US20060160739A1 - GRF-containing lyophilized pharmaceutical compositions - Google Patents

GRF-containing lyophilized pharmaceutical compositions Download PDF

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Publication number
US20060160739A1
US20060160739A1 US11/364,079 US36407906A US2006160739A1 US 20060160739 A1 US20060160739 A1 US 20060160739A1 US 36407906 A US36407906 A US 36407906A US 2006160739 A1 US2006160739 A1 US 2006160739A1
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US
United States
Prior art keywords
pharmaceutical composition
composition according
hgrf
saccharose
vial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/364,079
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English (en)
Inventor
Fabrizio Samaritani
Alessandra Del Rio
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Serono SA
Original Assignee
Applied Research Systems ARS Holding NV
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 Applied Research Systems ARS Holding NV filed Critical Applied Research Systems ARS Holding NV
Priority to US11/364,079 priority Critical patent/US20060160739A1/en
Publication of US20060160739A1 publication Critical patent/US20060160739A1/en
Priority to US11/744,073 priority patent/US8431534B2/en
Assigned to LABORATOIRES SERONO SA reassignment LABORATOIRES SERONO SA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: APPLIED RESEARCH SYSTEMS ARS HOLDING N.V.
Abandoned legal-status Critical Current

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Classifications

    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • 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
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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 concerns Growth Hormone Releasing Factor (GRF) containing pharmaceutical compositions. More precisely, it concerns compositions of saccharose-stabilized GRF.
  • GRF Growth Hormone Releasing Factor
  • GEF growth hormone releasing factor
  • GRF also called Somatorelin
  • GRF is a peptide secreted by the hypothalamus, which acts on its receptor and can promote the release of growth hormone (GH) from the anterior pituitary. It exists as 44-, 40-, or 37-amino acid peptide; the 44-amino acid form may be converted physiologically into shorter forms. All three forms are reported to be active, the activity residing mainly in the first 29 amino acid residues.
  • a synthetic peptide corresponding to the 1-29 amino acid sequence of human GRF [hGRF(1-29)], also called Sermorelin, has been prepared by recombinant DNA technology as described in European Patent EP 105 759.
  • Sermorelin has been used in the form of acetate for the diagnosis and treatment of growth hormone deficiency.
  • GRF has indeed a therapeutic value for the treatment of certain growth hormone related disorders.
  • the use of GRF to stimulate the release of GH is a physiological method in promoting long bone growth or protein anabolism.
  • WO 98/53844 describes stable liquid pharmaceutical compositions of hGRF containing nicotinamide and propylene glycol.
  • GRF formulations can be prepared by lyophilization and stabilized by human serum albumin or glycine.
  • JP 3083931 and EP 417 930 describe a GRF-containing nasal preparation which is rendered low-irritating to nasal mucosa by adding sodium chloride and/or sugar alcohols, such as mannitol or sorbitol thereto.
  • compositions In order that materials like hGRF be provided to health care personnel and patients, these materials must be prepared as pharmaceutical compositions. Such compositions must maintain activity for appropriate periods of time, must be acceptable in their own right to easy and rapid administration to humans, and must be readily manufacturable.
  • pharmaceutical formulations are provided in frozen or in lyophilized form. In this case, the composition must be thawed or reconstituted prior to use.
  • the frozen or lyophilized form is often used to maintain biochemical integrity and the bioactivity of the medicinal agent contained in the compositions under a wide variety of storage conditions, as it is recognized by those skilled in the art that lyophilized preparations often maintain activity better than their liquid counterparts.
  • Such lyophilized preparations are reconstituted prior to use by the addition of suitable pharmaceutically acceptable diluent(s), such as sterile water for injection or sterile physiological saline solution, and the like.
  • Human GRF is found on the market in lyophilized formulations stabilized with mannitol GEREF®, Serono.
  • the main object of the present invention is to provide pharmaceutical compositions comprising a solid intimate mixture of human GRF and a stabilizing amount of saccharose.
