AP983A - Freeze-dried composition of bone morphogenetic protein human MP52. - Google Patents

Freeze-dried composition of bone morphogenetic protein human MP52. Download PDF

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Publication number
AP983A
AP983A APAP/P/1999/001602A AP9901602A AP983A AP 983 A AP983 A AP 983A AP 9901602 A AP9901602 A AP 9901602A AP 983 A AP983 A AP 983A
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Prior art keywords
bone morphogenetic
morphogenetic factor
factor human
mannitol
composition
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APAP/P/1999/001602A
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AP9901602A0 (en
Inventor
Hideki Ichikawa
Mitsuko Inagaki
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Biopharm Gmbh
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Publication of AP9901602A0 publication Critical patent/AP9901602A0/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18Growth factors; Growth regulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18Growth factors; Growth regulators
    • A61K38/1875Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

By mixing bone morphogenetic factor human MP52 with mannitol at a weight ratio of 1 : 5-50, followed by lyophilization, a stable lyophilized composition of bone morphogenetic factor human MP52 is obtained which prevents coloring and atrophy of the lyophilized product of bone morphogenetic factor human MP52 during storage and also prevents cohesion at the time of reconstitution.

Description

LYOPHILIZED COMPOSITION OF
BONE MORPHOGENETIC FACTOR HUMAN MP52
FIELD OF THE INVENTION
The present invention relates to a lyophilized composition of bone morphogenetic factor human MP52 and a preparation process therefor. More specifically, this invention pertains to a lyophilized composition which contains bone morphogenetic factor human MP52 and mannitol and a preparation process therefor.
BACKGROUND OF THE INVENTION
The cDNA of bone morphogenetic factor human MP52 was isolated for the first time in 1994 as an osteogenesis-related factor classified as aTGF-β superfamily (Biochem. Biophy. Res. Comm., Vol. 204, No. 2, 1994).Then, an advanced genetic engineering technology has made it possible to prepare bone morphogenetic factor human MP52 without impairing its bone morphogenetic activity (WO96/33215). Bone morphogenetic factor human MP52 is stored under a lyophilized condition. It is , however, accompanied with a drawback that a volume reduction (shrink) occurs during storage and cohesion of powders occurs at the time of reconstitution.
With a view to overcoming the above-described problems, amino acids, saccharides or polyhydric alcohols are used for BMP-2 which is a protein classified as the same TGF-β superfamily and has properties closest to bone morphogenetic factor
AP/P/ 9 9 / 0 1 6 0 2
- 1AP 00983 human MP52 (JP-A No. HEI 6-508777). The present inventors, therefore, attempted the application of such additives to bone morphogenetic factor human MP52 but could not overcome the above problems. Described specifically, cohesion at the time of reconstitution was observed even if a neutral or basic amino acid such as alanine, valine or lysine was added to bone morphogenetic factor human MP52 in an amount of 0.5 to 2.5% prior to lyophilization. When a saccharide such as sucrose or dextran was added in an amount of 0.5 to 1%, followed by lyophilization, color development to pale yellowish green and shrink were observed from the lyophilized product. When a polyhydric alcohol such as sorbitol was added in an amount of 0.5 to 1%, followed by lyophilization, bone morphogenetic factor human MP52 was dissolved in the period of lyophilization , which made it
99/01602 impossible to prepare a lyophilized product.
THE INVENTION
DISCLOSURE OF
The present inventors have proceeded with an extensive investigation with a view to overcoming the above-described problems. As a result, it has been found that when mannitol is added to bone morphogenetic factor human MP52, followed by lyophilization, neither coloring or shrink is observed during the storage of the lyophilized product and cohesion does not occur at the time of reconstitution, leading to the completion of the present invention.
The present invention, therefore, provides a lyophilized
- 2 AP 00983 composition of bone morphogenetic factor human MP52 containing bone morphogenetic factor human MP52 and mannitol. As bone morphogenetic factor human MP52 in the present invention, bone morphogenetic factor human MP52 (which may hereinafter be called rhMP52 ) which has been prepared by genetic engineering technology disclosed in WO96/33215 is preferably used. As mannitol, that prescribed as D-mannitol in the Japanese Pharmacopoeia is preferably used. Bone morphogenetic factor human MP52 and mannitol are preferably mixed at a weight ratio of 1 : 5 - 50.
The composition according to the present invention can be prepared by lyophilizing an aqueous mixture solution of bone morphogenetic factor human MP52 and mannitol by a conventional method. Described specifically, the composition of the present invention is available by adding a predetermined amount of mannitol to an aqueous solution of purified bone morphogenetic factor human MP52, mixing them, filtering the resulting aqueous mixture solution, filling the filtrate in a sterile vial and carrying out lyophilization.
The composition of the present invention is administered to a patient in an amount effective for therapeutic treatment after being dissolved in distilled water for injection or weak acid (about pH 3), for example, a hydrochloric acid solution or citric acid buffer, upon use.
The preferred amount of mannitol incorporated in the composition of'the present invention was determined by a stability test. The stability test was conducted in accordance
ΑΡ/Γ7 9 9 / 0 1 6 0 2
