[go: up one dir, main page]

WO2002067989A1 - Preparations d'hormone de croissance aqueuses resistant a la cristallisation - Google Patents

Preparations d'hormone de croissance aqueuses resistant a la cristallisation Download PDF

Info

Publication number
WO2002067989A1
WO2002067989A1 PCT/EP2002/000114 EP0200114W WO02067989A1 WO 2002067989 A1 WO2002067989 A1 WO 2002067989A1 EP 0200114 W EP0200114 W EP 0200114W WO 02067989 A1 WO02067989 A1 WO 02067989A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
buffer
hgh
pluronic
citrate
Prior art date
Application number
PCT/EP2002/000114
Other languages
English (en)
Inventor
Bernhard Siebold
John Stevens
Original Assignee
Grandis Biotech Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grandis Biotech Gmbh filed Critical Grandis Biotech Gmbh
Publication of WO2002067989A1 publication Critical patent/WO2002067989A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH

Definitions

  • the present invention relates to liquid formulations of growth hormone (GH) which are storage stable, show reduced or no crystallisation on storage and are suitable for administration to the human or animal body. More particularly, the invention relates to liquid formulations of human growth hormone (hGH) which are stable and exhibit minimal or no crystallisation when stored at least for a time at temperatures above refrigeration temperatures.
  • GH growth hormone
  • hGH human growth hormone
  • Native hGH is a single polypeptide chain protein consisting of 191 amino acids.
  • the protein is internally cross-linked by two disulphide bridges and in monomeric form exhibits a molecular weight of 22kDa.
  • GH of animal species is closely homologous in amino acid sequence to that of humans and is therefore very similar in its characteristics.
  • GH responsive organs or tissues include the liver, intestine, kidneys, muscles, connective tissue and the skeleton.
  • Hypopituitary dwarfism is a condition which is readily treated by administering GH to a subject suffering the condition.
  • infectious agents eg the agent responsible for Creutzfeldt-Jakob disease (CJD)
  • CJD Creutzfeldt-Jakob disease
  • the isolation of the hGH gene and the construction of transformed host cells expressing hGH in cell culture has opened up not only a more reliable, safer and more cost effective treatment of hypopituitary dwarfism, but the possibility of using hGH for treatment of other diseases and conditions as well.
  • hGH in aqueous solution was known to undergo a variety of degradative changes. Chemical changes such as deamidation occur and this may be related to the pH of the solution during storage. Oxidation of methionine residues may occur. There is also the possibility of a clipping of the peptide backbone as a result of hydrolysis. Also, there is the physical change of aggregation, for example, resulting in the formation of opaque insolubles.
  • WO 89/09614 discloses an hGH formulation intended for lypohilization prior to reconstitution and administration.
  • the formulation is said to pocess greater stability during processing (including lypohilization) reconstitution and storage.
  • Much effort has therefore been expended in finding formulations which permit a simpler self-administration of GH by patients.
  • EP-A-0 131 864 (Hoechst Aktiengesellschaft) describes the prevention of aggregation in proteins of greater than 8.5 kDa in aqueous solution by using surfactants.
  • EP-A-0 211 601 International Minerals & Chemical Corporation
  • PLURONIC trade mark of BASF
  • GENAPOL trade mark of Hoechst
  • WO 94/03198 is another disclosure following the previous teachings about using non-ionic surfactant as an hGH stabiliser in liquid formulations.
  • the range 0.1-5% (w/v) non-ionic surfactant in the formulation is said to permit the formulation to be exposed to shear and surface stresses without causing denaturation of the GH protein.
  • the surfactant- containing formulations are seen as being useful in pulmonary dosing and needleless jet injector guns.
  • EP-A-0 303 746 International Minerals and Chemical Corporation teaches that aqueous GH may be stabilised by formulating it with a polyol, eg non- reducing sugars, sugar alcohols, sugar acids, lactose, pentaerythritol, water- soluble dextrans and Ficoll; an amino acid, eg glycine, arginine and betaine; an amino acid polymer having a charged side group of physiological pH; and finally a choline derivative, eg choline chloride, choline dihydrogen citrate or dicholine mucate.
  • a polyol eg non- reducing sugars, sugar alcohols, sugar acids, lactose, pentaerythritol, water- soluble dextrans and Ficoll
  • an amino acid eg glycine, arginine and betaine
  • an amino acid polymer having a charged side group of physiological pH and finally a choline derivative, eg choline chloride
  • WO 92/17200 (Genentech) is concerned with stabilising hGH, not just in liquid but also in lyophilised preparations. The suggestion is that stable zincihGH dimers are produced.
  • the zinc:hGH dimers are made up of two zinc ions and two hGH molecules.
  • WO 93/12811 discloses a liquid hGH formulation in which asparagine is used as the stabilising and buffering substance.
