AP983A - Freeze-dried composition of bone morphogenetic protein human MP52. - Google Patents
Freeze-dried composition of bone morphogenetic protein human MP52. Download PDFInfo
- 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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- AP
- ARIPO
- Prior art keywords
- bone morphogenetic
- morphogenetic factor
- factor human
- mannitol
- composition
- Prior art date
Links
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 title claims abstract description 37
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 title claims abstract description 37
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 101100472152 Trypanosoma brucei brucei (strain 927/4 GUTat10.1) REL1 gene Proteins 0.000 title claims abstract description 36
- 229940112869 bone morphogenetic protein Drugs 0.000 title 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 27
- 235000010355 mannitol Nutrition 0.000 claims abstract description 25
- 229930195725 Mannitol Natural products 0.000 claims abstract description 23
- 239000000594 mannitol Substances 0.000 claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000010353 genetic engineering Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 abstract description 8
- 238000004040 coloring Methods 0.000 abstract description 2
- 206010003694 Atrophy Diseases 0.000 abstract 1
- 230000037444 atrophy Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 7
- 230000011164 ossification Effects 0.000 description 6
- 238000001962 electrophoresis Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229940127557 pharmaceutical product Drugs 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 description 1
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001002 morphogenetic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
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
- A61K38/18—Growth factors; Growth regulators
-
- 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
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- 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
- A61K9/14—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
- A61P19/00—Drugs for skeletal disorders
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (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)
- 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. The composition according to claim 1, wherein said bone morphogenetic factor human MP52 has been produced by genetic engineering technology.
- 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. The process—according to claim 3, wherein said bone morphogenetic factor human MP52 has been produced by a genetic engineering technology.
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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9901602A0 AP9901602A0 (en) | 1999-09-30 |
| AP983A true AP983A (en) | 2001-07-16 |
Family
ID=11913900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1999/001602A AP983A (en) | 1997-01-30 | 1998-01-29 | Freeze-dried composition of bone morphogenetic protein human MP52. |
Country Status (22)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| BR0214275A (en) | 2001-11-19 | 2004-09-21 | Scil Technology Gmbh | Device having osteoconductive and osteoinductive properties |
| WO2004024199A1 (en) | 2002-09-10 | 2004-03-25 | Scil Technology Gmbh | Metal implant coated under reduced oxygen concentration with osteoinductive protein |
| EP1651272A1 (en) * | 2003-08-05 | 2006-05-03 | Fuji Photo Film B.V. | Use of recombinant or synthetic gelatin as a stabiliser in vaccines |
| EP1685160A1 (en) * | 2003-11-10 | 2006-08-02 | Arriva-Prometic Inc. | Dry recombinant human alpha 1-antitrypsin formulation |
| PL1737734T3 (en) | 2004-03-10 | 2011-02-28 | Scil Tech Gmbh | Coated implants, their manufacturing and use thereof |
| US20160344677A1 (en) | 2015-05-22 | 2016-11-24 | Microsoft Technology Licensing, Llc | Unified messaging platform for providing interactive semantic objects |
| US10360287B2 (en) | 2015-05-22 | 2019-07-23 | Microsoft Technology Licensing, Llc | Unified messaging platform and interface for providing user callouts |
Citations (1)
| 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 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080879B1 (en) * | 1981-11-28 | 1986-10-01 | Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
| US5037644A (en) * | 1986-10-27 | 1991-08-06 | Cetus Corporation | Pharmaceutical compositions of recombinant interleukin-2 and formulation processes |
| KR0145278B1 (en) * | 1991-06-21 | 1998-07-15 | 브루스 엠. 에이센 | Osteogenic protein drugs |
| JP2966592B2 (en) * | 1991-07-20 | 1999-10-25 | 萩原 義秀 | Stabilized human monoclonal antibody preparation |
| CZ287715B6 (en) * | 1992-02-12 | 2001-01-17 | Bioph Biotech Entw Pharm Gmbh | DNA sequence, recombinant DNA molecule containing thereof, process for preparing protein from the group of TGF-beta substances, pharmaceutical preparation containing such protein, antibody or fragment thereof and its use |
| CA2093836A1 (en) * | 1992-04-24 | 1993-10-25 | Wayne Gombotz | Biodegradable tgf-.beta. delivery system for bone regeneration |
| DE4239877C1 (en) * | 1992-11-27 | 1994-03-17 | Boehringer Ingelheim Int | Stabilized superoxide dismutase (SOD) composition |
| AU707796B2 (en) * | 1995-03-21 | 1999-07-22 | Merck Serono Sa | HCG liquid formulations |
-
1998
- 1998-01-29 PL PL98334852A patent/PL189381B1/en not_active IP Right Cessation
- 1998-01-29 EP EP98901044A patent/EP0972520B9/en not_active Expired - Lifetime
- 1998-01-29 AT AT98901044T patent/ATE302021T1/en active
- 1998-01-29 TR TR1999/01832T patent/TR199901832T2/en unknown
- 1998-01-29 IL IL13096798A patent/IL130967A0/en active IP Right Grant
- 1998-01-29 DK DK98901044T patent/DK0972520T3/en active
- 1998-01-29 EA EA199900694A patent/EA001579B1/en not_active IP Right Cessation
- 1998-01-29 SI SI9830798T patent/SI0972520T1/en unknown
- 1998-01-29 NZ NZ336509A patent/NZ336509A/en not_active IP Right Cessation
- 1998-01-29 WO PCT/JP1998/000371 patent/WO1998033514A1/en not_active Ceased
- 1998-01-29 JP JP53271798A patent/JP4209948B2/en not_active Expired - Fee Related
- 1998-01-29 DE DE69831223T patent/DE69831223T9/en active Active
- 1998-01-29 HU HU0002386A patent/HU226554B1/en not_active IP Right Cessation
- 1998-01-29 CN CNB988019841A patent/CN1152712C/en not_active Expired - Fee Related
- 1998-01-29 CA CA002278546A patent/CA2278546C/en not_active Expired - Fee Related
- 1998-01-29 AU AU56791/98A patent/AU737595B2/en not_active Ceased
- 1998-01-29 RS YUP-349/99A patent/RS49691B/en unknown
- 1998-01-29 ES ES98901044T patent/ES2244043T3/en not_active Expired - Lifetime
- 1998-01-29 KR KR1019997006833A patent/KR100548107B1/en not_active Expired - Fee Related
- 1998-01-29 AP APAP/P/1999/001602A patent/AP983A/en active
- 1998-01-29 BR BRPI9807537-3A patent/BR9807537B1/en not_active IP Right Cessation
-
1999
- 1999-07-15 IL IL130967A patent/IL130967A/en not_active IP Right Cessation
- 1999-07-29 NO NO19993702A patent/NO322334B1/en not_active IP Right Cessation
Patent Citations (1)
| 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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