WO1997002833A1 - Formulation pharmaceutique stabilisee comportant une hormone de croissance et un peptide contenant au moins un reste d'acide amine basique et au moins un reste d'acide amine acide - Google Patents

Formulation pharmaceutique stabilisee comportant une hormone de croissance et un peptide contenant au moins un reste d'acide amine basique et au moins un reste d'acide amine acide Download PDF

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Publication number
WO1997002833A1
WO1997002833A1 PCT/DK1996/000290 DK9600290W WO9702833A1 WO 1997002833 A1 WO1997002833 A1 WO 1997002833A1 DK 9600290 W DK9600290 W DK 9600290W WO 9702833 A1 WO9702833 A1 WO 9702833A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
growth hormone
acid residue
formulation
peptide
Prior art date
Application number
PCT/DK1996/000290
Other languages
English (en)
Inventor
Thorkild Christensen
Per Balschmidt
Hans Holmegaard Soerensen
Ole Hvilsted Olsen
Lars Thim
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP9505422A priority Critical patent/JPH11510483A/ja
Priority to EP96922774A priority patent/EP0837690A1/fr
Priority to AU63533/96A priority patent/AU699850B2/en
Priority to BR9609573A priority patent/BR9609573A/pt
Publication of WO1997002833A1 publication Critical patent/WO1997002833A1/fr
Priority to MXPA/A/1998/000309A priority patent/MXPA98000309A/xx
Priority to NO980103A priority patent/NO980103L/no

