as one or more periods when there is neither osteoclastic nor osteoblastic activity.
  • administration may be conducted in an uninterrupted regimen; such a regimen may be a long term regimen, e.g., a. permanent regimen.
  • compositions may if desired incorporate one or more further active ingredients.
  • the hormone can be administered regularly ⁇ e.g. , once or more each day or week), intermittently (e.g., irregularly during a day or week), or cyclically (e.g., regularly for a period of days or weeks followed by a period without administration).
  • Regular administration can include once daily, once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days (once/week).
  • PTH is administered once daily for 1-7 days for a period ranging from 3 months for up to 3 years in osteoporotic patients. In additional embodiments, PTH is administered for no less than 8 days.
  • the present invention also encompasses embodiments wherein PTH is administered on a weekly basis.
  • the present invention also encompasses a kit including the present pharmaceutical compositions and to be used with the methods of the present invention.
  • the kit can contain a vial, for example, which contains a formulation of the present invention and suitable carriers, either dried or in liquid form.
  • the kit further includes instructions in the form of a label on the vial and/or in the form of an insert included in a box in which the vial is packaged, for the use and administration of the compounds.
  • the instructions can also be printed on the box in which the vial is packaged.
  • the instructions contain information such as sufficient dosage and administration information so as to allow a worker in the field to administer the drug. It is anticipated that a worker in the field encompasses any doctor, nurse, or technician who might administer the drug, or a patient who might self-administer the pharmaceutical composition.
  • the kit contains a medication delivery pen that houses a cartridge assembly containing a vial or cartridge that has the capability of holding about a 60 day supply of daily doses of the pharmaceutical compositions described herein.
  • the pen has the capability of holding a 1, 2, 3, 4, 5, 6, 7, or 8 week supply of daily doses of the pharmaceutical compositions described herein.
  • the pen has the capability of holding a 2 or 4 week supply of daily doses of the
  • Such a device provides ease of use for self- administration of the pharmaceutical compositions described herein.
  • the cartridge can contain a liquid dosage of the
  • EXAMPLE 1 PHARMACOKINETICS OF PTH AFTER INTRA VENOUS OR SUBCUTANEOUSADMINISTRATION OF TERIPARATIDE OR FOR TEO ® IN FEMALE SPRA GUE DA WLEYRA TS.
  • the objective of this study was to evaluate the pharmacokinetics of PTH after single intravenous (IV) or subcutaneous (SC) doses of Teriparatide formulation in propylene glycol cosolvents or Forteo ® in female Sprague Dawley rats.
  • mice Thirty female Sprague Dawley rats were assigned to six dose groups with five rats per group. Animals in Groups 1 to 5 were administered a single subcutaneous fixed dose of 20 ⁇ g PTH(l-34) as teriparatide or as Forteo ® (pre-filled pen device) also marketed as
  • F abs mean absolute bioavailability values
  • Terminal half-life ( ⁇ 2 ) was similar for all five SC dose groups.
  • the mean ti /2 was 18 minutes following teriparatide administration in the 40% propylene glycol formulation, 17 minutes following teriparatide administration in the 30% propylene glycol formulation (low dosing volume), 18 minutes following teriparatide administration in the 20% propylene glycol formulation, 21 minutes following teriparatide administration in the 30% propylene glycol formulation (high dosing volume), and 20 minutes following Forteo ® administration.
  • Mean tm following IV administration of 5 ⁇ g teriparatide in saline was 10 minutes.
  • Dosing Formulations Formulations for IV and SC dosing were prepared on the day of dosing as described below.
  • Group 2 Formulation - teriparatide (1 mg/mL adjusted for 90.8% peptide assay) in 30% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer: 9.3 mg of teriparatide was weighed out and combined with 8.44 mL of 30% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer, Lot BA041409-06. The formulation was mixed for 5 minutes and vortexed for 1 minute after which the pH was determined to be 7.63. No pH adjustment was made. The total formulation weight was 8.7815 g.