  • WO 93/19776 (Kabi Pharmacia) teaches that when an aqueous hGH product is formulated with citrate buffer then it is more stable than when it is formulated with phosphate buffer.
  • WO 97/29767 discloses a method of preparing a stabilised liquid hGH formulation for storage at temperatures not exceeding freezing or refrigeration temperatures.
  • the present inventors have noticed how crystals tend to form in storage- stable aqueous growth hormone formulations known in the art, not just when they are stored at refrigeration temperatures, but also when they are stored above refrigeration temperatures, at least for a time.
  • the presence of crystals in liquid hGH formulations is undesirable because prior to administration such formulations need to be agitated or swirled and there may be instances when crystals are small or unobserved and the formulation is caused to be administered without dissolving the crystals sufficiently first.
  • An object of the invention is therefore to provide liquid hGH formulations which avoid the problem of crystal formation when stored for periods of time, e.g. from about one week to up to 6 or 18 months.
  • Another object of the invention is to provide liquid hGH formulations which exhibit minimal or no crystallisation when stored for at least a period of time outside a refrigerator, e.g. periods of several days, weeks or months.
  • the present invention therefore provides an aqueous growth hormone formulation comprising growth hormone and:
  • the inventors have perceived an advantage for patients, pharmacists and medical practitioners. Hitherto it has been necessary to ensure careful storage of growth hormone formulations at refrigeration temperatures in order to minimize crystallisation. Prior to receipt of the growth hormone by patients the formulations can usually be reliably stored at refrigeration temperatures (in the range of 4° to 8°C) by manufactures and pharmacists. However, once received and stored by patients in domestic refrigerators there is much less reliability in terms of storage temperature. The present inventors have observed how crystallisation tends to occur more readily at temperatures greater than 8°C, i.e. above refrigeration temperatures.
  • the formulations of the present invention provide a greater resistance to crystallisation if stored for any time above refrigeration temperatures. This therefore permits patients to be supplied with sufficient growth hormone to provide daily doses over longer periods of time than was hitherto recommendable or desirable.
  • patients might have kept a small number of doses for use over a period of a week or weeks, with the formulations of the present invention patients may keep at least one month, possibly two or three months supply of growth hormone in domestic refrigerator with no or only minimal crystallisation taking place. The frequency of prescription to patients can therefore be reduced significantly by the present invention.
  • this buffer preferably has a pH of no more than about 7.0, or 6.2 i.e. a pH in the range of about 5.6 to about 7.0, more preferably about 5.6 to 6.2, even more preferably a pH of 5.6 or 6.2.
  • this buffer preferably has a pH of no more than about 7.0 or 6.8, i.e. a pH in the range of about 6.0 to 7.0, more preferably about 6.2 to about 7.0, even more preferably about 6.2 to about 6.8.
  • the buffer other then citrate may be selected from phosphate, acetate, formate or glycine, preferably sodium phosphate, sodium acetate or ammonium acetate.
  • the formulations of the present invention may be kept at refrigeration temperature (in the range of 4° to 8°C) at all times.
  • at least some of the overall storage time may be at a temperature above refrigeration temperatures, possibly up to about a week on aggregate, possibly up to about a month on aggregate.
  • At least a part of the time that the formulation is stored may be at a storage temperature of at least 8°C, optionally a temperature in the range selected from 8° to 40°C, 8° to 25°C or 8° to 15°C.
  • the formulation is preferably substantially isotonic, more preferably wherein the agent for isotonicity is selected from one or more of a sugar alcohol, a monosaccharide, a disaccharide, propylene glycol or an inorganic salt, even more preferably the agent for isotonicity is selected from one or more of mannitol, lactose, sucrose, propylene glycol, sodium chloride or ammonium chloride.
  • the formulation preferably further comprises a non-ionic surfactant and/or a preservative.
  • Non-ionic surfactants may include poloxamers, such as poloxamer 184 or 188, Pluronic ® polyols, e.g. Pluronic F-68, polysorbates such as polysorbate 20 or 80, for example, and other ethylene/polypropylene block polymers. Amounts used may be in the range from about 0.1% (w/v) to about 5% (w/v), more preferably, 0.1% (w/v) to about 1% (w/v).
  • the preservative may be selected from one or more of phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, benzylalkonium chloride and benzethonium chloride.
  • Preferred preservatives are phenol at 0.2 - 0.4% (w/v) and benzyl alcohol at 0.7 - 1% (w/v).