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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
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a stabilized pharmaceutical formulation comprising growth hormone, to a method of making such formulation, to the use of a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue for stabilizing a formulation of growth hormone, and to a method for treating a disorder affectable by growth hormone.
  • the growth hormones from man and from the common domestic ani ⁇ mals are proteins of approximately 191 amino acids, synthesized and secreted from the anterior lope of the pituitary gland. Human growth hormone consists of 191 amino acids.
  • Growth hormone is a key hormone involved in the regulation of not only somatic growth, but also in the regulation of metabo ⁇ lism of proteins, carbohydrates and lipids. The major effect of growth hormone is to promote growth.
  • the organ systems affected by growth hormone include the ske ⁇ leton, connective tissue, muscles, and viscera such as liver, intestine, and kidneys.
  • human growth hormone could only be obtained by extraction from the pituitary glands of human cadavers.
  • the very limited supplies of growth hormone restricted the use thereof to longitudinal growth promotion in childhood and puberty for treatment of dwarfism, even though it has been proposed for inter alia treatment of short stature (due to growth hormone deficiency, normal short stature and Turner syndrome) , growth hormone deficiency in adults, infertility, treatment of burns, wound healing, dystrophy, bone knitting, osteoporosis, diffuse gastric bleeding, and pseudoarthrosis.
  • growth hormone has been proposed for increasing the rate of growth of domestic animals or for decreasing the proportion of fat in animals to be slaughtered for human con ⁇ sumption.
  • compositions of growth hormone tend to be un ⁇ stable.
  • Degradation products such as deamidated or sulfoxydated products and dimer or polymer forms are generated - especially in solutions of growth hormone.
  • the predominant degradation reactions of hGH are 1) deamidation by direct hydrolysis or via a cyclic succinimide intermediate to form various amounts of L-asp-hGH, L-iso-asp-hGH, D-asp-hGH, and D-iso-asp-hGH (ref 1-3), and 2) oxidation of the methionine residues in positions 14 and 125 (ref 4-9) .
  • the major degradation product of hGH in lyophilized state as well as in solution is deamidated hGH.
  • Deamidation especially takes place at the Asn in position 149 and to a minor extent in position 152.
  • hGH is also rather easily oxidized in positions 14 and 125, especially in solution (4-8) .
  • the oxidation of hGH in solution forming sulfoxides is normally due to the oxygen dissolved in the formulation.
  • the solubility of oxygen in distilled water is about 200 ⁇ M (9) .
  • concentration of hGH in a formulation comprising 4 IU/ml is 1.3 mg/ml corresponding to 60nM hGH, oxygen will, at normal storing conditions, be present in an excess of about 3000 times the stoichiometric amount for oxidation of hGH. It is not feasible to try to solve the problem by degassing of buffers before tapping and packing the formulations.
  • the kinetics of degradation depend on temperature, pH and various additives or adjuvants in the hGH formulation.
  • growth hormone is, at present, lyophi ⁇ lized and stored in the lyophilized form at 4°C until it is reconstituted for use in order to minimize the degradation.
  • the lyophilized pharmaceutical formulations comprising hGH are, at present, reconstituted by the patient and then stored as a solution during the use for a period of up to 14 days at 4°C, during which some degradation will take place.
  • the process of reconstitution of the lyophilized growth hormone tends to provide difficulties for the patient.
  • the chain from the manufacturer to the pharmacy is apt for handling the formula- tions at a controlled low temperature of e.g. 4°C which allows for a long shelf life of up to two years.
  • the extended use of pen systems for self-medication and the expanded field of use calls for a formulation which is stable for a sufficient long time with the end user under conditions where "sufficient" cooling is not always available..
  • a formulation should be stable in a lyophilized state for about one month with the end user and additionally for one month in a reconstituted state in a pen device for the intended period of use of a cartridge.
  • the shift in pattern of administration of growth hormone to the use of pen devices calls for a stable dissolved formulation comprising growth hormone in order to facilitate the handling to be performed by the patient.
  • a stable dissolved formulation comprising growth hormone may be produced ready to use in the form of cartridges fitting into the pen device used by the patient who may then avoid the reconstitution of the formulation and, hence, will not have to be in the possession of a lyophilized formulation, a suitable vehicle for reconstitution as well as the necessary skill and sterile equipment for sterile reconstitution of the formulation.
  • Lyophiiization is a time consuming and costly process and is also often a "bottleneck" in the production due to the limited capacity of the freeze drier.
  • animal growth hormone may be stabilized with various stabilizers to give decreased formation of insolubles and preservation of the soluble activity in aqueous environments, such stabilizers including certain polyols, amino acids, polymers of amino acids having a charged side group at physi- ological pH, and choline salts.
  • Polyols are selected from the group consisting of non-reducing sugars, sugar alcohols, sugar acids, pentaerythritol, lactose, water-soluble dextrans and Fi ⁇ coll; amino acids are selected from the group consisting of glycine, sarcosine, lysine or salts thereof, serine, arginine or salts thereof, betaine, N,N,-dimethyl-glycine, aspartic acid or salts thereof, glutamic acid or salts thereof; a polymer of an amino acid having a charged side group at physiological pH may be selected from polylysine, polyaspartic acid, polyglutamic acid, polyarginine, polyhistidine, polyornithine and salts thereof; and choline derivatives are selected from the group consisting of choline chloride, choline dihydrogen citrate, choline bitartrate, choline bicarbonate, tricholine citrate, choline ascorbate, choline borate, choline
  • US patent specification No. 4,917,685 discloses a delivery device designed to be implanted comprising growth hormone stabilized using the same stabilizers as mentioned in EP 303746.
  • WO 93/19776 discloses protein formulations comprising growth hormone comprising citrate as buffer substance being more stable than formulations comprising phosphate buffer.
  • the formulations may also comprise amino acids such as glycine and alanine and/or mannitol or other sugar alcohols and/or glycerol and/or other carbohydrates and optionally a preservative such as benzyl alcohol.
  • WO 94/03198 discloses a stable aqueous formulation containing human growth hormone, a buffer, a non-ionic surfactant, and, optionally, a neutral salt, mannitol, or, a preservative.
  • a formulation of human growth hormone comprising a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue as additive shows a very high stability against dea ⁇ midation and oxidation.
  • the stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved formulation.
  • the peptide comprising at least one basic amino acid residue and at least one acid amino acid residue to be used in accordance with the present invention may be a peptide com- prising up to from 10 to 20 amino acid residues, preferably from 3 to 10 amino acid residues, more preferred from 3 to 6 amino acid residues such as 3 or 4 amino acid residues.