  • Group 3 Formulation - Teriparatide (1 mg/mL adjusted for 90.8% peptide assay) in 20% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer: 8.7 mg of teriparatide was weighed out and combined with 7.90 mL of 20% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer. The formulation was mixed for 5 minutes and vortexed for 1 minute after which the pH was determined to be 7.55. No pH adjustment was made. The total formulation weight was 8.1944 g.
  • Group 4 Formulation - Teriparatide (0.4 mg/mL adjusted for 90.8% peptide assay) in 30% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer: to 4 mL of the 30% propylene glycol formulation used for Group 2 dosing (Lot # BA041509-02 above) was added 6 mL 30% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL methionine, 3 mg/mL m-cresol solvent buffer . The formulation was mixed for 5 minutes after which the pH was determined to be 7.61. No pH adjustment was made. The total formulation weight was 10.3073 g.
  • Group 5 Formulation - Forteo ® (0.25 mg/mL solution): the Forteo ® solution was removed directly from the pre-filled pen device into the dosing syringe using another needle to vent the device.
  • Group 6 Formulation - Teriparatide (0.25 mg/mL adjusted for 90.8% peptide assay) in 0.9% NaCl (sterile saline): 5.3 mg of teriparatide was weighed out and combined with 19.25 mL of saline, mixed for 5 minutes and vortexed for 1 minute after which the pH was determined to be 5.5. No pH adjustment was made. The total formulation weight was 19.341O g. The formulation was clear and assigned.
  • Dose Administration Thirty female Sprague Dawley rats (25 JVC, 5 FVC/JVC) were received was and there was a minimum of 2 days acclimation prior to releasing all animals to this study. Animals were assigned to six dose groups with 5 rats per group. Animals in Groups 1 to 5 were administered a single SC fixed dose of teriparatide or Forteo ® at 20 ⁇ g/animal. Animals in Group 6 were administered a single IV fixed dose of teriparatide at 5 ⁇ g/animal via FVC. The dose groups and doses are as follows:
  • Acceptance criteria for ⁇ determination required regression of at least three points from the elimination phase and r 2 equal to or greater than 0.85.
  • the area under the plasma concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUCi as t) was determined by the linear trapezoidal method.
  • AUC, nf was calculated as:
  • AUC inf AUC last + C Iast / ⁇
  • Bioavailability was calculated using AUCi 3 St- Absolute bioavailability (%F abs ) for individual rats in the SC dose groups was calculated relative to the IV dose group, calculated as:
  • %Frel (AUCiast tenparat.de SC / mean AUCiast Forteo Sc) X 100
  • the objective of this study was to evaluate the pharmacokinetics of PTH after single subcutaneous (SC) doses of TERIPARATIDE or Forteo ® in female Sprague Dawley rats.
  • teriparatide compared to Forteo ® .
  • Mean relative F of PTH(I -34) following teriparatide dosing was 143% for the 50% glycerol low volume formulation, 112% for the 50% glycerol high volume formulation, and 294% for the 40% propylene glycol formulation.
  • the mean terminal half-life ranged from 19 to 23 minutes in the 4 groups.
  • Formulations for SC dosing were prepared on the day of dosing as described below.
  • Tris, 5 mg/mL Methionine buffer: 4 mL of Group 1 Formulation was combined with 6 mL of 50% Glycerol in Tris aqueous buffer stock. The formulation was mixed on a magnetic stirrer for 5 minutes, and the pH was determined to be 7.6. No pH adjustment was made. The formulation was clear and colorless. The nominal concentration of teriparatide was 0.4 mg/mL after adjusting for 90.8% peptide assay.
  • Group 3 Formulation - 1 mg/mL teriparatide in 40% propylene glycol, 0.7% NaCl, 50 mM Tris, 5 mg/mL Methionine buffer: 7.92 mg of teriparatide was weighed and combined with 7.2 mL of 40% Propylene Glycol in Tris aqueous buffer stock. The formulation was mixed on a magnetic stirrer for 5 minutes, after which the pH was determined to be 7.6. No pH adjustment was made. The formulation was clear and colorless.