  • the growth hormone is human growth hormone (hGH).
  • Pluronic F-68 2mg/ml (0.2% w/v) Phenol 2.5mg/ml (0.25% v/v)
  • the present invention also provides a method of inhibiting crystallisation in an aqueous growth hormone formulation comprising formulating the growth hormone in citrate buffer of about pH 5.6 or more, or a buffer other than citrate of about pH 6.0 or more.
  • the present invention also includes the use of an aqueous formulation of growth hormone buffered with:
  • the invention therefore provides for the use of growth hormone buffered with citrate at pH 5.6 or more, or a buffer other than citrate at about pH 6.0 or more, for the manufacture of a stable aqueous formulation substantially free of crystallisation on storage and for treatment of patients in need of growth hormone.
  • hGH formulations Prior to storage, hGH formulations normally comprise about 4% of "related proteins” being proteinaceous materials generated by degradative processes of deamidation and oxidation. Such "related proteins” are defined in the European Pharmacopoiea and measured by reversed phase HPLC. The inventors propose a maximum of 20% "related proteins" as a target at the end of the shelf life of the formulations.
  • the degradation rate of hGH is not exactly linear and the rate of degradation increases with an increase in temperature.
  • At 2° - 8°C formulations usually exhibit an increase in "related proteins” of about 0.75% per month. At 25°C this rises to 12.7% per month, and at 40°C to about 70% per month.
  • Storage at 25°C for 1 month is approximately equivalent to 17 months storage at 2° -8°C. Storage at 15°C for 1 month is approximately equivalent to 5 months storage at 2° - 8°C. Continuous storage at a temperature in the range of about 25° to 40°C is therefore impractical.
  • formulations of the present invention offer good resistance to crystallisation even up to 40°C, particularly up to 25°C, the rapid formation of "related proteins" at these temperatures will usually place a more immediate limit on the potential shelf life of formulations.
  • formulations of the present invention can readily be subjected to a daily rise in temperature slightly above about 8°C due to the opening and closing of a refrigerator door or removal from a refrigerator for periods of an hour or so each day for the purposes administration without significant loss of shelf life.
  • formulations of the present invention would not suffer adversely in terms of degradation or crystallisation if left out of the refrigerator at room temperature for a day or so.
  • the period of storage may be at least 4 weeks, possibly at least 3 months, or up to 18 months.
  • the pharmaceutical product preferably comprises at least two, rrtore preferably a multiplicity of doses of growth hormone.
  • the pharmaceutical product is preferably in the form of a container for use with an injection device, e.g. a cartridge for use in a pen injector.
  • the pharmaceutical product may be contained within an injection device, preferably a pen injector.
  • Growth hormone formulations arising out of the uses of aqueous growth hormone formulations in accordance of the invention include formulations I to VII described above.
  • any crystallisation in the liquid formulation is detected directly by eye, more preferably under the light microscope at 5x magnification, even more preferably under the light microscope at 10x magnification.
  • Prior to observation under the light microscope formulations may be filtered and the presence or absence of crystals on the filter determined.
  • the filter When viewing under the light microscope the filter may have a pore size of about 5 ⁇ m.
  • a particularly preferred test for crystallisation is to store the formulation in a sealed container with no airspace for 3 months at 15°C in the absence of light and then observe the presence or absence of crystals by eye.
  • aqueous growth hormone formulations of the present invention are preferably storage stable in the sense that there is no or minimal aggregation of growth hormone during the period of storage. Also, there is preferably no or minimal chemical degradation of growth hormone, e.g. by deamidation. Suitable tests for measuring stability of growth hormone in aqueous solution are well known in the art e.g. as described in WO 94/03198 (Genentech) incorporated herein by way of reference.
  • the growth hormone exhibits less than 10% aggregation, preferably less than 1%, more preferably less than 0.1 %, even more preferably less than 0.01 % aggregation.
  • the invention also provides a cartridge containing any of the liquid formulations as hereinbefore described for use with a pen injector device.
  • the preferred growth hormone is human growth hormone.
  • Particularly preferred human growth hormone is produced by recombinant means, for example as taught in EP-A- 0 217 822 (Scios Nova) and incorporated herein by way reference.
  • Variants of human growth hormone which may be used in accordance with the invention, alone or in combination with one another and the native hormone, include the 191 amino acid species known as somatropin and the 192 amino acid N-terminal methionine (met) species known as somatrem.
