CN103070906A - Quality control method of injection composition for treating orthopedic diseases - Google Patents
Quality control method of injection composition for treating orthopedic diseases Download PDFInfo
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- CN103070906A CN103070906A CN2013100235801A CN201310023580A CN103070906A CN 103070906 A CN103070906 A CN 103070906A CN 2013100235801 A CN2013100235801 A CN 2013100235801A CN 201310023580 A CN201310023580 A CN 201310023580A CN 103070906 A CN103070906 A CN 103070906A
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Abstract
The invention belongs to the field of medicine analysis and in particular relates to a quality control method of an injection composition for treating orthopedic diseases. The injection composition is prepared by respectively extracting raw materials of pig limb bones and melon seeds. The injection composition contains a polypeptide bone metabolism factor, an melon seed extract, a plurality of free amino acids and inorganic salts as well as trace elements, contains a plurality of bone metabolism active peptides and has an effect of treating a plurality of orthopedic diseases. It is especially noteworthy as follows: the raw material prefers posterior tribial bones; the ultraviolet absorption peak of a polypeptide component in an extracting liquid of the posterior tribial bones is about 258 nm; and the ultraviolet absorption peak of the polypeptide components in the common pig limb bones. And moreover, through respectively monitoring a melon seed extract solution and a pig limb bone extracting liquid at the ultraviolet absorption peak of 258 nm and bringing a medicine standard monitoring procedure forward, medicine standards are enhanced and the effectiveness and safety of the medicine are more effectively guaranteed.
Description
Technical field
The invention belongs to the pharmaceutical analysis field, specifically relate to a kind of method of quality control for the treatment of the composition for injection of orthopaedic disease.
Background technology
The bone-melon extract injection contains various active polypeptide and free amino acid, has the adjusting bone metabolism, and stimulated osteoblastic proliferation promotes new bone formation, regulates calcium, phosphorus metabolism, increases bone calcium deposition, prevents the effects such as osteoporosis.
The effect polypeptides bone metabolic factor of polypeptides bone metabolic factor can effectively promote affect in the body the synthesizing of bdgf of bone formation and absorption, comprise bone morphogenetic protein (BMPs), β-transforming growth factor (TGF-β), fibroblast growth factor (FGF) etc., thereby have multiple biological activity, its main pharmacological has: promote cell mitogen, differentiation, chemotaxis and molten bone active.Wherein BMPs is one group of acid low-molecular-weight glycoprotein, as a kind of efficient bone Induced substance, BMPs is that mesenchymal cell is the initially signal molecule of cell differentiation to bone, the bone that the mesenchymal cell that moves about around the energy induction of vascular is converted into irreversibility is cell, be chondrocyte and osteoblast, thereby the promotion callus formation is induced new bone formation, promotes fracture repair; In addition, BMPS is the change of scalable extracellular matrix components also, and by inducing better new bone formation with TGF-β and FGF coordinative role each other, makes osseous tissue more ripe.TGF-β then is one group of protein polypeptide with several functions, osteoblast and chondroblast are had the differentiation of promotion or fall PD dual regulation effect, with the multiple factor such as extracellular matrix and the collaborative adjusting that participates in cell differentiation of other differentiation growth regulation factors; TGF-β can promote extracellular matrix synthetic, can directly stimulate the synthetic of fibroblast epimatrix, and its substrate degradation that newly synthesizes is had remarkable inhibitory action; For osteoblast, TGF-β can promote its synthetic type i collagen, osteonectin and fracture albumen; Simultaneously, TGF-β shows that to the effect of lymphocyte and macrophage it can alleviate the destructiveness of inflammatory reaction, can assist again some macrophage derived cytokine to play a role in tissue repair.FGF is that one group of heparin binds polypeptide, but the trend of irritation cell move, breed and break up, increase the quantity of rubber polymer archeocyte, promote the synthetic of bone collagen and noncollagen protein, increase synthesizing of Bone Gla protein.
The effect melon seed extract of melon seed extract is to extract through special process from the dry seed of the maturation of cucurbitaceous plant Fructus Melo (CucumismeloL.) to form, can reduce the local capillary permeability of fracture, reduce inflammatory exudation, promote the recovery of local blood fortune obstacle; Simultaneously can also reduce whole blood viscosity and cell aggregation degree, improve the blood circulation of callus part, for osteocyte provides a good blood for environment, can also suppress in addition the release of prostaglandin, reach analgesic effect; In promoting fracture heals in early days, the melon seed extract has synergism with the polypeptides bone metabolic factor that replenishes, and promotes the synthetic of bdgf.
The multiple free amino acid that the effect bone-melon extract injection of other compositions is rich in is supplied raw materials for the synthetic BMPs of osteocyte, the bone source property biotic factors such as TGF-β, FGF, promotes the synthetic of bone source property biotic factor.Organic calcium, the phosphorus factor can participate in alcium and phosphor metabolization, keep bone volume.
Summary of the invention
The purpose of invention is achieved through the following technical solutions: a kind of composition for injection for the treatment of orthopaedic disease, raw material comprises following composition: pig limbs bone extracting solution and melon seed extract solution.
Pig ossa tibiale posterius (note: the pig ossa tibiale posterius is equivalent to the bone of the inboard in people's the focile) is different with the content of peptides of the forelimb bone of pig, the ultraviolet absorption peak of the polypeptide constituents that pig limbs bone contains is about 240-250nm, and the ultraviolet absorption peak of the polypeptide constituents that pig ossa tibiale posterius extracting solution contains is about 258nm, and the ultraviolet absorption peak of the polypeptide constituents of melon seed extract solution is also about 258nm.