  • Group 4 Formulation - Forteo ® (0.25 mg/mL solution): The Forteo ® solution was removed directly from the pre-f ⁇ lled pen into the dosing syringe using a second needle to vent the chamber.
  • PTH(I -34) concentrations were quantifiable at least to 60 minutes post-dose. Exposure to PTH(I -34) following a single fixed 20 ⁇ g SC dose, measured by mean C max and mean AUC, was greater following administration of teriparatide in three different formulations compared to Forteo ® . Of the teriparatide dose groups (Groups 1-3), exposure to PTH(I -34) was greatest when teriparatide was administered in the 40% propylene glycol formulation.
  • Mean C max was 23440 pg/mL following administration of teriparatide formulated in 50% glycerol (low dosing volume), 16180 pg/mL following administration of teriparatide formulated in 50% glycerol (high dosing volume), 32120 pg/mL following administration of teriparatide formulated in 40% propylene glycol, and 16960 pg/mL following administration of Forteo ® .
  • mean AUC mf was 1118442 pg-min/mL following administration of teriparatide formulated in 50% glycerol (low dosing volume), 870975 pg-min/mL following administration of teriparatide formulated in 50% glycerol (high dosing volume),
  • the terminal half-life ( ⁇ /2 ) was similar for all four dose groups.
  • the mean terminal half-life was 19 minutes following teriparatide administration in the 50% glycerol formulation (low dosing volume), 23 minutes following teriparatide administration in the 50% glycerol formulation (high dosing volume), 22 minutes following teriparatide administration in the 40% propylene glycol formulation, and 21 minutes following administration of Forteo ® .
  • Formulation 1 40% propylene glycol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 1 mg/mL teriparatide, pH 7.4
  • Formulation 2 30% propylene glycol, 0.7% NaCl, 50 niM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 1 mg/mL teriparatide, pH 7.4
  • Formulation 3 20% propylene glycol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 1 mg/mL teriparatide, pH 7.4
  • Formulation 4 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 0.4 mg/mL teriparatide, pH 7.4
  • Formulation 4 dosing solution by diluting Formulation 2 dosing solution with aliquot of 30% propylene glycol solvent stock solution, according to Table 3-3 below, and mix.
  • dosing formulations 1-4 are stored at -20°C.
  • Formulations are prepared by repeating the steps of Example 20 wherein a polyol is added, the preservative is benzyl alcohol and the pH adjusted to 7.1.
  • the following formulations are produced:
  • Formulation 1 40% propylene glycol 50 mM TRIS, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 7.1.
  • Formulation 2 30% propylene glycol 50 mM TRIS, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol 0.5 mg/mL teriparatide, pH 7.1.
  • Formulation 3 20% propylene glycol 50 mM TRIS, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol 0.5 mg/mL teriparatide, pH 7.1.
  • Formulations are prepared by repeating the steps of Example 20 wherein a polyol is added, the preservative is benzyl alcohol and the pH adjusted to 4.5.
  • the following formulations are produced:
  • Formulation 1 40% propylene glycol, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 4.5.
  • Formulation 2 30% propylene glycol, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 4.5.
  • Formulation 3 20% propylene glycol, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 4.5.
  • Formulations are prepared by repeating the steps of Example 20 wherein diethylene glycol monoethyl ether (DEGMEE) is used instead of propylene glycol.
  • DEGMEE diethylene glycol monoethyl ether
  • Formulation 1 40% 1 ,2-ethanediol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 1 mg/mL teriparatide, pH 7.4.
  • Formulation 2 30% 1 ,2-ethanediol, 0.7% NaCl, 50 niM TRIS, 5 mg/mL methionine, 3 mg/mL m-cresol, 1 mg/mL teriparatide, pH 7.4.