AP 00983 with the method described in the instruction for the standard operation procedure prepared based on the Japanese Pharmacopoeia XIII, where properties such as appearance and clarity of solution, electrophoresis and water content at the beginning time of the test and 3 months later and ectopic hone formation after 6 months were observed or measured.
As a result, no change in the properties such as appearance and clarity of solution were observed at the beginning time of the test and 3 months later. From the results of the measurement on the electrophoresis and water content, the preparation containing mannitol at the above-described weight ratio was stable both at the beginning time of the test and months later.
It is said that the preferred water content of a lyophilized product is generally 2% or lower. It was judged from the above findings that a bone morphogenetic factor human MP52 composition containing mannitol in an amount of 5 to 50 mg, desirably 10 mg, per 1 mg of bone morphogenetic factor human MP52 is preferred as a pharmaceutical product.
In addition, the ectopic bone formation of each of lyophilized compositions of bone morphogenetic factor human MP52 containing 10, 25 and 50 mg of mannitol, respectively was measured after stored for 6 months. As a result, ectopic hone formation was observed from any composition regardless of the storage temperature or amount of mannitol. Based on the above-described test results, it has been confirmed that the addition of mannitol to bone morphogenetic factor human MP52
AP/P/ 9 9 / 0 1 6 0 2
- 4AP 00983 prior to lyophilization does not have adverse effects on the bone morphogenetic factor human MP52 and the resulting composition remains stable for a long period of time.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will hereinafter be described more specifically by the following examples.
Example 1 Preparation of an rhMP52 composition
To 1 mg/ml of an aqueous solution of purified rhMP52, which had been obtained by the preparation process disclosed in WO96/33215, D-mannitol of the Japanese Pharmacopoeia was added in an amount of 10, 25 and 50 mg, respectively, and they were mixed. After the resulting mixture was filtered through a 0.22 pm membrane filter, 1 ml portions of the filtrate so obtained were filled in vials sterilely. They were lyophilized, whereby a composition of the pre s ent invent ion was - pr epar ed in the form of pharmaceutical product.
Example 2 Stability test of the rhMP52 composition
The rhMP52 lyophilized composition obtained in Example 1 was filled in a vial bottle (air-tight, transparent) and was stored at 2 - 8° C, 25° C and 40° C, respectively. The stability was evaluated based on the following criteria after threemonth storage. The criteria for evaluation are as follows:
Properties :
(Appearance) : The composition, which remained in the form of a white cake and was not colored was judged as not changed.
(Clarity of solution): A solution having the composition
AP/P/ 9 9 / 0 1 6 0 2
- 5 AP 00983 dissolved in 1 ml of distilled water for injection was judged as not changed when it was colorless, transparent and cohesion-free.
(Electrophoresis) : A purity of a main band was calculated from an area percentage, after introducing a picture by a film scanner which adopts transmission using a red film and then finding an integration optical density (IOD) % of each band.
(Water content) : The water content of the composition was measured by a micro-moisture meter.
As a result, concerning properties, the composition of the present invention remained unchanged in appearance and clarity of solution, whereas cohesion was observed in a lyophilized product of rhMP52 alone. As a result of electrophoresis, each composition showed good stability (%).
The measurement results.of water content (%) are shown in Table 1 which shows that there is not a large change in the water content (%) among the compositions. Table 1 shows that compared with the product composed only of rhMP52, the water content of each of the compositions according to the present invention is lower at the time of preparation or after storage and therefore shrink does not occur easily.
AP/P/ 99/01602
- 6 AP 00983
Table 1 months later composition Initial
- 8° C 25’C
40’ C rhMP5 2 alone
9.7% 9.2% 7.6% 7.8% + Mannitol, 10 mg
1.6% 1.6% 1.4%
1.2%
Mannitol, 25 mg
0.9% 0.7% 0.6%
0.5%
Mannitol, 50 mg
0.6% 0.5% 0.4% 0.4%
Example 3 Ectopic bone formation of rhMP52
One vial (1 mg/vial) containing the rhMP52 composition obtained, in Example 1 was stored at 4’C and 25’C for 6 months, respectively, then, 1 ml of distilled water for injection was added to the vial, whereby a solution for administration was prepared. The solution thus prepared was intramuscularly administered to an ICR mouse (purchased from Nippon Crea Co. , Ltd. ) in an amount of 20 pg/20 pi. Two weeks later, the presence or absence of ectopic bone formation was observed through a soft X-ray photographing (n=2) . The results are shown in Table .
AP/P/ 9 9 / 0 1 6 0 2
- 7AP 00983
Table 2
composition 4° C 25° C
rhMP52 alone ebf* was observed ebf was observed
+ Mannitol, 10 mg ebf was observed ebf was observed
+ Mannitol, 25 mg ebf was observed ebf was observed
+ Mannitol, 50 mg ebf was observed ebf was observed
ebf: ectopic bone formation
INDUSTRIAL APPLICABILITY
The lyophilized product of bone morphogenetic factor human MP52 involves problems that it is colored or it shrinks during storage and it coheres at the time of reconstitution. The lyophilized composition according to the present invention, however, is free from such problems . Bone morphogenetic factor human MP52 in the lyophilized composition of the present invention remains stable and no substantial change is observed in purity, water content and ectopic bone formation even after storage for along time. Thus, the present invention is applicable in the field of pharmaceutical product.
AP/P/ 99/01602

Claims (4)

  1. What is claimed is:
    1. A lyophilized composition of bone morphogenetic factor human MP52, which comprises a mixture of bone morphogenetic factor human MP52 with mannitol at a mixing ratio in the range of 1 : 5 - 50 (ratio by weight).
  2. 2. The composition according to claim 1, wherein said bone morphogenetic factor human MP52 has been produced by genetic engineering technology.
  3. 3. A process for the preparation of a lyophilized composition of bone morphogenetic factor human MP52, which comprises adding mannitol to a purified solution of bone morphogenetic factor human MP52 in an amount to give a mixing ratio of bone morphogenetic factor human MP52 to mannitol in the range of 1 : 5 - 50 (ratio by weight) and then lyophilizing the resultant mixed solution.
  4. 4. The process—according to claim 3, wherein said bone morphogenetic factor human MP52 has been produced by a genetic engineering technology.
APAP/P/1999/001602A 1997-01-30 1998-01-29 Freeze-dried composition of bone morphogenetic protein human MP52. AP983A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1634997 1997-01-30
PCT/JP1998/000371 WO1998033514A1 (en) 1997-01-30 1998-01-29 Freeze-dried composition of bone morphogenetic protein human mp52

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AP9901602A0 AP9901602A0 (en) 1999-09-30
AP983A true AP983A (en) 2001-07-16

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EP (1) EP0972520B9 (en)
JP (1) JP4209948B2 (en)
KR (1) KR100548107B1 (en)
CN (1) CN1152712C (en)
AP (1) AP983A (en)
AT (1) ATE302021T1 (en)
AU (1) AU737595B2 (en)
BR (1) BR9807537B1 (en)
CA (1) CA2278546C (en)
DE (1) DE69831223T9 (en)
DK (1) DK0972520T3 (en)
EA (1) EA001579B1 (en)
ES (1) ES2244043T3 (en)
HU (1) HU226554B1 (en)
IL (2) IL130967A0 (en)
NO (1) NO322334B1 (en)
NZ (1) NZ336509A (en)
PL (1) PL189381B1 (en)
RS (1) RS49691B (en)
SI (1) SI0972520T1 (en)
TR (1) TR199901832T2 (en)
WO (1) WO1998033514A1 (en)

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JP4388602B2 (en) 1997-02-07 2009-12-24 ストライカー コーポレイション Bone-forming device not containing matrix, graft, and method of use thereof
WO2003030873A1 (en) * 2001-10-09 2003-04-17 Cellfactors Plc Therapeutic biological product and method for formation of new vascularised bone
CA2466947C (en) 2001-11-19 2012-05-22 Scil Technology Gmbh A homogeneously coated device having osteoinductive and osteoconductive properties
ATE322916T1 (en) 2002-09-10 2006-04-15 Scil Technology Gmbh METAL IMPLANT COATED WITH AN OSTEOINDUCTIVE PROTEIN UNDER REDUCED OXYGEN CONCENTRATION
EP1651272A1 (en) * 2003-08-05 2006-05-03 Fuji Photo Film B.V. Use of recombinant or synthetic gelatin as a stabiliser in vaccines
CA2545458A1 (en) * 2003-11-10 2005-05-26 Arriva-Prometic Inc. Dry recombinant human alpha 1-antitrypsin formulation
JP4944010B2 (en) 2004-03-10 2012-05-30 サイル テクノロジー ゲーエムベーハー Coated implant, its manufacture and use
US10360287B2 (en) 2015-05-22 2019-07-23 Microsoft Technology Licensing, Llc Unified messaging platform and interface for providing user callouts
US20160344677A1 (en) 2015-05-22 2016-11-24 Microsoft Technology Licensing, Llc Unified messaging platform for providing interactive semantic objects

Citations (1)

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WO1996033215A1 (en) * 1995-04-19 1996-10-24 Hoechst Pharmaceuticals & Chemicals K.K. Novel protein and process for producing the same

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US5037644A (en) * 1986-10-27 1991-08-06 Cetus Corporation Pharmaceutical compositions of recombinant interleukin-2 and formulation processes
AU663328B2 (en) * 1991-06-21 1995-10-05 Genetics Institute, Llc Pharmaceutical formulations of osteogenic proteins
JP2966592B2 (en) * 1991-07-20 1999-10-25 萩原 義秀 Stabilized human monoclonal antibody preparation
UA48105C2 (en) * 1992-02-12 2002-08-15 Біофарм Гезельшафт Цур Біотехнологішен Ентвіклунг Вон Фармака Мбх DNA FRAGMENT CODING THE PROTEIN OF THE FAMILY TGF-в (VERSIONS), RECOMBINANT DNA MOLECULE (VERSIONS), CELL-HOST (VERSIONS), METHOD FOR OBTAINING THE PROTEIN OF THE FAMILY TGF-в (VERSIONS), PHARMACEUTICAL COMPOSITION (VERSIONS), ANTIBODY OR AN ANTIBODY FRAGMENT (VERSIONS), CDNA MOLECULE (VERSIONS)
CA2093836A1 (en) * 1992-04-24 1993-10-25 Wayne Gombotz Biodegradable tgf-.beta. delivery system for bone regeneration
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Publication number Priority date Publication date Assignee Title
WO1996033215A1 (en) * 1995-04-19 1996-10-24 Hoechst Pharmaceuticals & Chemicals K.K. Novel protein and process for producing the same

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IL130967A0 (en) 2001-01-28
SI0972520T1 (en) 2006-02-28
DE69831223T9 (en) 2006-12-07
EA199900694A1 (en) 2000-04-24
WO1998033514A1 (en) 1998-08-06
HUP0002386A2 (en) 2000-11-28
ES2244043T3 (en) 2005-12-01
CA2278546A1 (en) 1998-08-06
HUP0002386A3 (en) 2002-09-30
NO993702D0 (en) 1999-07-29
RS49691B (en) 2007-12-31
DE69831223T2 (en) 2006-02-16
NO993702L (en) 1999-09-29
BR9807537A (en) 2000-03-21
NZ336509A (en) 2001-03-30
KR20000070586A (en) 2000-11-25
EP0972520B1 (en) 2005-08-17
ATE302021T1 (en) 2005-09-15
BR9807537B1 (en) 2009-01-13
AU5679198A (en) 1998-08-25
DK0972520T3 (en) 2005-12-19
AP9901602A0 (en) 1999-09-30
KR100548107B1 (en) 2006-02-02
DE69831223D1 (en) 2005-09-22
TR199901832T2 (en) 1999-12-21
NO322334B1 (en) 2006-09-18
CN1244127A (en) 2000-02-09
AU737595B2 (en) 2001-08-23
IL130967A (en) 2006-12-10
YU34999A (en) 2002-08-12
JP4209948B2 (en) 2009-01-14
EA001579B1 (en) 2001-06-25
CA2278546C (en) 2008-04-01
EP0972520A4 (en) 2002-11-05
PL334852A1 (en) 2000-03-27
HU226554B1 (en) 2009-03-30
EP0972520A1 (en) 2000-01-19
CN1152712C (en) 2004-06-09
PL189381B1 (en) 2005-07-29
EP0972520B9 (en) 2006-03-22

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