Therefore, the present invention is defined as 258nm to the ultraviolet absorption peak of the polypeptide in the quality standard requirement of the composition for injection for the treatment of orthopaedic disease, and the front and back that merge patent medicine at two kinds of solution, all 258nm is monitored, strengthen the process monitoring of medicine preparation, guarantee safety and the effectiveness of medicine, improved purposiveness and accuracy that medicine is accused.
Of particular concern is, the preferred pig ossa tibiale posterius that adopts in the raw material of the present invention, the ultraviolet absorption peak of the polypeptide constituents that its extracting solution contains is about 258nm, and the ultraviolet absorption peak of the polypeptide constituents that common pig limbs bone contains is about 240-250nm.Experiment showed, and adopt the pig ossa tibiale posterius as pharmaceutical raw material, can bring into play better therapeutic effect.And by in the preparation process, respectively the polypeptide constituents of melon seed extract solution and pig ossa tibiale posterius extracting solution is monitored at ultraviolet 258nm, preposition drug standard monitoring link has improved drug standard, has more effectively guaranteed effectiveness and the safety of medicine.
The composition for injection for the treatment of orthopaedic disease is compound preparation, and its component is fresh or freezing pig limbs bone and the ripe dry seed of Fructus Melo, through extracting respectively the sterile water solution of making.Mainly contain polypeptides bone metabolic factor, melon seed extract, multiple free amino acid and organic calcium, inorganic calcium, inorganic salt and trace element.
The composition for injection of the treatment orthopaedic disease for the treatment of osteopathia of the present invention, raw material comprises following composition: the extracting solution 10-100 weight portion of pig limbs bone, the extracting solution 10-30 weight portion of melon seed.
The composition for injection for the treatment of orthopaedic disease of the present invention, wherein, raw material contains following adjuvant:
Buffer is selected from: phosphate buffer or glycine-HCl buffer solution 1-10 weight portion
PH adjusting agent is selected from: sodium bicarbonate, sodium carbonate or sodium acetate 1-4 weight portion
Stabilizing agent, be selected from: disodiumedetate, mannitol, lactose 0.05-5 weight portion.
The present invention treats the composition for injection of orthopaedic disease, is prepared as follows:
(1) preparation of Os Sus domestica extracting solution:
The quarantine bones of limbs of qualified pig cuts off residual meat, disconnects degrease, pulverize, according to 1: 2 amount of bone slag purified water, 120 ℃ of hot pressing 2 hours, filter, sediment extracts 2 times again with method, merging filtrate, 2-8 ℃, cold preservation 24 hours, centrifugal 15 minutes, defat, supernatant is used the ultrafilter ultrafiltration, concentrated original volume 1/4 is regulated PH5.9-6.3
Filtrate is collected in ultrafiltration, obtains the Os Sus domestica extracting solution, and is for subsequent use;
(2) preparation of melon seed extract solution:
Rinsing 2-3 time, 1: 2 amount of the clean melon seed of rinsing purified water, 120 ℃ of hot pressing 2 hours, filter, sediment extracts 2 times again with method, merging filtrate, the 2-8 degree, cold preservation 24 hours, centrifugal 15 minutes, defat, supernatant is used the ultrafilter ultrafiltration, concentrated original volume 1/4 is regulated PH5.9-6.3, ultrafiltration, collect filtrate, obtain the melon seed extract solution;
(3) Os Sus domestica extracting solution, melon seed extract solution are mixed, sterilized 30 minutes for 121 ℃, fill, check, packing obtains finished product.
The composition for injection for the treatment of orthopaedic disease of the present invention can also be prepared as follows:
(1) preparation of Os Sus domestica extracting solution:
Gather the bones of limbs of the qualified pig of quarantine, keep fresh or freezing preservation under-20 ℃ of conditions.
Get bones of limbs, cut off residual meat with shears, disconnect degrease, aseptic water washing, dry is put in the pulverizer and is pulverized.
The bone slag is put in the heating kettle, adds sterilized water by 1: 1 amount, 121 ℃ of hot pressing 60 minutes, and 2～3 layers of filtered through gauze, sediment extracts 2 times again with method, merges three times filtrate.Stand at low temperature, defat.
Add ethanol in the solution and make determining alcohol reach 80%, regulating pH value is 4.5～5.0, and stand at low temperature 24 hours is filtered, and medicinal liquid adds ethanol precipitation 2 times again, and heating recovery ethanol is regulated pH value to 6.5～7.1.
Medicinal liquid is concentrated, uses the ultrafilter ultrafiltration, and the film relative molecular weight is preferably 1 * 10
4Sterilized 30 minutes for 121 ℃.
(2) melon seed extract solution
Get the drying and ripening muskmelon seeds, put in the pulverizer and pulverize.
Ground product is put in the heating kettle, adds sterilized water by 1: 1 amount, 121 ℃ of hot pressing 30 minutes, and 2～3 layers of filtered through gauze, sediment extracts 2 times again with method, merges three times filtrate.
Add ethanol in the filtrate and make determining alcohol reach 80%, regulating pH value is 4.5～5.0, and stand at low temperature 24 hours is filtered, and medicinal liquid adds ethanol precipitation 2 times again, and heating recovery ethanol is regulated pH value to 6.5～7.1.
