CN1068793C - Bone growth stimulating hormone injection and preparation method thereof - Google Patents
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- CN1068793C CN1068793C CN97108463A CN97108463A CN1068793C CN 1068793 C CN1068793 C CN 1068793C CN 97108463 A CN97108463 A CN 97108463A CN 97108463 A CN97108463 A CN 97108463A CN 1068793 C CN1068793 C CN 1068793C
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a bone growth factor injection extracted from natural animal bone materials and a preparation method thereof. Contains bovine bone morphogenetic protein bBMP, fibroblast growth factor bFGF and polyvinyl pyrrolinone PVP; the preparation process comprises the following steps: urea is infiltrated, a homogenizer is used for homogenate, the bBMP is dialyzed by a dialysis membrane, PVP is heated and dissolved at the same time, and then the bFGF is dissolved by the solution; mixing the two solutions, quick freezing, drying, sterilizing, volatilizing, culturing aerobic bacteria and anaerobic bacteria, and if the culture is negative, obtaining the final product. Compared with the prior art, the medicine has the advantages of small dosage, less frequency and obvious effects of promoting bone healing and ectopic osteogenesis.
Description
The invention belongs to medical configuration product technical field, relate to a kind of bone growth factor injection of from the natural animal bone material, extracting and preparation method thereof.
At Osteopathic Medicine circle, bone is induced theoretical effect in bone is repaired, and more and more comes into one's own.Orthopaedic diseases such as, bone does not connect damaged with skeletal growth factor treatment fracture, bone are the research topics of carrying out mutually unexpectedly both at home and abroad.A large amount of research reports is verified, bone morphogenetic protein BONE MORPHOGE PROTNETIN (hereinafter to be referred as BMP) but bone that the mesenchymal cell that moves about around the induction of vascular is converted into irreversibility is a cell, thereby can produce cartilage or osseous tissue in the position beyond skeleton or skeleton, this mechanism is generally acknowledged by domestic and international Osteopathic Medicine circle.In the domestic and international prior art before the present invention, based on the research work of every induced osteogenesis of BMP carry out a lot, for example: to the research of BMP immunity principle and regulatory function; The research of BMP and other factor Application of composite; The research of gene recombinaton BMP; Carrier is to research of BMP activity influence or the like.Existing experiment showed, that the partially purified BMP of natural extract has fine bone-inducting active, contain the BMP of several molecular weight,, but when cost height, manufacturing cost, can not satisfy the demand than the bone-inducting active height of purification unimodal molecular weight.The active relation of carrier and BMP is an inevitable problem in the experimentation of BMP and the clinical practice, because the content of BMP in bone seldom, extracted amount is limited, uses the BMP of high purification easily to be organized absorption again, is difficult to play a role.Therefore, the application of BMP must consider to adopt the problem of which kind of optimum carrier simultaneously.Carrier commonly used in the prior art has decalcified bone matrix (DBM), porous calcium phosphate (TCP), hydroxyapatite (HA), biological active glass ceramic and fibrin etc., but all there is such-and-such problem more or less in these carriers.In sum, though formed climax based on the research of the bone induced osteogenesis of BMP in recent years, some work also has innovation very much, up to now, belongs to very sophisticated, to can be used in the medical configuration product of clinical BMP actually rare.Induce in the different another kind of prior art of mechanism with above-mentioned bone, China's CN89105016.7 patent disclosure a kind of " cell growth stimulant and manufacture method thereof ", main component in this medicine is the antibacterial plasma-coagulase, and contain protein, polypeptide and several amino acids, be that pig myocardium albumen freezes the extracting solution of making the yellow golden staphylococci metabolite of culture medium with sodium-chloride water solution.This injection that impels union of fracture and treatment ulcer, what emphasize on the mechanism of curing the disease is the synergism of multiple bioactive substance, do not need to consider effective ingredient or the effective site mechanism of action and separation problem, therefore, this medicine consumption in actual use is also very big, need carry out just produce effects fruit of multiple injection.At present, oneself several years that appears on the market of this medicine, but so far medical mechanism and actual efficacy are not had clear and definite saying.Induce skeletal growth factor treatment mechanism under the theoretical direction that difference on the level is arranged with above-mentioned bone.
At above-mentioned prior art situation, the objective of the invention is to: provide a kind of and have based on the compound skeletal growth factor of natural extract, partially purified BMP and have the medical configuration product of injection type and the preparation method of the best sensitization carrier of slow releasing function, and make every effort to make that its effect is remarkable, expense is few, be easy to preserve, easy to use.