  • somatropin the 191 amino acid species known as somatropin and the 192 amino acid N-terminal methionine (met) species known as somatrem.
  • hGH-V found naturally in the placenta during pregnancy and for which the gene sequence is known and a recombinant protein has been prepared.
  • the amount of hGH in the liquid formulation of the invention depends on the volume of the formulation and the number of doses of hGH that volume is intended to provide.
  • a preferred dosage volume is 0.4ml but volumes in the range 0.01ml to 1.0ml may be used. Other preferred dosage volumes may fall in the range 0.1ml to 0.6ml.
  • the amount of hGH administered is 1.3mg although the precise dosage amount may vary depending on the particular individual. Dosage amounts in the range 0.033mg to 3.33mg hGH may be employed, preferably dosages in the range 0.33mg to 2.0mg. Increased dosage amounts are appropriate where the frequency of administration is reduced.
  • the volumes and/or dosage amounts may vary from individual to individual in accordance with specific advice from the clinician in charge.
  • formulations in accordance with the invention may comprise hGH in the range 0.5mg/ml to 20mg/ml, preferably 1 mg/ml to 15mg/ml, more preferably 2mg/ml to 10mg/ml, even more preferably 3mg/ml to 5mg/ml.
  • kits comprising an injection device and a separate container containing a liquid growth hormone formulation as hereinbefore described.
  • the administration device is simply a hypodermic syringe then the kit may comprise the syringe, a needle and a vial or ampoule containing the hGH formulation for use with the syringe.
  • the injection device is other than a simple hypodermic syringe and so the separate container is adapted to engage with the injection device such that in use the liquid formulation in the container is in fluid connection with the outlet of the injection device.
  • administration devices include but are not limited to hypodermic syringes and pen injector devices.
  • Particularly preferred injection devices are the pen injectors in which case the container is a cartridge, preferably a disposable cartridge.
  • the invention provides a cartridge containing a liquid growth formulation as hereinbefore described for use with a pen injector device.
  • the cartridge may contain a single dose or multiplicity of doses of growth hormone.
  • the buffer other than citrate is phosphate then the formulation pH is not 6.15 or more.
  • Recombinant hGH is produced in cell cultures of CHO cells transformed with the hGH gene to express the hGH protein under culture conditions. Details of how the cells are made and grown are described in EP-A-0 217 822
  • the hGH needs to be extracted and purified into a form suitable for pharmaceutical use. This is carried out according to the procedures described in AU 629177 (University of New South Wales & Garvan Institute of Medical Research) incorporated herein by way of reference.
  • the resultant hGH preparation is in the form of a bulk solution and this is employed in making the formulations described below.
  • the concentration of hGH in bulk solution was 12.17mg/ml.
  • the formulations were prepared by adding double strength excipient solution to bulk hGH solution which is diluted to give an hGH concentration of about 7mg/ml. The pH of the formulation is then adjusted as required.
  • 0.1M phosphate buffer pH 6.0 was made by mixing 200ml of 0.1 M disodium phosphate with 43ml of 0.1 M sodium dihydrogen phosphate.
  • the phosphate salt solutions were prepared as shown in Table 2 below:
  • 0.1M ammonium acetate buffer solution pH 6.0 was made by mixing 1.4ml of 0.1 M acetic acid with 50g of 0.1M solution of ammonium acetate in accordance with Table 4 below:
  • 0.1 M formate buffer solution was prepared by mixing components in accordance with Table 5 below:
  • 0.1 M glycine buffer solution was prepared by mixing components in accordance with Table 6 below:
  • Formulations 1-23 were prepared by taking sufficient bulk hGH to give final concentration of hGH of 3.33mg/ml in 10ml of solution.
  • the hGH concentration in bulk solution was 12.17mg/ml.
  • 3.28mg/g of hGH in bulk solution was added to a tared 50ml beaker.
  • the bulk hGH solution was diluted to approximately 4,5 ml with WFI. 5g (with the exception of formulation 5 (5.4g), and formulation 6 (5.5g) of the double concentrated excipient solution prepared above was then added slowly. The pH was checked and adjusted and the solution increased 10g with WFI.
  • compositions of the 23 formulations are as shown in Table 10 below:
  • Table 11 below shows the results for formulations at pH 6.0.
  • the shaded boxes show formulations where crystallisation was observed.
  • Formulations 17, 19 and 23 at pH 6.2 are most recommendable to avoid crystallisation on storage above refrigeration temperatures.
  • Formulations 13 and 14 are also recommendable but the glycine buffer is probably outside its reliable range at pH 6.0.
  • Formulations 24-38 were prepared having the compositions shown in Table 12 below: Table 12