Medicinal liquid is concentrated, uses the ultrafilter ultrafiltration, and the film relative molecular weight is preferably 1 * 10
4Sterilized 30 minutes for 121 ℃.Quality Control requires: checks by melon seed extract solution Quality Control requirement, and should be up to specification.
The composition for injection production technology for the treatment of orthopaedic disease: will detect qualified bone extract solution and melon seed extract solution and mix, inject dilute with water, preferably to 80% recipe quantity, regulate pH value, pH is preferably 6.0～6.5, the supplementary injection water is to full dose, measure semi-finished product content, fill is preferably 2,5,10ml in ampoule, sealing by fusing was sterilized 30 minutes for 121 ℃.Lamp inspection.The full review of sampling.The certified products packing.
The preferred production technology of composition for injection for the treatment of orthopaedic disease: Os Sus domestica extracting solution, melon seed extract solution are mixed, add adjuvant of the present invention, inject dilute with water, preferably to 80% recipe quantity, regulate pH value, pH is preferably 6.0～6.5, and the supplementary injection water is measured semi-finished product content to full dose, fill is in ampoule, be preferably 2,5,10ml, sealing by fusing, 121 ℃ of sterilizations 30 minutes.Lamp inspection.The full review of sampling.The certified products packing.
The raw material standard of neonatal pig bones of limbs: selected raw material is preferred healthy neonatal pig (being born 12 months in) bones of limbs, should choose and process according to the quality standard of following raw materials according.Raw material sources are in the neonatal pig of Suidae, pig genus, pig kind.Healthy neonatal pig is taken out bones of limbs after being put to death by arterial blood letting immediately, and whole process was finished in 1 hour.Healthy neonatal pig bones of limbs is being located attached meat, is cerise, and sclerotin is pure white, and without rancid, epiphysis is soft, and sclerotin is plentiful, and epiphysis is larger, the long appropriateness (20～40cm) of bone.The clean plastic bag packaging of bones of limbs ,-18 ℃ of freezing preservations, for subsequent use.The useful life is 1 year.
Check:
The brucella rose bengal precipitation test is examined serum and positive reaction must not be occurred under the condition that the contrast of positive and negative serum is set up.
Rotavirus elisa (ELISA) is examined serum and positive reaction must not be occurred under the condition that the contrast of positive and negative serum is set up.
Examined serum under the condition that foot and mouth disease liquid phase blocking-up-elisa matched group is set up and positive reaction to be occurred.
Being examined serum under the condition that epidemic encephalitis type B hemagglutination inhibition test matched group is set up must not have epidemic encephalitis type B to pollute.
Examined serum under the condition that pseudorabies latex agglutination test matched group is set up and positive reaction to be occurred.
Swine fever peroxidase connection neutralization test is examined serum and positive reaction must not be occurred.
Selected raw material preferably adopts healthy neonatal pig (being born 12 months in), preferred pig ossa tibiale posterius, the ossa tibiale posterius of preferred healthy neonatal pig.
Ossa tibiale posterius is through extracting gained Os Sus domestica extracting solution, and its ultraviolet characteristic absorption peak is 258nm.
The raw material standard of melon seed: this product is the dry mature seed of cucurbitaceous plant Fructus Melo CucumismeloL..Character: it is avette that this product is flat length, long 5～7mm, wide 2～4mm.Surface yellow or light brown red, level and smooth, little glossy, an end is point slightly, the blunt circle of another end.Kind of skin is harder and crisp, in 2 of membranous endosperm and cotyledons are arranged.Feeble QI, lightly seasoned.
Differentiate: (1) gets this product powder 5g, add water 50ml, heated 30 minutes, and filtered, get filtrate 2ml, add biuret reagent and (get copper sulfate 0.75g and sodium potassium tartrate tetrahydrate 3.0g, add water 250ml and make dissolving, under agitation add 10% sodium hydroxide solution 150ml, add water to 500ml) 4ml, room temperature was placed 15 minutes, and solution should show bluish violet to aubergine.Storage: put dry place, mothproof.
The melon seed extract solution of gained of the present invention, its ultraviolet characteristic absorption peak is 258nm.
Melon seed extract solution and Os Sus domestica extracting solution are merged the composition for injection of the treatment orthopaedic disease of the present invention that forms, and the ultraviolet absorption peak of its polypeptide is preferably 258nm.
The composition for injection of above-mentioned treatment orthopaedic disease can be made injection, infusion solutions and powder pin.
The pharmaceutical applications of the composition for injection for the treatment of orthopaedic disease: the application in the medicine of preparation treatment orthopaedic disease.At preparation treatment hypertrophy osteoarthrosis, osteoarthritis disease rheumatism, rheumatoid arthritis, the immediate union of promotion fracture, treatment wound, recovery, adjusting bone metabolism, stimulated osteoblastic proliferation, promote new bone formation, and regulate calcium, phosphorus metabolism, increase bone calcium deposition, prevent and treat osteoporosis, antiinflammatory, analgesia, the application in the medicine of ischemic necrosis of femoral head.
Os Sus domestica extracting solution quality standard of the present invention
This product is extracted preparation by fresh or freezing pig limbs bone bone, contains polypeptides matter in bovine serum albumin among every 1ml, must not be lower than 15.0mg.
Character this product is yellow clear liquid.
This product 0.5ml is got in discriminating, adds biuret reagent and (gets copper sulfate 0.75g and sodium potassium tartrate tetrahydrate 3.0g, add water 250ml and make dissolving, under agitation add 10% sodium hydroxide solution 150ml, add water to 500ml) 4ml, room temperature was placed 15 minutes, the solution displaing amaranth.