  • the basic and acid amino residues of shorter peptides are separated by 1 or 2 amino acid residues.
  • the pharmaceutical formulations of the . invention may be formulated for administration in any suitable way, e.g. by parenteral or oral administration or administration to a mucosal membrane, e.g. nasal administration.
  • the pharmaceutical formulation may be presented in the form of a dose comprised in a vial or cartridge or any other suitable container such as a prefilled syringe or a pen device.
  • the formulation of the invention may be in the form of a lyophilized powder to be reconstituted later using conventional vehicles such as distilled water or water for injection or in the form of a solution comprising growth hormone.
  • vehicles such as distilled water or water for injection or in the form of a solution comprising growth hormone.
  • vehicles may comprise conventional preservatives such as benzyl alcohol and phenoles, e.g. phenol or m-cresol or a mixture hereof.
  • a preferred embodiment of the invention is in the form of a pharmaceutical formulation of human growth hormone comprising a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue and further comprising a carrier in the form of a buffered aqueous solution of growth hormone.
  • Such formulation is in a ready-to-use form and may be stored and shipped as an aqueous solution without any consi ⁇ derable degradation.
  • a buffer to be used in a solution of growth hormone may e.g. be histidine, citrate, tartrate or phosphate buffer.
  • the pH of a solution is preferably ad ⁇ justed to a value in the interval from about 2 to about 8, preferably from about 5 to about 7, more preferred from about 6.0 to about 7.0, even more preferred from about 6.0 to about 6.8.
  • a peptide comprising at least one basic amino acid residue and. at least one acid amino acid residue is preferably added in an amount of up to 100 mM, more preferred in an amount of about 1-10 mM, preferably about 2-6 mM, most preferred about 3-5 mM.
  • the pharmaceutical formulation of the invention may furthermore comprise salts for adjusting the tonicity and optionally an excipient in order to facilitate the processing thereof, e.g. lyophiiization and the rapid and complete dissolution of a lyophilized formulation when reconstituting the formulation before use.
  • An excipient may be selected from disaccharides such as lactose trehalose, and sucrose, sugar alcohols such as sorbitol or man ⁇ nitol, polysaccharides such as the polymers commercialized as Dextran® products such as Dextran® 40, Dextran® 70 or Dextran®
  • Ficoll® and polyvalent alcohols such as polyethylene glycol or polyvinyl alcohol or a combination of two or more of these.
  • the invention relates to a method of pre-
  • 20 one acid amino acid residue by dissolving a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue in deionized water optionally containing of benzyl alcohol, adding the growth hormone and optionally adjusting the pH to from about 2 to about 8.
  • the pH may be adjusted by adding an acid which has no adverse effect on the growth hormone, preferably a physiologically acceptable acid e.g. a mineral acid such as hydrochloric acid, sulphuric acid or nitric acid or an organic acid such as acetic
  • Still another aspect of the invention relates to the use of a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue for the formulation of a stabilized formulation of growth hormone.
  • the invention relates to a method for treating a disorder affectable by growth hormone comprising administering a formulation which comprises a growth hormone and a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue.
  • growth hormone may be growth hormone from any origin such as avian, bovine, equine, human, ovine, porcine, salmon, trout or tuna growth hormone, preferably bovine, human or porcine growth hormone, human growth hormone being most preferred.
  • the growth hormone used in accordance with the invention may be native growth hormone isolated from a natural source, e.g. by extracting pituitary glands in a conventional manner, or a growth hormone produced by recombi- nant techniques, e.g as described in E.B. Jensen and S. Carlsen in Biotech and Bioeng. 3_6, 1-11 (1990) .
  • the "growth hormone” may also be a truncated form of growth hormone wherein one or more amino acid residues has (have) been deleted; an analogue thereof wherein one or more amino acid residues in the native molecule has (have) been substituted by another amino acid residue, preferably a natural amino acid residue, as long as the substitution does not have any adverse effect such as antigenicity or reduced action; or a derivative thereof, e.g having an N- or C-terminal extension such as Met-hGH.
  • the preferred growth hormone is hGH.
  • dose of growth hormone refers to . that amount that provides therapeutic effect in an administration regimen.
  • the formulations hereof are prepared containing amounts of hGH at least about 0.1 mg/ml, preferably upwards of about 10 mg/ml, preferably from about 1 mg/ml to about 40 mg/ml, more prefer- preferably from about 1 mg/ml to about 40 mg/ml, more prefer ⁇ ably from about 1 mg/ml to about 25 mg/ml, e.g. from 1 mg/ml to about 5 mg/ml, calculated on the ready-to-use formulation.
  • these formulations For use of these compositions in administration to human beings suffering from hypopituitary dwarfism, for example, these formulations contain from about 0.1 mg/ml to about 10 mg/ml, corresponding to the currently contemplated dosage regimen for the intended treatment.
  • concentration range is not critical to the invention and may be varied by the physician supervising the administration.
  • a peptide comprising at least one basic amino acid residue and at least one acid amino acid residue to be used in accordance with the present invention is preferably comprising the nat- urally occurring alpha amino acid residues.
  • the amino acid(s) may be 1 or d amino acid(s) or a mixture thereof.
  • Acid amino acid residues are e.g. Glu or Asp
  • basic amino acid residues are e.g. Lys or Arg.
  • high stability is obtained when the formulation is more stable than the conventional formulation comprising phosphate buffer and preferably as stable as a corresponding formulation comprising histidine as stabilizer in which the deamidation of hGH is reduced by approximately 20% as compared with phosphate buffer as disclosed in WO 93/12812.
  • the solvent used in the method of the invention may be water, alcohols such as ethyl, n-propyl or isopropyl, butyl alcohol or mixtures thereof.
  • the solvent may comprise a preservative such as benzyl alcohol and phenoles, e.g. phenol or m-cresol or a mixture hereof.
  • the rate of deamidation was examined at 37°C for hGH formula ⁇ tions comprising 4 mg/ml hGH at pH 6.8 in the presence of 5 mM peptide comprising at least one basic amino acid residue and at least one acid amino acid residue (Lys-Gly-Asp-Ser) as compared to histidine at pH 6.8.
  • the hGH formulations were prepared by dissolving 8 mg hGH in 2 ml of 10 mM solution of Lys-Gly-Asp-Ser or histidine. Thus, 2 ml 3.0% of benzyl alcohol was added to give a final formulation of 4 mg/ml hGH, 5 mM Lys-Gly-Asp-Ser or histidine, 1.5% benzyl alcohol, pH 6.8 (adjusted adding HCl or NaOH) .
  • the above results show that the rate of deamidation is reduced to a very great extent by adding Lys-Gly-Asp-Ser in a low con ⁇ centration of up to 100 mM, preferably 1-10 mM, more preferred 2-6 mM and most preferred about 3-5 mM.
  • the rate of deamidation may thus be reduced by more than 30% by substituting the phosphate buffer with Lys-Gly-Asp-Ser.