  • a further object is to provide a process for the preparation of said pharmaceutical composition, comprising the step of lyophilizing an aqueous solution of the components in the containers.
  • Another object is to provide a presentation form of said pharmaceutical composition comprising the said solid mixture hermetically closed in a sterile condition within containers suitable for storage before use and suitable for reconstitution of the mixture for injectable substances.
  • Such containers may be suitable for single dose administration or for multidose administration.
  • Such lyophilized compositions also preferably contain a bacteriostatic agent.
  • the bacteriostatic agent is preferably m-cresol.
  • the lyophilized compositions of the invention may further comprise buffering agents.
  • Any buffer which is appropriate for pharmaceutical preparations may be used, for example acetate, phosphate or citrate.
  • the amount of buffering agent to be added to the preparation will be such that the pH of the lyophilized compositions is kept within the desired range after reconstitution.
  • the desired pH range according to this invention is between 2 and 7, preferably between 4 and 6.
  • Another object is to provide a solution of said solid mixture reconstituted into an injectable solution, such as water for injectable or physiological saline solution. Conveniently such reconstitution is carried out just before use for injection.
  • an injectable solution such as water for injectable or physiological saline solution.
  • saccahrose there is no critical limitation to the amount of saccahrose to be added to the active ingredient, but it will be appropriate to add from 1 to 200 mg/vial, preferably from 20 to 100 mg/vial of saccharose.
  • hGRF is intended to cover any human GRF peptide, with particular reference to the 1-44, 1-40, 1-29 peptides and the corresponding amides thereof (containing —NH 2 at their end) or even a mixture thereof. They are all commercial compounds.
  • the preferred hGRF is hGRF(1-29)-NH 2 .
  • amount of active ingredient present in each vial is preferably comprised between 0.1 and 100 mg/vial.
  • the preparation of the lyophilizate was performed by dissolving the hGRF bulk powder in the solutions containing the stabilizers. The obtained solutions were filtered and filled into glass vials and lyophilized. The study of the stability of such formulations stored at 40° C. and 50° C. for 4 weeks, was performed by determinations of pH and peptide purity.
  • the chromatographic assay methodology to evaluate the purity of hGRF was a gradient elution through a C-18 column, using a mobile phase (TFA/water/acetonitrile) at 1 ml/min and UV detection at 214 nm.
  • the pH was determined by a pHmeter on vials reconstituted with 5 ml of water for injection.
  • Results showed that the formulation containing saccharose presented a better stability profile when compared to the formulations containing mannitol or mannitol/phosphate buffer.
  • the formulations were stored at 5° C., 25° C. and 40° C. and tested for stability using the analytical methods described before (pH, purity and titre by RP).
  • Saccharose (17.1 g) are dissolved into water for injectables (500 ml) in order to obtain the starting saccharose solution.
  • the bulk of the hGRF 2 g) is added to the saccharose solution so as to obtain a final weight of 400 g the solution is filtered through a 0.22 ⁇ m Durapore sterile filter (Millipore).
  • the vials are filled up with 0.6 and 2 ml of hGRF sterile solution, transferred to the freeze-dryer and lyophilized according to the following cycle:

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (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)
US11/364,079 1999-06-30 2006-03-01 GRF-containing lyophilized pharmaceutical compositions Abandoned US20060160739A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/364,079 US20060160739A1 (en) 1999-06-30 2006-03-01 GRF-containing lyophilized pharmaceutical compositions
US11/744,073 US8431534B2 (en) 1999-06-30 2007-05-03 GRF-containing lyophilized pharmaceutical compositions

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP99112421A EP1064934A1 (fr) 1999-06-30 1999-06-30 Compositions lyophilisées contenant du GRF
EP99112421.5 1999-06-30
PCT/EP2000/006061 WO2001001965A1 (fr) 1999-06-30 2000-06-29 Compositions pharmaceutiques lyophilisees a base de facteur de regulation de la croissance
US938002A 2002-04-01 2002-04-01
US11/364,079 US20060160739A1 (en) 1999-06-30 2006-03-01 GRF-containing lyophilized pharmaceutical compositions