Check
PH value should be 6.5～7.1 (two appendix VI of Chinese Pharmacopoeia version in 2005 H).
Protein is got this product 1ml, adds sulfosalicylic acid solution (3 → 10) 3ml, and muddiness must not occur.
It is an amount of that high molecular weight material is got this product, adds water and make the solution that contains polypeptide 1mg among every 1ml, as need testing solution; It is an amount of that other gets cytochron-Sinjection15, adds water and make the solution that contains 5mg among every 1ml, in contrast solution.Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D).Adopt gel chromatographic columns (such as TSKgelG2000SW, PROTEN PAK60); With dipotassium hydrogen phosphate 13.93g, potassium dihydrogen phosphate 5.32g, add isopropyl alcohol 50ml, add water to 1000ml, regulating pH value to 7.0 with phosphoric acid is mobile phase; Flow velocity is per minute 0.8ml, and the detection wavelength is 280nm.Each 20 μ l of contrast solution and need testing solution, the injection liquid chromatography records chromatogram respectively.In the need testing solution chromatogram, the retention time at each peak all should be greater than the retention time of contrast solution main peak.
The undue toxicity gets this product, adds the chlorination sodium injection and makes the solution that contains polypeptide 5mg among every 1ml, checks in accordance with the law and (two appendix XIC of Chinese Pharmacopoeia version in 2005) presses intravenous administration, should be up to specification.
Pyrogen is got this product, checks (two appendix XI of Chinese Pharmacopoeia version in 2005 D) in accordance with the law, and dosage should be up to specification by the every 1kg injection of rabbit body weight 0.3ml.
Hypersensitive test is got this product, adds the chlorination sodium injection and makes the solution that contains polypeptide 5mg among every 1ml, gets
6 of the healthy qualified Cavia porcelluss of body weight 250～350g, lumbar injection 0.5ml next day of continuous 3 times after 14 days, again from intravenous injection 2ml, injects in rear 15 minutes, all anaphylaxis must not occur.If any two or more person occurring in the phenomenons such as perpendicular hair, dyspnea, retch, cough three, or rale is arranged, jerk take out, the one of collapse or the phenomena of mortality, should be judged to the positive.
Depressor substance is got this product, adds 0.9% sodium chloride injection and makes the solution that contains polypeptide 5mg among every 1ml, checks (two appendix XI of Chinese Pharmacopoeia version in 2005 G) in accordance with the law, should be up to specification.
The aseptic this product of getting checks (two appendix XI of Chinese Pharmacopoeia version in 2005 H) in accordance with the law, should be up to specification.
The assay precision is measured this product 1ml, puts in the 100ml measuring bottle, and thin up shakes up to scale, as need testing solution, measures according to forint phenol algoscopy (See Attachment 1).
Preserve-20 ℃ freezing
Melon seed extracting solution quality standard of the present invention
This product is extracted preparation by the dry mature seed of cucurbitaceous plant Fructus Melo Cucumis melo L., contains polypeptides matter in bovine serum albumin among every 1ml, must not be lower than 15.0mg.
Character this product is yellow clear liquid.
Differentiate
(1) gets this product 0.5ml, add biuret reagent and (get copper sulfate 0.75g and sodium potassium tartrate tetrahydrate 3.0g, add water 250ml and make dissolving, under agitation add 10% sodium hydroxide solution 150ml, add water to 500ml) 4ml, room temperature was placed 15 minutes, the solution displaing amaranth.
(2) get this product 0.3ml, put in the 50ml measuring bottle, add water to scale, shake up, measure according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2005), at the wavelength place of 258nm absorption maximum is arranged.
Check that pH value should be 6.5～7.1 (two appendix VI of Chinese Pharmacopoeia version in 2005 H).
Protein is got this product 1ml, adds sulfosalicylic acid solution (3 → 10) 3ml, and muddiness must not occur.
It is an amount of that high molecular weight material is got this product, adds water and make the solution that contains polypeptide 1mg among every 1ml, as need testing solution; It is an amount of that other gets cytochron-Sinjection15, adds water and make the solution that contains 5mg among every 1ml, in contrast solution.Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D).Adopt gel chromatographic columns (such as TSKgelG2000SW, PROTEN PAK60); With dipotassium hydrogen phosphate 13.93g, potassium dihydrogen phosphate 5.32g, add isopropyl alcohol 50ml, add water to 1000ml, regulating pH value to 7.0 with phosphoric acid is mobile phase; Flow velocity is per minute 0.8ml, and the detection wavelength is 280nm.Each 20 μ l of contrast solution and need testing solution, the injection liquid chromatography records chromatogram respectively.In the need testing solution chromatogram, the retention time at each peak all should be greater than the retention time of contrast solution main peak.
The undue toxicity gets this product, adds the chlorination sodium injection and makes the solution that contains polypeptide 5mg among every 1ml, checks in accordance with the law and (two appendix XIC of Chinese Pharmacopoeia version in 2005) presses intravenous administration, should be up to specification.
Pyrogen is got this product, checks (two appendix XI of Chinese Pharmacopoeia version in 2005 D) in accordance with the law, and dosage should be up to specification by the every 1kg injection of rabbit body weight 0.3ml.