Now design of the present invention and technical solution are described below:
Induced osteogenesis theory based on BMP is thought: induced osteogenesis must possess three conditions, that is: (1) induces stimulus object (as skeletal growth factor); (2) mesenchymal cell; (3) be beneficial to the blood supply environment of osteogenesis.The present invention to the associating topical application of bone morphogenic protein BMP-2 and basic fibroblast growth factor BASIC FIBROBLAST GROWTH FACTOR (hereinafter to be referred as bFGF), has done deep research on the basis of a large amount of experiments.Experimental result confirms, but except the mesenchymal cell that moves about around the bone morphogenic protein BMP-2 induction of vascular be converted into irreversibility bone be cell, the position produces outside cartilage and the osseous tissue beyond skeleton or the skeleton, basic fibroblast growth factor (bFGF) has the osteocyte of stimulation proliferation function, be a kind of powerful capillary proliferation stimulant, and the formation of endochondral ossification and blood capillary is the important step of bone induced osteogenesis.Experiment is proof also, polyvinylpyrrolidone (PVP) has the good adsorption effect to the protein high molecular material, and is fairly obvious to the sensitization of BMP and bFGF, and fine with the intermiscibility of the two, can form suspension completely, be a kind of effective slow-released carrier.In view of the above, the present invention at first provides a kind of osteogenesis stimulin medicinal preparation, it is characterized in that: contain more than one exogenous skeletal growth factor and carriers; Exogenous skeletal growth factor is that Os Bovis seu Bubali forms generation albumen (bBMP) or recombinant human bone morphogenetic protein (rhBMP) and basic fibroblast growth factor (bFGF) or gene recombinaton human fibroblastic growth factor (rhFGF); The sensitization carrier is polyvinylpyrrolidone (PVP); Exogenous skeletal growth factor Bovine Bone Morphoge Protnetin (bBMP) or hBMP (rhBMP) are that (IU is equivalent to 1～2ng) for iu 1IU to 30mg: 100mg: 8000IU with the proportioning of sensitization carrier polyvinylpyrrolidone (PVP), alkaline fiber cell growth factor (bFGF) or gene recombinaton human fibroblastic growth factor (rhFGF).
The present invention also provides the preparation method of osteogenesis stimulin injection, it is characterized in that, the preparation process of these configuration product is:
(1), take by weighing BMP1.5 gram, pulverize, with the carbamide dissolving of 20ml 4M, place 4 ℃ of refrigerators, after 12 hours, use homogenizer homogenate;
(2), BMP that homogenate is good, install the back packing with dialyzer, under 4 ℃ of conditions, with 4000ml distill water dialysis 5～10 times, each 5～6 hours at interval; After having dialysed, homogenate once more, stand-by;
(3), 5 gram PVP are added in 40 mL of saline, heating for dissolving is put cold after-filtration, and transfers PH to 7.2 with the sodium hydroxide of 2M, dilutes bFGF with this liquid then, and is stand-by;
(4), with (2) liquid and (3) liquid mix homogeneously, transfer to 100ml with Sterile Saline and go into hundred grades of clean rooms, be distributed into bottle; Put-75 ℃ of refrigerator quick-freezings 5 minutes, put again in-30 ℃ of refrigerators and froze 20 minutes, send lyophilizing in the freeze dryer.
(5), take out sample, put in the drying tower, and use oxirane disinfection; And then put in hundred grades of clean rooms and volatilize, do aerobe, anaerobic culture simultaneously;
(6), if aerobe, anaerobic culture are positive, be finished product, preserve through gland, the rearmounted 4 ℃ of refrigerators of labelling.
Below, strengthen Bovine Bone Morphoge Protnetin (bBMP) in the intravital experiment of mice in conjunction with basic fibroblast growth factor (bFGF), the stimulation of the osteogenesis of the medical configuration product of the present invention is described further:
1, material and method: the method for pressing bibliographical information is extracted partially purified BMP from the fresh calf bone, and the implantation experiment through mice flesh bag confirms its bone-inducting active.The bBMP of 96mg is dissolved in the urea liquid of 24ml 16M, to water dialysis 24 hours, gets the bBMP suspension in the time of 4 ℃, on average packs into 24 and pacifies bottle, and lyophilizing is sealed standby.BFGF is a dried frozen aquatic products.48 kunming mices, male, body weight 25 grams are divided into 4 groups at random.
A group: with phosphate normal saline buffer solution (PBS liquid) 0.3ml that contains bFGF100mg, inject the peace bottle that contains bBMP4mg, make into suspension, suck the skin test syringe, inject mice osseous part intramuscular.
The B group: bBMP4mg/PBS liquid 0.3ml suspension, inject mice osseous part intramuscular.