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
PCT/EP2000/006061 Continuation WO2001001965A1 (fr) 1999-06-30 2000-06-29 Compositions pharmaceutiques lyophilisees a base de facteur de regulation de la croissance
US10009380 Continuation 2000-06-29
US938002A Continuation 1999-06-30 2002-04-01

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/744,073 Continuation US8431534B2 (en) 1999-06-30 2007-05-03 GRF-containing lyophilized pharmaceutical compositions

Publications (1)

Publication Number Publication Date
US20060160739A1 true US20060160739A1 (en) 2006-07-20

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Family Applications (2)

Application Number Title Priority Date Filing Date
US11/364,079 Abandoned US20060160739A1 (en) 1999-06-30 2006-03-01 GRF-containing lyophilized pharmaceutical compositions
US11/744,073 Expired - Fee Related US8431534B2 (en) 1999-06-30 2007-05-03 GRF-containing lyophilized pharmaceutical compositions

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/744,073 Expired - Fee Related US8431534B2 (en) 1999-06-30 2007-05-03 GRF-containing lyophilized pharmaceutical compositions

Country Status (14)

Country Link
US (2) US20060160739A1 (fr)
EP (2) EP1064934A1 (fr)
JP (1) JP4880845B2 (fr)
AR (1) AR024613A1 (fr)
AT (1) ATE249207T1 (fr)
AU (1) AU778208C (fr)
CA (1) CA2374933C (fr)
DE (1) DE60005188T2 (fr)
DK (1) DK1189600T3 (fr)
ES (1) ES2204661T3 (fr)
IL (2) IL147413A0 (fr)
PT (1) PT1189600E (fr)
SI (1) SI1189600T1 (fr)
WO (1) WO2001001965A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080249017A1 (en) * 2007-04-04 2008-10-09 Theratechnologies Inc. Pharmaceutical formulations of ghrh molecules
US20090023646A1 (en) * 2002-09-18 2009-01-22 Centre Hospitalier De L'universite De Montreal (Chum) GHRH analogues
US20100222607A1 (en) * 2007-09-07 2010-09-02 The Nisshin Oillio Group, Ltd. Fractionation method of 1,3-disaturated-2-unsaturated triglyceride

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1301200A2 (fr) * 2000-05-19 2003-04-16 Bionebraska, Inc. Preparations pharmaceutiques peptidiques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963529A (en) * 1984-12-24 1990-10-16 Sumitomo Pharmaceuticals Company, Limited Stable growth hormone releasing factor preparation
US5017557A (en) * 1987-07-24 1991-05-21 Industria Farmaceutica Serono S.P.A. Treatment of infertility with somatotrophin releasing factor
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US5863549A (en) * 1992-10-14 1999-01-26 Hoffmann-La Roche Inc. Methods for the sustained release of biologically active compounds
US6284282B1 (en) * 1998-04-29 2001-09-04 Genentech, Inc. Method of spray freeze drying proteins for pharmaceutical administration

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5822445B2 (ja) * 1982-07-08 1983-05-09 株式会社 ミドリ十字 安定な固体の人血漿コリンエステラ−ゼ製剤の製法
JPH0725696B2 (ja) * 1986-05-29 1995-03-22 株式会社ミドリ十字 プラスミノ−ゲンの安定化方法
US4880777A (en) * 1987-09-01 1989-11-14 Eastman Kodak Company Synthetic peptides having growth hormone releasing activity
AU634529B2 (en) * 1989-03-17 1993-02-25 Pitman-Moore, Inc. Controlled release delivery device for macromolecular proteins
JPH0383931A (ja) 1989-08-29 1991-04-09 Sumitomo Pharmaceut Co Ltd 低刺激性ｇｒｆ経鼻投与製剤
US5132401A (en) * 1989-09-19 1992-07-21 George Washington University, Office Of Sponsored Research MB-35 a peptide enhancing the production of growth hormone and prolactin from the anterior pituitary
JPH04264020A (ja) * 1991-02-18 1992-09-18 Yamanouchi Pharmaceut Co Ltd 安定な凍結乾燥製剤
EP0580778B1 (fr) * 1991-04-19 1999-08-11 LDS Technologies, Inc. Formulations de microemulsions a inversion de phase
JP3140797B2 (ja) * 1991-04-26 2001-03-05 生化学工業株式会社 安定化コンドロイチナーゼａｂｃ、その保存方法及び治療剤
YU87892A (sh) * 1991-10-01 1995-12-04 Eli Lilly And Company Lilly Corporate Center Injektibilne formulacije produženog otpuštanja i postupci za njihovo dobijanje i primenu
JP3083931B2 (ja) 1993-02-24 2000-09-04 大阪瓦斯株式会社 吸収式冷凍機の故障診断システム
IS1796B (is) 1993-06-24 2001-12-31 Ab Astra Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband
WO1995035116A1 (fr) 1994-06-17 1995-12-28 Applied Research Systems Compositions pharmaceutiques renfermant l'hch
US6524557B1 (en) * 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
BR9609743A (pt) * 1995-07-27 1999-03-02 Genentech Inc Formulação reconstituída estável método para a preparação de uma formulação artigo manufaturado e uso da formação
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
EP0880969A1 (fr) * 1997-05-28 1998-12-02 Applied Research Systems ARS Holdings N.V. Compositions pharmaceutiques de peptides de faible solubilité dans un milieu physioloqique
US6759393B1 (en) * 1999-04-12 2004-07-06 Pfizer Inc. Growth hormone and growth hormone releasing hormone compositions
JP4330280B2 (ja) 2001-01-12 2009-09-16 株式会社小松製作所 エンジンの燃料噴射制御方法及びその制御装置

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US4963529A (en) * 1984-12-24 1990-10-16 Sumitomo Pharmaceuticals Company, Limited Stable growth hormone releasing factor preparation
US5017557A (en) * 1987-07-24 1991-05-21 Industria Farmaceutica Serono S.P.A. Treatment of infertility with somatotrophin releasing factor
US5863549A (en) * 1992-10-14 1999-01-26 Hoffmann-La Roche Inc. Methods for the sustained release of biologically active compounds
US6284282B1 (en) * 1998-04-29 2001-09-04 Genentech, Inc. Method of spray freeze drying proteins for pharmaceutical administration

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090023646A1 (en) * 2002-09-18 2009-01-22 Centre Hospitalier De L'universite De Montreal (Chum) GHRH analogues
US20080249017A1 (en) * 2007-04-04 2008-10-09 Theratechnologies Inc. Pharmaceutical formulations of ghrh molecules
US20100222607A1 (en) * 2007-09-07 2010-09-02 The Nisshin Oillio Group, Ltd. Fractionation method of 1,3-disaturated-2-unsaturated triglyceride

Also Published As

Publication number Publication date
CA2374933C (fr) 2010-10-12
IL147413A0 (en) 2002-08-14
DE60005188T2 (de) 2004-04-01
DE60005188D1 (de) 2003-10-16
SI1189600T1 (en) 2003-12-31
AU778208C (en) 2006-03-09
AU778208B2 (en) 2004-11-25
WO2001001965A1 (fr) 2001-01-11
JP4880845B2 (ja) 2012-02-22
ATE249207T1 (de) 2003-09-15
AU6266300A (en) 2001-01-22
AR024613A1 (es) 2002-10-16
CA2374933A1 (fr) 2001-01-11
JP2003503443A (ja) 2003-01-28
DK1189600T3 (da) 2004-01-26
US20070203069A1 (en) 2007-08-30
US8431534B2 (en) 2013-04-30
IL147413A (en) 2006-10-31
ES2204661T3 (es) 2004-05-01
PT1189600E (pt) 2003-12-31
EP1064934A1 (fr) 2001-01-03
EP1189600B1 (fr) 2003-09-10
EP1189600A1 (fr) 2002-03-27

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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:APPLIED RESEARCH SYSTEMS ARS HOLDING N.V.;REEL/FRAME:019808/0379