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Abstract

Formulation pharmaceutique comportant une hormone de croissance et un peptide contenant au moins un reste d'acide aminé basique et au moins un reste d'acide aminé acide en tant qu'additif ou substance de tamponnage, qui possède une stabilité très élevée contre la déamidation, l'oxydation et le clivage des liaison peptidiques. La stabilité du produit en permet le stockage et le transport sous forme lyophilisée ou sous forme d'une formulation dissoute ou redissoute à température ambiante.
PCT/DK1996/000290 1995-07-12 1996-06-28 Formulation pharmaceutique stabilisee comportant une hormone de croissance et un peptide contenant au moins un reste d'acide amine basique et au moins un reste d'acide amine acide WO1997002833A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP9505422A JPH11510483A (ja) 1995-07-12 1996-06-28 成長ホルモン並びに少なくとも１個の塩基性アミノ酸残基及び少なくとも１個の酸性アミノ酸残基を含むペプチドを含む、安定化された医薬製剤
EP96922774A EP0837690A1 (fr) 1995-07-12 1996-06-28 Formulation pharmaceutique stabilisee comportant une hormone de croissance et un peptide contenant au moins un reste d'acide amine basique et au moins un reste d'acide amine acide
AU63533/96A AU699850B2 (en) 1995-07-12 1996-06-28 A stabilized pharmaceutical formulation comprising a growth hormone and a peptide comprising at least, one basic amino acid residue and at least one acid amino acid residue
BR9609573A BR9609573A (pt) 1995-07-12 1996-06-28 Formulação farmacêutica processo para sua preparaç o uso de um peptídeo e processo para o tratamento de distúrbios afetáveis pelo hormônio de crescimento
MXPA/A/1998/000309A MXPA98000309A (en) 1995-07-12 1998-01-09 Stabilized pharmaceutical formulation comprising a hormone of growth and a peptide that comprises at least one residue of basic amino acid and at least one waste of aminoacido ac
NO980103A NO980103L (no) 1995-07-12 1998-01-09 Stabilisert farmasöytisk preparat som omfatter et veksthormon og et peptid omfattende minst én basisk aminosyrerest og minst én sur aminosyrerest