The C group: bBMP4mg/PBS liquid 0.3ml, inject mice osseous part intramuscular.
The D group: PBS liquid 0.3ml, inject mice osseous part intramuscular.
All inject for above-mentioned 4 groups with method.Put to death mice in the time of 21 days, cut the tissue of injection site, fix with 10% neutral formalin, hydrochloric acid decalcification 24 hours, washing, decalcification, paraffin embedding, section, HE dyeing, light microscopic is observed down.Each is organized all the other specimen and measures as calcium content.Remove specimen surface muscle, homogenate, centrifugal with 10000rpm, precipitate digests with hydrochloric acid, in the atomic absorption spectrophotometer calcium content, as the quantitative index of skeletonization.
2, result:
A group: a bone scleroma can be touched in mice intramuscular injection position, and as seen lamellar bone is arranged under the histological examination mirror, and bone trabecula and red bone marrow form, and fibrous tissue is arranged.
B group: new bone formation is also arranged, but do not see new capillary vessel.
C group: do not see new bone.
D group: do not see new bone.
Calcium content is measured: the A group is 3 times of B group, is 8 times of C group; The B group is greater than C group and D group.
3, conclusion: contain multiple bone-inducing factor and with suitable carrier-bound medical configuration product, in orthopaedics is clinical, have broad prospects.
The present invention compares with prior art, and using dosage is little, number of times is few, to promoting knitting and ectopic osteogenesis effect Obviously, having can be used as ripe medical configuration product is used for clinical.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97108463A CN1068793C (en) | 1997-04-17 | 1997-04-17 | Bone growth stimulating hormone injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97108463A CN1068793C (en) | 1997-04-17 | 1997-04-17 | Bone growth stimulating hormone injection and preparation method thereof |
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| Publication Number | Publication Date |
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| CN1163780A CN1163780A (en) | 1997-11-05 |
| CN1068793C true CN1068793C (en) | 2001-07-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN97108463A Expired - Fee Related CN1068793C (en) | 1997-04-17 | 1997-04-17 | Bone growth stimulating hormone injection and preparation method thereof |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0896825B1 (en) | 1997-08-14 | 2002-07-17 | Sulzer Innotec Ag | Composition and device for in vivo cartilage repair comprising nanocapsules with osteoinductive and/or chondroinductive factors |
| US7087577B2 (en) * | 1998-10-16 | 2006-08-08 | Zimmer Orthobiologies, Inc. | Method of promoting natural bypass |
| US6992066B2 (en) * | 1998-10-16 | 2006-01-31 | Zimmer Orthobiologics, Inc. | Povidone-containing carriers for polypeptide growth factors |
| US6723335B1 (en) | 2000-04-07 | 2004-04-20 | Jeffrey William Moehlenbruck | Methods and compositions for treating intervertebral disc degeneration |
| US7232802B2 (en) | 2001-12-21 | 2007-06-19 | Zimmer Orthobiologics, Inc. | Compositions and methods for promoting myocardial and peripheral angiogenesis |
| US7622562B2 (en) | 2002-06-26 | 2009-11-24 | Zimmer Orthobiologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
| CN1279973C (en) * | 2004-07-22 | 2006-10-18 | 徐放 | Injected gel type bone repairing biological active material and its preparing method |
| CN101816634B (en) * | 2010-02-05 | 2012-05-23 | 深圳兰度生物材料有限公司 | Technology for preparing bone growth factor-carrying microspheres by ultrasonic atomization method |
| CN103990181B (en) * | 2014-05-26 | 2015-07-08 | 中国人民解放军第四军医大学 | A preparation method and application of a microcarrier-cell complex with inducible activity |
| CN111714285B (en) * | 2020-06-29 | 2022-08-19 | 温州大学 | Layer-by-layer self-assembled film and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019510A1 (en) * | 1990-06-18 | 1991-12-26 | Genetics Institute, Inc. | Osteoinductive pharmaceutical formulations |
| WO1996039169A1 (en) * | 1995-06-05 | 1996-12-12 | Genetics Institute, Inc. | Methods and compositions for healing and repair of connective tissue attachment |
-
1997
- 1997-04-17 CN CN97108463A patent/CN1068793C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019510A1 (en) * | 1990-06-18 | 1991-12-26 | Genetics Institute, Inc. | Osteoinductive pharmaceutical formulations |
| WO1996039169A1 (en) * | 1995-06-05 | 1996-12-12 | Genetics Institute, Inc. | Methods and compositions for healing and repair of connective tissue attachment |
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| CN1163780A (en) | 1997-11-05 |
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