Hypersensitive test is got this product, adds the chlorination sodium injection and makes the solution that contains polypeptide 5mg among every 1ml, gets 6 of the healthy qualified Cavia porcelluss of body weight 250～350g, lumbar injection 0.5ml next day of continuous 3 times is after 14 days, again from intravenous injection 2ml, inject in rear 15 minutes, all anaphylaxis must not occur.If any two or more person occurring in the phenomenons such as perpendicular hair, dyspnea, retch, cough three, or rale is arranged, jerk take out, the one of collapse or the phenomena of mortality, should be judged to the positive.
Depressor substance is got this product, adds 0.9% sodium chloride injection and makes the solution that contains polypeptide 5mg among every 1ml, checks (two appendix XI of Chinese Pharmacopoeia version in 2005 G) in accordance with the law, should be up to specification.
The aseptic this product of getting checks (two appendix XIH of Chinese Pharmacopoeia version in 2005) in accordance with the law, should be up to specification.
The assay precision is measured this product 1ml, puts in the 100ml measuring bottle, and thin up shakes up to scale, as need testing solution, measures according to forint phenol algoscopy.
Preserve-20 ℃ of freezing preservations.
The present invention treats the quality standard of the injection of orthopaedic disease
This product is fresh or freezing pig limbs bone bone and the dry mature seed of cucurbitaceous plant Fructus Melo CucumismeloL., the sterile water solution of making after extracting separately.Contain polypeptides matter in bovine serum albumin among every 1ml, must not be lower than 5.0mg.Character this product is that little yellow is to flaxen clear liquid.
Differentiate:
(1) get this product 2ml, add biuret reagent (get copper sulfate 0.75g and sodium potassium tartrate tetrahydrate 3.0g, add water 250ml and make dissolving, under agitation add 10% sodium hydroxide solution 150ml, add water to 500ml) 4ml, room temperature was placed 15 minutes, the solution displaing amaranth.
(2) get this product 1ml, put in the 50ml measuring bottle, add water to scale, shake up, measure according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2005), at the wavelength place of 258nm absorption maximum is arranged.
Check that pH value should be 5.5～7.0 (two appendix VIH of Chinese Pharmacopoeia version in 2005).
Protein is got this product 1ml, adds sulfosalicylic acid solution (3 → 10) 3ml, and muddiness must not occur.
The undue toxicity gets this product, checks (two appendix XIC of Chinese Pharmacopoeia version in 2005) to press intravenous administration in accordance with the law, should be up to specification.
Pyrogen is got this product, checks (two appendix XID of Chinese Pharmacopoeia version in 2005) in accordance with the law, and dosage should be up to specification by the every 1kg injection of rabbit body weight 1ml.
Hypersensitive test is got 6 of the healthy qualified Cavia porcelluss of body weight 250～350g, and lumbar injection this product 0.5ml next day of continuous 3 times after 14 days, again from intravenous injection this product 2ml, injects in rear 15 minutes, all anaphylaxis must not occur.If any two or more person occurring in the phenomenons such as perpendicular hair, dyspnea, retch, cough three, or rale is arranged, jerk take out, the one of collapse or the phenomena of mortality, should be judged to the positive.
Depressor substance is got this product, checks (two appendix XIG of Chinese Pharmacopoeia version in 2005) in accordance with the law, should be up to specification.
Other should meet every regulation relevant under the injection item (two appendix I of Chinese Pharmacopoeia version in 2005 B).
The assay precision is measured this product 1ml, puts in the 25ml measuring bottle, and thin up shakes up to scale, as need testing solution, measures according to forint phenol algoscopy (See Attachment 1).
The classification anti-inflammatory analgesic.
Specification (1) 5ml:25mg (2) 10ml:50mg
Preserve airtightly, preserve below 25 ℃.
18 months effect duration
The composition for injection of the treatment orthopaedic disease of the present invention preparation is compared with former bone-melon extract injection, and following advantage is arranged: the utilization rate of medical material is high, and cost is few, and active component height, determined curative effect, safety are good.The present invention treats the composition for injection of orthopaedic disease, adopt hyperfiltration technique, content of peptides reaches 50-100mg, content of peptides is 16-24mg in the cervus and cucumis polypeptide injection, in every consumption per day in the bone melon content of peptides be cervus and cucumis polypeptide 3-5 doubly, and content of peptides what with clinical efficacy be positively related, the curative effect that the present invention treats the composition for injection of orthopaedic disease will obviously be better than cervus and cucumis polypeptide.
Stability is high, and this product is studied through 24 months stability test, and the result shows that this product has good stability.
Quality controllable, pig ossa tibiale posterius (note: the pig ossa tibiale posterius is equivalent to the bone of the inboard in people's the focile) is different with the content of peptides of other bones of limbs of pig, the ultraviolet absorption peak of the polypeptide constituents that pig limbs bone contains is about 240-250nm, and the ultraviolet absorption peak of the polypeptide constituents that the pig ossa tibiale posterius contains is about 258nm, therefore, the present invention is defined as 258nm to the ultraviolet absorption peak of the polypeptide in the quality standard requirement of the composition for injection for the treatment of orthopaedic disease, strengthen the safety of medicine, improved purposiveness and accuracy that medicine is accused.
The specific embodiment
Following examples further specify content of the present invention, but should not be construed as limitation of the present invention.Without departing from the spirit and substance of the case in the present invention, modification or replacement to the inventive method, step or condition are done all belong to scope of the present invention.