  • Formulation 3 20% 1 ,2-ethanediol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3
  • Formulation 4 30% 1,2-ethanediol, 0.7% NaCl, 50 mM TRIS, 5 mg/mL methionine, 3
  • Formulations are prepared by repeating the steps of Example 20 wherein insulin is used instead of hPTH. The following formulations are produced:
  • Formulation 1 40% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 1
  • Formulation 2 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 1
  • Formulation 3 20% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 1 mg/mL insulin, pH 7.4.
  • Formulation 4 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 0.4 mg/mL insulin, pH 7.4.
  • EXAMPLE 8 INTRA VENOUS OR SUBCUTANEOUS FORMULA TIONS OF CALCITONIN
  • Formulations are prepared by repeating the steps of Example 20 wherein calcitonin is used instead of hPTH The following formulations are produced:
  • Formulation 1 40% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 1 mg/mL calcitonin, pH 7.1.
  • Formulation 1 40% diethylene glycol monoethyl ether, 50 mM TRIS, 5 mg/mL methionine,
  • Formulation 2 30% diethylene glycol monoethyl ether 50 mM TRIS, 5 mg/mL methionine,
  • Formulation 3 20% diethylene glycol monoethyl ether 50 mM TRIS, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol 0.5 mg/mL calcitonin, pH 7.1.
  • Formulations are prepared by repeating the steps of Example 20 wherein a polyol is added, the preservative is benzyl alcohol and the pH adjusted to 4.5.
  • the following formulations are produced:
  • Formulation 1 40% diethylene glycol monoethyl ether, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH
  • Formulation 2 30% diethylene glycol monoethyl ether, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 4.5.
  • Formulation 3 20% diethylene glycol monoethyl ether, 1OmM sodium acetate, 5 mg/mL methionine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 0.5 mg/mL teriparatide, pH 4.5.
  • Formulations are prepared by repeating the steps of Example 20 wherein etanercept is used instead of hPTH The following formulations are produced:
  • Formulation 1 40% propylene glycol, 100 mg/ml sucrose, 50 mM TRIS, 0.9% benzyl
  • Formulation 2 30% propylene glycol, 100 mg/ml sucrose, 50 mM TRIS, 0.9% benzyl
  • Formulation 3 20% propylene glycol, 100 mg/ml sucrose, 50 mM TRIS, 0.9% benzyl
  • Formulation 4 20% propylene glycol, 100 mg/ml sucrose, 50 mM TRIS, 0.9% benzyl
  • Formulations are prepared by repeating the steps of Example 20 wherein efalizumab is used instead of hPTH. The following formulations are produced:
  • Formulation 1 40% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/niL m-cresol, 100 mg/mL efalizumab, pH 7.4.
  • Formulation 2 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 100 mg/mL efalizumab, pH 7.4.
  • Formulation 3 20% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 100 mg/mL efalizumab, pH 7.4.
  • Formulation 4 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 40 mg/mL efalizumab, pH 7.4.
  • EXAMPLE 12 SUBCUTANEOUS FORMULA TIONS OF RAPTIVA
  • Formulations are prepared by repeating the steps of Example 24 wherein a polyol is added, the preservative is benzyl alcohol and the pH adjusted to 6.2.
  • the following formulations are produced: Formulation 1 : 40% diethylene glycol monoethyl ether, 50 mM histidine, 100 mg/ml
  • Formulation 2 30% diethylene glycol monoethyl ether, 50 mM histidine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 100 mg/ml efalizumab, pH 6.2..
  • Formulation 3 20% diethylene glycol monoethyl ether, 50 mM histidine, 100 mg/ml sucrose, 0.9% benzyl alcohol, 100 mg/ml efalizumab, pH 6.2.
  • EXAMPLE 13 INTRA VENOUS OR SUBCUTANEOUS FORMULATIONS OF GLUCAGON
  • Formulations are prepared by repeating the steps of Example 20 wherein glucagon is used instead of hPTH The following formulations are produced:
  • Formulation 1 40% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 10 mg/mL glucagon, pH 7.4.
  • Formulation 2 30% propylene glycol, 0.7% NaCl, 50 niM TRIS, 3 mg/mL m-cresol, 10 mg/mL glucagon, pH 7.4.
  • Formulation 3 20% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 10 mg/mL glucagon, pH 7.4.
  • Formulation 4 30% propylene glycol, 0.7% NaCl, 50 mM TRIS, 3 mg/mL m-cresol, 5
  • EXAMPLE 14 A RANDOMIZED, SINGLE-BLIND, 5-PERIOD CROSSOVER
  • Teriparatide 20 ⁇ g is the currently marketed dose for all indications.
  • Preclinical data suggest that teriparatide formulated in propylene glycol (PG) may provide improved bioavailability and stability relative to Forteo ® .
  • a dose range of teriparatide from 15 ⁇ g to 25 ⁇ g was selected in order to obtain relative bioavailability data.
  • the 15 ⁇ g dose of IV teriparatide was selected to provide a 1 :1 absolute bioavailability comparison with 2 of the teriparatide SC injections. This dose is less than the dose that was administered in the absolute bioavailability study conducted for teriparatide (17.5 ⁇ g), as documented in the Food and Drug Administration (FDA) approval package notes of Forteo R .
  • FDA Food and Drug Administration
  • teriparatide was formulated as a clear and colorless sterile solution containing PG (concentration varies), Tris 5OmM, L-methionine 5 mg/mL, sucrose 100 mg/mL, and benzyl alcohol 0.9% which was injected subcutaneously into the abdominal wall following measurement of the appropriate volume for a given dose.
  • Regimen A was formulated with 20% PG and given as 15 ⁇ g in 30 ⁇ L.
  • Regimens B and C were formulated with 30% PG.
  • Regimen B was given as 15 ⁇ g in 30 ⁇ L
  • Regimen C was given as 25 ⁇ g in 50 ⁇ L.
  • Teriparatide (Forteo ® ) is formulated as a clear and colorless sterile isotonic solution in a glass cartridge which was pre-assembled into a disposable delivery device (pen) for SC injection.
  • Each mL of solution contains 250 ⁇ g teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and water for injection.
  • hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
  • Each cartridge, pre-assembled into a delivery device delivers 20 ⁇ g of teriparatide per dose each day for up to 28 days. For this study, all subjects received the 20 ⁇ g (in 80 ⁇ l) injection in the abdominal wall for consistency.
  • Teriparatide was manufactured by Lilly France - F-67640 Fegersheim, France for Eli Lilly and Company - Indianapolis, IN, USA. It was supplied in a pre-filled pen delivery device, NDC 0002-8400-01 (MS8400).
  • teriparatide was formulated as a clear and colorless sterile solution containing mannitol 45.4 mg/mL, Na + acetate (anhydrous) 0.1 mg/mL, and acetic acid 0.41 mg/mL. It was injected intravenously using an angiocath in a volume of 60 ⁇ L (containing 15 ⁇ g). The angiocath was primed with 1 ml of sterile saline (0.9% NaCl, preservative-free) and following administration of teriparatide flushed with 2 ml of sterile saline (0.9% NaCl, preservative-free) in order to ensure that all the teriparatide reaches the blood stream. Pharmacokinetics
  • PK parameters were calculated for each subject with sufficient plasma teriparatide or teriparatide concentration data for analysis using the standard non compartmental method.
  • Plasma PK parameters were tabulated by treatment regimen and summary statistics, including number of subjects, arithmetic mean, standard deviation (SD), minimum, maximum, median, coefficients of variation (CV%) , and geometric mean.
  • SD standard deviation
  • CV% coefficients of variation
  • the upper and lower limits of the 90% confidence intervals (CI) were presented for C max , t /2 , AUCs, CLfF, and V z /F.