Landscapes

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

Abstract

La présente invention concerne des préparations aqueuses et stables d'hormone de croissance humaine dans des milieux tamponnés, comprenant du mannitol, un tensioactif non ionique et un conservateur. Ces préparations sont exemptes de cristallisation lors d'un stockage au dessus de la température de réfrigération pendant n'importe quelle durée grâce à un pH de 5,6 assuré pour le milieu tamponné de citrate et à un pH de 6,0 voire supérieur assuré pour les autres milieux tamponnés.
PCT/EP2002/000114 2001-01-10 2002-01-08 Preparations d'hormone de croissance aqueuses resistant a la cristallisation WO2002067989A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0100658.4 2001-01-10
GB0100658A GB2371227A (en) 2001-01-10 2001-01-10 Crystallisation - resistant aqueous growth hormone formulations

Publications (1)

Publication Number Publication Date
WO2002067989A1 true WO2002067989A1 (fr) 2002-09-06

Family

ID=9906597

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/000114 WO2002067989A1 (fr) 2001-01-10 2002-01-08 Preparations d'hormone de croissance aqueuses resistant a la cristallisation

Country Status (2)

Country Link
GB (1) GB2371227A (fr)
WO (1) WO2002067989A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049061A3 (fr) * 2003-11-20 2005-10-20 Novo Nordisk As Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
EP1603588A2 (fr) * 2003-03-18 2005-12-14 Ares Trading S.A. Stabilisation d'hormones de croissance en solution
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
CN112494638A (zh) * 2020-12-22 2021-03-16 深圳科兴药业有限公司 一种人生长激素注射剂组合物及其制备方法
EP3811962A4 (fr) * 2018-06-25 2022-03-16 JCR Pharmaceuticals Co., Ltd. Formulation liquide aqueuse contenant des protéines
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA05000412A (es) * 2002-07-09 2005-07-22 Sandoz Ag Formulacioneks liquidas con una alta concentracion de hormona de crecimiento humana (hgh) que comprenden glicina.
KR101337797B1 (ko) * 2010-07-14 2013-12-06 한미사이언스 주식회사 지속형 인간 성장 호르몬 결합체 액상 제제