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US88195P 1995-07-12 1995-07-12
US60/000,881 1995-07-12

Publications (1)

Publication Number Publication Date
WO1997002833A1 true WO1997002833A1 (fr) 1997-01-30

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Application Number Title Priority Date Filing Date
PCT/DK1996/000290 WO1997002833A1 (fr) 1995-07-12 1996-06-28 Formulation pharmaceutique stabilisee comportant une hormone de croissance et un peptide contenant au moins un reste d'acide amine basique et au moins un reste d'acide amine acide

Country Status (14)

Country Link
EP (1) EP0837690A1 (fr)
JP (1) JPH11510483A (fr)
KR (1) KR19990028908A (fr)
CN (1) CN1190896A (fr)
AU (1) AU699850B2 (fr)
BR (1) BR9609573A (fr)
CA (1) CA2226553A1 (fr)
CZ (1) CZ6198A3 (fr)
HU (1) HUP9802286A3 (fr)
IL (1) IL122519A0 (fr)
NO (1) NO980103L (fr)
PL (1) PL324386A1 (fr)
WO (1) WO1997002833A1 (fr)
ZA (1) ZA965367B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6566329B1 (en) 1999-06-28 2003-05-20 Novo Nordisk A/S Freeze-dried preparation of human growth hormone
US6569406B2 (en) 2000-08-07 2003-05-27 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
WO2004052403A1 (fr) * 2002-12-11 2004-06-24 Santen Pharmaceutical Co., Ltd. Conservateur pour l'ophtalmologie
CN103751769A (zh) * 2013-12-25 2014-04-30 楼秀余 一种冻干重组人生长激素胶囊及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100236393B1 (ko) * 1996-02-02 1999-12-15 나까니시 히로유끼 사람성장호르몬을 함유하는 의약제제

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
WO1993012812A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comportant une somatotrophine et de l'histidine
WO1993012811A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comprenant une hormone de croissance et de l'asparagine
WO1996021460A1 (fr) * 1995-01-13 1996-07-18 Novo Nordisk A/S Formulation pharmaceutique stabilisee comprenant une hormone de croissance et lys-x

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
WO1993012812A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comportant une somatotrophine et de l'histidine
WO1993012811A1 (fr) * 1991-12-20 1993-07-08 Novo Nordisk A/S Formulation pharmaceutique stabilisee comprenant une hormone de croissance et de l'asparagine
WO1996021460A1 (fr) * 1995-01-13 1996-07-18 Novo Nordisk A/S Formulation pharmaceutique stabilisee comprenant une hormone de croissance et lys-x

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6566329B1 (en) 1999-06-28 2003-05-20 Novo Nordisk A/S Freeze-dried preparation of human growth hormone
US6569406B2 (en) 2000-08-07 2003-05-27 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
US6838075B2 (en) 2000-08-07 2005-01-04 Nektar Therapeutics Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation
WO2004052403A1 (fr) * 2002-12-11 2004-06-24 Santen Pharmaceutical Co., Ltd. Conservateur pour l'ophtalmologie
CN103751769A (zh) * 2013-12-25 2014-04-30 楼秀余 一种冻干重组人生长激素胶囊及其制备方法

Also Published As

Publication number Publication date
EP0837690A1 (fr) 1998-04-29
HUP9802286A3 (en) 1999-06-28
CZ6198A3 (cs) 1998-06-17
AU6353396A (en) 1997-02-10
AU699850B2 (en) 1998-12-17
ZA965367B (en) 1997-01-23
NO980103D0 (no) 1998-01-09
PL324386A1 (en) 1998-05-25
MX9800309A (es) 1998-07-31
NO980103L (no) 1998-01-09
IL122519A0 (en) 1998-06-15
HUP9802286A2 (hu) 1999-02-01
CN1190896A (zh) 1998-08-19
CA2226553A1 (fr) 1997-01-30
BR9609573A (pt) 1999-03-02
JPH11510483A (ja) 1999-09-14
KR19990028908A (ko) 1999-04-15

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