Embodiment 1
(1) preparation of Os Sus domestica extracting solution:
The quarantine bones of limbs of qualified pig cuts off residual meat, disconnects degrease, pulverizes, according to bone slag 1: 2 amount purified water, 120 ℃ of hot pressing 2 hours is filtered, and sediment extracts 2 times again with method, merging filtrate, 5 degrees centigrade, cold preservation 24 hours, centrifugal 15 minutes, defat, supernatant is used the ultrafilter ultrafiltration, concentrated original volume 1/4 is regulated PH6.0, ultrafiltration, collect filtrate, obtain the Os Sus domestica extracting solution, for subsequent use; Ultraviolet absorption peak is 240-250nm.
(2) preparation of melon seed extract solution:
Rinsing 2-3 time, according to 1: 2 amount of the melon seed of cleaning purified water, 120 ℃ of hot pressing 2 hours, filter, sediment extracts 2 times again with method, merging filtrate, 5 degrees centigrade, cold preservation 24 hours, centrifugal 15 minutes, defat, supernatant is used the ultrafilter ultrafiltration, concentrated original volume 1/4 is regulated PH6.0, ultrafiltration, collect filtrate, obtain the melon seed extract solution; The ultraviolet characteristic absorption peak is 258nm.
(3) 50 weight portion Os Sus domestica extracting solution, 10 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, the adding sodium bicarbonate is an amount of, and regulating pH value is 6.2,121 ℃ of sterilizations 30 minutes, fill, and check, packing obtains finished product.
Embodiment 2
On the basis of embodiment 1: 50 weight portion Os Sus domestica extracting solution, 10 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, add 5 weight portion phosphate buffers, add sodium bicarbonate 1 weight portion, add disodiumedetate 0.1 weight portion, sterilized 30 minutes for 121 ℃, fill, check, packing obtains finished product.
Embodiment 3
On the basis of embodiment 1: 50 weight portion Os Sus domestica extracting solution, 10 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, add 5 weight portions glycine-HCl buffer solution, add sodium acetate 2 weight portions, add mannitol 0.2 weight portion, sterilized 30 minutes for 121 ℃, fill, check, packing obtains finished product.
Embodiment 4
(1) preparation of Os Sus domestica extracting solution:
Gather the qualified pig ossa tibiale posterius of quarantine (the pig ossa tibiale posterius is equivalent to the bone of the inboard in people's the focile), keep fresh or freezing preservation under-20 ℃ of conditions, get the pig ossa tibiale posterius, cut off residual meat with shears, disconnect degrease, aseptic water washing, dry, put in the pulverizer and pulverize, the bone slag is put in the heating kettle, adds sterilized water by 1: 1 amount, 121 ℃ of hot pressing 60 minutes, 3 layers of filtered through gauze, sediment extracts 2 times again with method, merges three times filtrate, stand at low temperature, defat adds ethanol in the solution and makes determining alcohol reach 80%, and regulating pH value is 4.8, stand at low temperature 24 hours, filter, medicinal liquid adds ethanol precipitation 2 times, heating recovery ethanol again, regulate pH value to 6.8, medicinal liquid is concentrated, uses the ultrafilter ultrafiltration, and the film relative molecular weight is 1 * 10
4, sterilized 30 minutes for 121 ℃.
Quality Control requires: by specification described " Os Sus domestica extracting solution quality standard of the present invention " Quality Control requires to check, should be up to specification, and the ultraviolet characteristic absorption peak is 258nm.
(2) melon seed extract solution
Get the drying and ripening muskmelon seeds, put in the pulverizer and pulverize, ground product is put in the heating kettle, add sterilized water by 1: 1 amount, 121 ℃ of hot pressing 30 minutes, 2～3 layers of filtered through gauze, sediment extracts 2 times again with method, merges three times filtrate, adds ethanol in the filtrate and makes determining alcohol reach 80%, regulating pH value is 4.8, and stand at low temperature 24 hours is filtered, medicinal liquid adds ethanol precipitation 2 times again, and heating recovery ethanol is regulated pH value to 6.8, medicinal liquid is concentrated, uses the ultrafilter ultrafiltration, and the film relative molecular weight is 1 * 10
4, sterilized 30 minutes for 121 ℃,
Quality Control requires: by specification described " melon seed extracting solution quality standard of the present invention " Quality Control requires to check, should be up to specification, and the ultraviolet characteristic absorption peak is 258nm.
(3) merge:
50 weight portion Os Sus domestica extracting solution, 20 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, the adding sodium bicarbonate is an amount of, and regulating pH value is 6.2,121 ℃ of sterilizations 30 minutes, fill, and check, packing obtains finished product.
Quality Control requires: by specification described " quality standard of the injection for the treatment of orthopaedic disease " Quality Control requires to check, should be up to specification, and the ultraviolet characteristic absorption peak is 258nm.
Embodiment 5
On the basis of embodiment 4: 50 weight portion Os Sus domestica extracting solution, 20 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, add 5 weight portion phosphate buffers, add sodium bicarbonate 1 weight portion, add mannitol 0.1 weight portion, sterilized 30 minutes for 121 ℃, fill, check, packing obtains finished product.
Quality Control requires: with embodiment 4
Embodiment 6
On the basis of embodiment 4: 50 weight portion Os Sus domestica extracting solution, 20 weight portion melon seed extract solutions are mixed, add the dilution of 20 weight portion waters for injection, add 5 weight portions glycine-HCl buffer solution, add sodium acetate 2 weight portions, add lactose 0.5 weight portion, sterilized 30 minutes for 121 ℃, fill, check, packing obtains finished product.
Quality Control requires: with embodiment 4
Embodiment 7: the present invention treats the clinical verification of the composition for injection of orthopaedic disease
The effect of preparation for treating osteoarthritis of the present invention
Method: 70 routine Osteoarthritis (meeting the osteoarthritis diagnostic criteria) are divided into 7 groups at random.
The 1st group of the present invention, the present invention treats the composition for injection 1 of orthopaedic disease
The 2nd group of the present invention, the present invention treats the composition for injection 2 of orthopaedic disease
The 3rd group of the present invention, the present invention treats the composition for injection 3 of orthopaedic disease
The 4th group of the present invention, the present invention treats the composition for injection 4 of orthopaedic disease
The 5th group of the present invention, the present invention treats the composition for injection 5 of orthopaedic disease
The 6th group of the present invention, the present invention treats the composition for injection 6 of orthopaedic disease
The present invention 1-6 group, the each patient treated 12mg intravenous drip every day in continuous 7 days with the composition for injection for the treatment of orthopaedic disease.
Matched group, with calcium tablet and vitamin D treatment, 7 days courses for the treatment of,
The standard of curative effect evaluation:
The Observation of pain index represents than scale (VAS) with vision.
Tenderness, swelling, dysfunction are observed, and estimate every day 1 time.Concrete point system is by the content score.
Produce effects: swelling and tenderness obviously alleviate, and joint motion improves obviously, and total score descends 〉=2/3 after the treatment;
Effectively: swelling and tenderness alleviate, and joint motion has obviously, and total score descends 〉=1/3 after the treatment;
Invalid: symptom is without improvement, and total score descends＜1/3 after the treatment.The statistical procedures measurement data adopts the t check, and enumeration data adopts variance analysis, and ranked data are checked with Ridit, and all data are processed with SPSS6.0.
Tenderness, swelling, dysfunction score standard:
The result:
Medicine of the present invention can reduce pain score, can subside a swelling, and pain relieving can be regulated bone metabolism, and safety is good, and generally speaking, 4-6 group effect is better than the 1-3 group.
Embodiment 8: the present invention is to the therapeutical effect of union of fracture
Adopt respectively year April in August, 2005-2006, the composition for injection of the treatment orthopaedic disease of the quiet embodiment of the invention 4, oral Gu Wang is treated two groups of fracture patients, is intended to observe the composition for injection for the treatment of orthopaedic disease, to the therapeutical effect of union of fracture.
Physical data 84 examples are Extremity in Orthopedic Inpatients.Be divided at random 2 groups.
Matched group: 41 examples, male 26 examples, women 15 examples: year at age (36 ± 8); Comprise fracture of shaft of femur 13 examples, fracture of tibia and fibula 18 examples, humeral fracture 6 examples, forearm fracture 4 examples.
Treatment group: 43 examples, male 28 examples, women 17 examples; Year at age (35 ± 9); Comprise fracture of shaft of femur 11 examples, fracture of tibia and fibula 19 examples, humeral fracture 7 examples, forearm fracture 6 examples.Two groups have comparability.
The diagnosis of fracture standard: clear and definite trauma history is arranged, be fresh fracture, medical in the 3d; Clinical symptoms and sign: pain is arranged, swelling and dysfunction, there is bony crepitus the part, and deformity is movable; X-ray and three dimensional CT are rebuild and are shown that fracture line is clear, without callus formation.
Two groups of cases of Therapeutic Method are capable reduction of the fracture internal fixation operation all, and postoperative reaches anti-infective therapy to the ill, routine is carried out functional exercise.On this basis, the composition for injection 10mg of 1 group for the treatment of of treatment group Application Example orthopaedic disease dissolves in the 250mL normal saline quiet of 1 time/d; The oral Gu Wang of matched group, 20mL/ time, 3 times/d is oral, is for 2 weeks the course for the treatment of.
Curative effect judging standard: standard of fracture healing, 1. fracture site is without pain, and without unusual movable, range of motion is normal; 2. the x-ray plain film shows that fracture line is fuzzy, has continuous callus to pass through fracture line; 3. contact outer fixing after, upper limb is held the 1kg weight greater than 1min to protracting, lower limb not cane and were no less than for 30 steps at level land continuous walking 3min; 4. Continuous Observation was checked after 2 weeks, and the general activity bone is undeformed.
Common healing time: fracture of the surgical neek of the humerus: 4-6 week; Humeral shaft fracture 5-8 week; Supracondylar fracture of the humerus 3-4 week; Chi fracture of radial shaft 8-12 week; Radius far-end fracture 3-4 week; Femur intertrochanteric fracture 6-10 week; Fracture of shaft of femur 8-14 week; Fracture of tibia and fibula 8-12 week.
Curative effect judging standard:
Clinical cure: administration time shifts to an earlier date more than 1/3 than similar healing time clinically, reaches clinical healing standard person;
Produce effects: the clinical application time shifts to an earlier date 1/3-1/4 than similar healing time, reaches clinical healing standard person;
Effectively: administration time shifts to an earlier date 1/4-1/5 than similar healing time clinically, reaches clinical healing standard person;
Invalid: administration time is identical with the normal healing time of similar fracture clinically.
The result:
The Comparison of therapeutic of two kinds of medicines
Treatment group cure rate 93.02% obviously is better than matched group (78.24%). and healing has good curative effect to the composition for injection of conclusion treatment orthopaedic disease to extremity fracture.
Embodiment 9: the present invention is on the hemorheological impact of ischemic necrosis of femoral head
Ischemic necrosis of femoral head is clinical refractory disease, because ischemic necrosis of femoral head has the pathological process of a complexity, as not treated timely and effectively in early days, will make collapse of the femoral head, the joint space narrows down, cause at last the gangrenosum acne osteoarthritis, make patient's hip joint function obstacle and disable.So the treatment of femur head necrosis is still a great problem of domestic and international medical circle at present.Use the composition for injection of the treatment orthopaedic disease of the embodiment of the invention 4 and treat 168 routine ischemic necrosis of femoral head, and observe the treatment hemorheological variation in front and back.
Physical data:
Among the treatment group 168 routine patients, male 97 examples, women 71 examples, age 8--69 year, average 38 years old; One-sided pathological changes 113 examples (right side 56 examples, left side 57 examples), bilateral 55 examples; Course of disease 2-36 month, average 10 months; 85 examples have trauma history, and 48 examples have long-term history of drinking history or use the hormone medicine history, and 35 examples are without obvious inducement.Matched group 35 examples, male 22 examples, women 13 examples, one-sided pathological changes 15 examples, bilateral pathological changes 20 examples.
Two groups at aspect there was no significant differences such as age, sex, course of disease medical histories, has comparability.Clinical manifestation is the hip arthralgia, large skelalgia or knee-joint pain, with hip joint limitation of activity and limping in various degree, suffers from limb straight-leg raising test (+).All patients all take the photograph sheet, CT or MRI through x-ray and are diagnosed as ischemic necrosis of femoral head.
Therapeutic Method
Treatment group is at composition for injection (embodiment of the invention 4) 10mL (adding among the 5% glucose 250mL) that suffers from limb intravenous drip treatment orthopaedic disease.Matched group simple oral blood-activating and stasis-removing, potion on the one.15d was 1 course for the treatment of.
The empty stomach vein haemospasia is done hemorheological indexes and is detected employing Beijing generation Supreme Being R80-A Analysis of Hemorheology Property instrument and the 7170A of Hitachi biochemistry analyzer mensuration before and after the hemorheology detection method patient treatment.
(x ± s) expression adopts the SPSS10.0 statistical software to organize a t check to the statistical method experimental data with mean ± standard deviation.The hemorheology index variation sees Table 1 before and after the treatment.
The variation of hemorheology index before and after table 1 treatment
Annotate: * represents with treatment relatively front, P＜0.05; # represents to compare P＜0.05 with matched group.
Find after the variation of hemorheology index before and after the treatment of research ischemic necrosis of femoral head:
Significantly descend (P＜0.05) after the treatment of matched group plasma viscosity, show that simple oral Chinese medicine can reduce plasma viscosity;
High and low whole blood viscosity and rear significantly descend (P＜0.05) of erythrocyte aggregation index treatment of cutting for the treatment of group;
The treatment group height is cut whole blood viscosity and the also significantly decline (P＜0.05) of erythrocyte aggregation index contrast group;
Show and suffer from effectively blood vessel dilating of composition for injection that limb intravenous drip the present invention treats orthopaedic disease that improve microcirculation, the minimizing erythrocyte aggregation can prevent ischemic necrosis of femoral head.
Embodiment 10: medicaments injection treatment postmenopausal osteoporosis of the present invention
Treatment postmenopausal osteoporosis: select more than 50 years old the sufferers of osteoporosis face in 5～10 years of menopause, 10 examples.Composition for injection (embodiment of the invention 5) 10mL (adding among the 5% glucose 250mL) of intravenous drip treatment orthopaedic disease, 15d was 1 course for the treatment of.
The bone density of its lumbar vertebra is lower than two standard deviations of normal pre-menopausal women bone density meansigma methods, lumbago persistent period 3-8.Before the medication and after 4 weeks of medication, carry out hepatic and renal function 1 time, blood calcium, phosphorus, alkali phosphatase, erythrocyte sedimentation rate, routine blood test, urine calcium, phosphorus, Ca/Cr check.
Adopt dual energy X-ray absorptiometry to measure the bone density of lumbar vertebra.Effectively: bone density remains unchanged or rises; Invalid: patient's bone density continuous decrease.The result shows: effective 9 examples among the 10 routine patients, invalid 1 example.
Conclusion: the present invention can be used for the treatment of osteoporosis, increase bone density.
Claims (2)
1. composition for injection method of quality control for the treatment of orthopaedic disease, it is characterized in that containing following composition: it is characterized in that, the weight proportion of each composition is: the extracting solution 10-100 weight portion of pig limbs bone, the extracting solution 10-30 weight portion of melon seed, the ultraviolet absorption peak of its polypeptide is 258nm.
2. composition for injection method of quality control for the treatment of orthopaedic disease, it is characterized in that containing following composition: it is characterized in that, the weight proportion of each composition is: the extracting solution 10-100 weight portion of pig limbs bone, the extracting solution 10-30 weight portion of melon seed, the ultraviolet absorption peak of the polypeptide of wherein said Os Sus domestica extracting solution and melon seed extract solution is 258nm.
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| CN107988302A (en) * | 2018-01-23 | 2018-05-04 | 吉林省吉诺生物工程有限责任公司 | A kind of application of the preparation method and cervus and cucumis polypeptide of cervus and cucumis polypeptide in special medicine purposes food is prepared |
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Application publication date: 20130501 |