  • the geometric mean and CV% were calculated for C max and AUC values.
  • a mixed model was used for the analysis of bioavailability on the logarithm- transformed PK parameters (AUC 0-t , AUC 0- j nf , and C max ).
  • the mixed model included treatment (formulation), period and sequence as fixed factors and subject within sequence as random effect. A 10% level of significance was used to test the sequence effect.
  • Pharmacokinetic parameters (AUC 0-t , AUC 0- j nf , and C max ) of SC teriparatide doses and teriparatide were used for the bioavailability analyses (relative, absolute, and apparent absolute).
  • the PK parameters were logarithm-transformed for statistical analyses.
  • the least- square (LS) means, the difference between LS means of the different drug formulations, and the standard error associated with the difference were calculated with the mixed model. These values were back-transformed to the original scale.
  • the bioavailability was evaluated by calculating a 90% CI of the difference between LS mean (expressed as a percentage relative to the reference formulation).
  • the geometric mean for AUCo- t for PTH (1-34) concentration was 126.98 hr*pg/mL for treatment A, 103.20 hr*pg/mL for treatment B, 183.84 hr*pg/mL for treatment C, 80.44 hr*pg/mL for treatment D, and 141.60 hr*pg/mL for treatment E.
  • the mean AUCo- t for PTH (1-34) concentration was 133.27 hr*pg/mL for treatment A, 110.34 hr*pg/mL for treatment B, 188.81 hr*pg/mL for treatment C, 88.93 hr*pg/mL for treatment D, and 147.82 hr*pg/mL for treatment E.
  • the absolute bioavailability analysis (test formulations vs. IV formulation) demonstrated the following for dn-AUC 0- t:
  • Table 14-3 presents the PK results for each treatment for the PK Evaluable
  • CV% coefficients of variance
  • IV intravenous
  • PG propylene glycol
  • SD
  • the ratios of the geometric LS means for dn-AUCo -inf for treatment regimens A, B and C versus teriparatide were 2.064, 2.128 and 1.645, respectively.
  • the ratios of the geometric LS means for dn-C max for treatment regimens A, B and C versus teriparatide were 1.099, 1.035 and 0.857, respectively.

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Abstract

L'invention porte sur des compositions comprenant une quantité pharmaceutiquement efficace d'un médicament à base de peptidyle et un amplificateur de biodisponibilité dans une quantité suffisante pour augmenter la biodisponibilité du médicament à base de peptidyle, l'amplificateur de biodisponibilité comprenant un diol ou éther de diol.
PCT/US2010/043038 2009-07-23 2010-07-23 Formulations/compositions pharmaceutiquement acceptables pour des médicaments à base de peptidyle Ceased WO2011011675A1 (fr)

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Cited By (14)

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US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US20180236079A1 (en) * 2015-09-04 2018-08-23 Latitude Pharmaceuticals, Inc. Stabilized glucagon solutions
WO2019059302A1 (fr) 2017-09-22 2019-03-28 旭化成ファーマ株式会社 Composition pharmaceutique liquide contenant du tériparatide ayant une excellente stabilité
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US20180236079A1 (en) * 2015-09-04 2018-08-23 Latitude Pharmaceuticals, Inc. Stabilized glucagon solutions
US10888616B2 (en) * 2015-09-04 2021-01-12 Latitude Pharmaceuticals, Inc. Stabilized glucagon solutions
CN110996988A (zh) * 2017-09-22 2020-04-10 旭化成制药株式会社 稳定性优异的含有特立帕肽的液态药物组合物
WO2019059302A1 (fr) 2017-09-22 2019-03-28 旭化成ファーマ株式会社 Composition pharmaceutique liquide contenant du tériparatide ayant une excellente stabilité
EP3685849A4 (fr) * 2017-09-22 2021-12-22 Asahi Kasei Pharma Corporation Composition pharmaceutique liquide contenant du tériparatide ayant une excellente stabilité

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