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096885A (en) * 1988-04-15 1992-03-17 Genentech, Inc. Human growth hormone formulation
WO1994003198A1 (fr) * 1992-07-31 1994-02-17 Genentech, Inc. Composition aqueuse a base d'hormone de croissance humaine
US5567677A (en) * 1992-04-03 1996-10-22 Pharmacia Ab Protein formulation comprising growth hormone
EP0938902A1 (fr) * 1998-02-04 1999-09-01 Jcr Pharmaceuticals Co., Ltd. Composition pharmaceutique a base d'hormone de croissance humaine
WO2001003741A1 (fr) * 1999-07-12 2001-01-18 Grandis Biotech Gmbh Preparations d'hormones de croissance

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6073386A (en) * 1985-07-30 1987-02-05 International Minerals & Chemical Corporation Stabilization of growth promoting hormones
US5981485A (en) * 1997-07-14 1999-11-09 Genentech, Inc. Human growth hormone aqueous formulation
AUPN801296A0 (en) * 1996-02-12 1996-03-07 Csl Limited Stabilised growth hormone formulation and method of preparation thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096885A (en) * 1988-04-15 1992-03-17 Genentech, Inc. Human growth hormone formulation
US5567677A (en) * 1992-04-03 1996-10-22 Pharmacia Ab Protein formulation comprising growth hormone
WO1994003198A1 (fr) * 1992-07-31 1994-02-17 Genentech, Inc. Composition aqueuse a base d'hormone de croissance humaine
EP0938902A1 (fr) * 1998-02-04 1999-09-01 Jcr Pharmaceuticals Co., Ltd. Composition pharmaceutique a base d'hormone de croissance humaine
WO2001003741A1 (fr) * 1999-07-12 2001-01-18 Grandis Biotech Gmbh Preparations d'hormones de croissance

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
EP1603588A2 (fr) * 2003-03-18 2005-12-14 Ares Trading S.A. Stabilisation d'hormones de croissance en solution
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
EP1687019B1 (fr) 2003-11-20 2017-11-22 Novo Nordisk A/S Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
EP2394656A3 (fr) * 2003-11-20 2012-01-18 Novo Nordisk A/S Formulations de peptide contenant du propylèneglycol qui sont optimales pour la production et l'utilisation dans des dispositifs d'injection
US8114833B2 (en) 2003-11-20 2012-02-14 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
WO2005049061A3 (fr) * 2003-11-20 2005-10-20 Novo Nordisk As Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
US12214017B2 (en) 2017-08-24 2025-02-04 Novo Nordisk A/S GLP-1 compositions and uses thereof
EP3811962A4 (fr) * 2018-06-25 2022-03-16 JCR Pharmaceuticals Co., Ltd. Formulation liquide aqueuse contenant des protéines
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
CN112494638A (zh) * 2020-12-22 2021-03-16 深圳科兴药业有限公司 一种人生长激素注射剂组合物及其制备方法
CN112494638B (zh) * 2020-12-22 2023-12-19 深圳科兴药业有限公司 一种人生长激素注射剂组合物及其制备方法

Also Published As

Publication number Publication date
GB0100658D0 (en) 2001-02-21
GB2371227A (en) 2002-07-24

Similar Documents

Publication Publication Date Title
WO2002067989A1 (fr) Preparations d'hormone de croissance aqueuses resistant a la cristallisation
JP5941496B2 (ja) 成長ホルモン製剤
CN100475267C (zh) 含甘氨酸的高浓度人生长激素液体制剂
WO2008098212A2 (fr) Formulations à libération modifiée de glucagon et d'autres peptides et protéines
EP0938902B1 (fr) Composition pharmaceutique a base d'hormone de croissance humaine
US20070065469A1 (en) Liquid formulations with high concentration of human growth hormone (high) comprising glycine
ZA200200176B (en) Growth hormone formulations.
RU2298415C2 (ru) Композиции, включающие гормон роста
AU2003249991B8 (en) Liquid formulations with a high concentration of human growth hormone (hGH) comprising glycine
AU2007216686A1 (en) Liquid formulations with high concentration of human growth hormone (hGH) comprising phenol
MXPA06006535A (en) Stable growth hormone liquid formulation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LT LU LV MA MD MK MN MX NO NZ OM PH PL PT RO RU SE SG SI SK TJ TM TN TR TT UA US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
WWE Wipo information: entry into national phase

Ref document number: 200402306

Country of ref document: ZA

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP