CN104248651A - Pharmaceutical composition prepared from deer bone and melon seed as raw materials - Google Patents
Pharmaceutical composition prepared from deer bone and melon seed as raw materials Download PDFInfo
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- CN104248651A CN104248651A CN201310257398.2A CN201310257398A CN104248651A CN 104248651 A CN104248651 A CN 104248651A CN 201310257398 A CN201310257398 A CN 201310257398A CN 104248651 A CN104248651 A CN 104248651A
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Abstract
The invention belongs to the technical field of medicine and discloses a pharmaceutical composition prepared from deer bone and melon seed as raw materials. The pharmaceutical composition can be processed to form an injection preparation. A weight ratio of substances having molecular weight more than 10000 to polypeptide in the injection preparation is less than or equal to 5.0%. A research result shows that the injection preparation has high safety and high stability.
Description
Technical field
The invention belongs to medical art, be specifically related to the pharmaceutical composition that a kind of raw material is Os Cervi and Semen Melo.
Background technology
With the pharmaceutical preparation that Os Cervi and Semen Melo are raw material, mainly cervus and cucumis polypeptide ejection preparation, said preparation has the effect regulating bone metabolism, stimulated osteoblastic proliferation, promotion new bone formation, also scalable calcium phosphorus metabolism, increase bone doped calcium, prevent osteoporosis, and there is the effects such as antiinflammatory, analgesia, rheumatism, widely use clinical.
In cervus and cucumis polypeptide ejection preparation, self-bone grafting polypeptide class biotic factor effectively can promote the synthesis affecting the bdgf of bone formation and absorption in body, comprise bone morphogenetic protein (BNPs), β-transforming growth factor (TGF-β) and fibroblast growth factor (FGF) etc., thus there is multiple biological activity, promote the effect of cell mitogen and differentiation, and there is appearance bone active.Wherein BMPs is a kind of efficient inductive substance, the initially signal molecule of mesenchymal cell to bone system cell differentiation, around energy induction of vascular, travelling mesenchymal cell is converted into the bone system cell of irreversibility, i.e. chondrocyte and osteoblast, thus promotion callus formation, induction new bone formation, promotes fracture repair; The also change of scalable extracellular matrix components, by with TGF-β and FGF coordinative role each other, induce new bone formation better, make osseous tissue more ripe.TGF-β Ze Shi gang has multiple protein polypeptide, have osteoblast and chondroblast and promote differentiation or fall PD dual function, with the multiple factor as extracellular matrix and other break up the collaborative adjustment participated in cell differentiation together with the growth regulation factor, also can promote the synthesis of extracellular matrix, and have remarkable inhibitory action to the substrate degradation of its new synthesis; Also its synthesis type i collagen, osteonectin and osteopontin can be promoted for osteoblast; Meanwhile, the effect of TGF-β to lymphocyte and macrophage shows, it can alleviate the destructiveness of inflammatory reaction, and some macrophage derived cytokine can be assisted again to play a role in tissue repair.FGF is one group of heparin bonding polypeptide, the trend of irritation cell can move, breeds and break up, increase the quantity of rubber polymer archeocyte, promote the synthesis of bone collagen and noncollagen protein, the synthesis of increase Bone Gla protein.Semen Melo extract forms from the ripe dry seed of cucurbitaceous plant Fructus Melo through special process extraction, can reduce fracture local capillary permeability, reduce the recovery that inflammatory exudation promotes locally poor arterial inflow; Whole blood viscosity and erythrocyte aggregation degree can be reduced, improve the blood circulation of callus local, for osteocyte provides a good blood supply environment; The release of prostaglandin can also be suppressed, reach analgesic effect.In promotion fracture heals in early days, Semen Melo extract has synergism with the self-bone grafting polypeptide class biotic factor supplemented, and can promote the synthesis of bdgf.The multiple free amino acid that cervus and cucumis polypeptide is rich in is that the bdgfs such as osteocyte synthesis BNPs, TGF-β and FGF are supplied raw materials, thus promotes the synthesis of bdgf.Organic calcium wherein, phosphonium ion can participate in alcium and phosphor metabolization, maintain bone volume.
Clinical practice shows, the ejection preparation being raw material with Os Cervi and Semen Melo is the active drug for the treatment of nonunion, osteoporosis, rheumatism, rheumatoid arthritis, wrist navicular bone ischemic necrosis and soft tissue injury etc., having a extensive future at orthopaedics.
Along with the clinical practice of said preparation is more and more extensive, occur some untoward reaction, although untoward reaction rate is lower, drug relationship is to the life of people, and improving its product quality is the most important thing.
Summary of the invention
For these reasons, applicant passes through years of researches, determine in the ejection preparation prepared for raw material with Os Cervi and Semen Melo, the material that molecular weight is greater than 10000 is less than and equals 5.0%, research shows, the material that molecular weight is greater than 10000 is less than or equal to the ejection preparation of 5.0%, has better safety.
The present invention is achieved through the following technical solutions.
Raw material is a pharmaceutical composition for Os Cervi and Semen Melo, and drug regimen raw material is ejection preparation prepared by Os Cervi and Semen Melo, and the material that the preparation middle-molecular-weihydroxyethyl that this pharmaceutical composition is prepared into is greater than 10000 accounts for polypeptide weight and is less than or equal to 5.0%.
The material that preferred preparation middle-molecular-weihydroxyethyl described above is greater than 10000 accounts for polypeptide weight and is less than or equal to 3.0%.
The material that preferred formulation middle-molecular-weihydroxyethyl described above is greater than 10000 accounts for polypeptide weight and is less than or equal to 1.0%.
In pharmaceutical composition described above, the weight ratio of Os Cervi and Semen Melo is 1-4: 1-4.
Ejection preparation described above comprises injection and injectable powder.
The preparation method of ejection preparation described above includes but not limited to following:
(1) get Os Cervi and remove bone marrow, pulverize, add the 2-4 water for injection doubly of Os Cervi weight, 120 DEG C-125 DEG C are extracted 3 times, each 3 hours-5 hours, merge extractive liquid, filter, filtrate is 2.5-3.5 with sour adjust pH, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate uses adjusting PH with base 9.0-11.0, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate is with sour adjust pH 6.5-7.5, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the 2-4 water for injection doubly of Semen Melo weight, 120 DEG C-125 DEG C are extracted 3 times, each 3 hours-5 hours, merge extractive liquid, filter, filtrate is 2.5-3.5 with sour adjust pH, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate uses adjusting PH with base 9.0-11.0, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate is with sour adjust pH 6.5-7.5, at the centrifugal 5-10 minute of 15000-17000r/min, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Semen Melo extracting solution,
(3) according to content of peptides weight ratio 1-3: 0.5-1 mixing Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 3-6mg/ml, and fill, obtains injection;
Or according to content of peptides weight ratio 1-3: 0.5-1 mixing Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate using intercepts the ultrafilter membrane ultrafiltration of molecular weight 8000, retain permeate, permeate is through 0.22 μm of filter element filtering, and being concentrated into content of peptides is 3-6mg/ml, fill, lyophilization, obtains lyophilized injectable powder.
In the preparation method of injection described above, acid is acetic acid, citric acid, maleic acid, lactic acid or tartaric acid.
In the preparation method of injection described above, alkali is sodium citrate, sodium acetate, diethanolamine or ethylenediamine.
One, anaphylactic reaction experimental study
Test 1 group: pharmaceutical composition Os Cervi 400g, Semen Melo 100g, is prepared into injection, injection middle-molecular-weihydroxyethyl be greater than that 10000 materials account for polypeptide weight 5.5%.
(1) get Os Cervi and remove bone marrow, pulverize, get 400g, add water 1200g, extract 3 times in 121 DEG C, each 4 hours, merge extractive liquid, filter, filtrate hydrochloric acid adjust pH is 3.0, 0 DEG C leaves standstill 16 hours, filter, filtrate adjusts pH10.0 with sodium hydroxide, 0 DEG C leaves standstill 16 hours, filter, filtrate is with hydrochloric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo 100g is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate hydrochloric acid adjust pH is 3.0, 0 DEG C leaves standstill 18 hours, filter, filtrate adjusts pH10.0 with sodium hydroxide, 0 DEG C leaves standstill 12 hours, filter, filtrate is with hydrochloric acid adjust pH 7.0, at 16000r/min centrifugal 10 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 4mg/ml, and fill, obtains injection;
Test 2 groups: pharmaceutical composition Os Cervi 400g, Semen Melo 100g, is prepared into injection, injection middle-molecular-weihydroxyethyl be greater than that 10000 materials account for polypeptide weight 5.0%.
(1) get Os Cervi and remove bone marrow, get 400g to pulverize, add the water for injection of 2 times of Os Cervi weight, 125 DEG C are extracted 3 times, each 3 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 2.5, 5 DEG C leave standstill 12 hours, filter, filtrate adjusts pH9.0 with sodium citrate, 5 DEG C leave standstill 12 hours, filter, filtrate is with citric acid adjust pH 6.5, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1.5mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo 100g is got, pulverize, add the water for injection of 2 times of Semen Melo weight, 125 DEG C are extracted 3 times, each 3 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 5 DEG C leave standstill 12 hours, filter, filtrate adjusts pH9.0 with sodium citrate, 5 DEG C leave standstill 24 hours, filter, filtrate is with citric acid adjust pH 6.5, at 15000r/min centrifugal 5 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1.5mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 4mg/ml, and fill, obtains injection;
Test 3 groups: pharmaceutical composition Os Cervi 400g, Semen Melo 100g, is prepared into injection, injection middle-molecular-weihydroxyethyl be greater than that 10000 materials account for polypeptide weight 4.0%.
(1) get Os Cervi and remove bone marrow, get 400g to pulverize, add the water for injection of 2.5 times of Os Cervi weight, 122 DEG C are extracted 3 times, each 4.5 hours, merge extractive liquid, filter, filtrate lactic acid adjust pH is 3.3, 3 DEG C leave standstill 20 hours, filter, filtrate adjusts pH10.5 with sodium acetate, 3 DEG C leave standstill 20 hours, filter, filtrate is with lactic acid adjust pH 7.3, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2.5mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo 100g is got, pulverize, add the water for injection of 2.5 times of Semen Melo weight, 124 DEG C are extracted 3 times, each 3.5 hours, merge extractive liquid, filter, filtrate lactic acid adjust pH is 3.0, 3 DEG C leave standstill 22 hours, filter, filtrate adjusts pH10.5 with sodium acetate, 3 DEG C leave standstill 22 hours, filter, filtrate is with lactic acid adjust pH 7.2, at 15500r/min centrifugal 6 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2.5mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 4mg/ml, and fill, obtains injection;
Test 4 groups: pharmaceutical composition Os Cervi 400g, Semen Melo 100g, is prepared into injection, injection middle-molecular-weihydroxyethyl be greater than that 10000 materials account for polypeptide weight 2.8%.
(1) get Os Cervi and remove bone marrow, get 400g to pulverize, add the water for injection of 3.5 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, when 0 DEG C standing 16, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, 0 DEG C leaves standstill 16 hours, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 4mg/ml, and fill, obtains injection;
Test 5 groups: pharmaceutical composition Os Cervi 400g, Semen Melo 100g, is prepared into injection, injection middle-molecular-weihydroxyethyl be greater than that 10000 materials account for polypeptide weight 0.80%.
(1) get Os Cervi and remove bone marrow, get 400g to pulverize, add the water for injection of 3 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4.5 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 20 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 20 hours, filter, filtrate is with citric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 22 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 22 hours, filter, filtrate is with citric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 4mg/ml, and fill, obtains injection;
Experimental animal: male BN rats, SPF level, body weight 180-200g.
Test method: get rat, random packet, matched group, trial drug 1 group are to trial drug 5 groups, and give BN rat, 0.8mL/kg by the clinical multiple dose lumbar injection that waits, the next day injects 1 time, continuous 3 times.Matched group injection physiological saline solution.The next day of 3rd injectable drug, then give medicine 1.6mL/kg, tail vein injection administration, matched group gives physiological saline solution, and each treated animal administration 30 minutes, gets eye socket blood, by sacrifice of animal after blood sampling, takes out lungs and trachea, gets serum for test set amine content.Get the lung of rat, bronchial tissue 100mg, add 1mL homogenate, multigelation 3 times in liquid nitrogen, each 10min, then ultrasonic 3 × 4s in ice bath, 4 DEG C of centrifugal 30min of 12000r/min.Get supernatant, after protein quantification, ELISA surveys histamine content, and the method adopting test kit to provide measures.
Result of the test: in table 1.
Table 1 is on the impact of histamine content in BN rat blood serum and tissue
Note: compare * * P < 0.01, * P < 0.05 with matched group; ##P < 0.01, #P < 0.05 is compared with test 1 group.
Conclusion (of pressure testing): above-mentioned test shows, but when the high molecular weight material that preparation middle-molecular-weihydroxyethyl is greater than 10000 is less than or equal to 5%, histamine in serum significantly reduces (comparing P < 0.05 with the group being greater than 5%), and when high molecular weight material is less than 3%, in serum, histamine reduces further, absolutely prove, controlling Os Cervi and Semen Melo is high molecular weight material in the preparation that is prepared into of raw material, has great importance.
[high molecular weight material] measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability are with gel chromatographic columns (TSKgelG2000SW); Mobile phase is acetonitrile-water-trifluoroacetic acid (35: 65: 0.1); Flow velocity is 0.7ml/mim; Determined wavelength is 214nm.Number of theoretical plate calculates by ribonuclease A peak and is not less than 2000.
Ribonuclease A (molecular weight 13700), insulin human (molecular weight 5808), Thymosin alpha are got in the preparation of standard curve respectively
1(molecular weight 3108), somatostatin (molecular weight 1638) are appropriate, with mobile phase to make in every 1ml respectively containing the solution of 0.5mg as molecular weight standard solution.Get molecular weight standard solution 10 μ L injection liquid chromatography respectively, record chromatogram, repeat sample introduction, its relative deviation of retention time must not be greater than 2.0%.With the retention time at each peak for abscissa, molecular weight logarithm is that vertical coordinate makes standard curve, and carry out linear regression, correlation coefficient must not be less than 0.99.
Algoscopy gets test sample 10 μ L, injection liquid chromatography, and record chromatogram, calculate with area normalization method, test sample middle-molecular-weihydroxyethyl is greater than the content of 10000 daltonian components.
Two, stability test
Test method: by above-mentioned preparation temperature 40 DEG C ± 2 DEG C, place under the condition of relative humidity 75% ± 5%, detect content, pH, the bacterial endotoxin of 0 month, 1 month, 2 months, 3 months injection respectively, testing result is in Table 2-table 5.
Table 2 stability test result (0 month)
Table 3 stability test result (1 month)
Table 4 stability test result (2 months)
Table 5 stability test result (3 months)
Conclusion (of pressure testing): above-mentioned test shows that the material being greater than 10000 when preparation middle-molecular-weihydroxyethyl accounts for polypeptide weight when being greater than 5.0%, 2 months time, its bacterial endotoxin is undesirable, 3 months time, content and endotoxin are all undesirable, and be less than or equal to 5.0% preparation stability better, absolutely prove the high molecular weight material controlling preparation middle-molecular-weihydroxyethyl and be greater than 10000, significant.
Above-mentioned detection method is as follows:
(1) pH value: should be 5.5 ~ 7.0 (Chinese Pharmacopoeia version in 2010 two annex VIH).
(2) bacterial endotoxin: get this product, checks (Chinese Pharmacopoeia version in 2010 two annex XIE) in accordance with the law, should be less than 4EU in every 1ml containing endotoxic amount.
(3) assay: precision measures this product 1ml, puts in 25ml measuring bottle, adds 0.1mol/L sodium hydroxide solution and is diluted to scale, as need testing solution, measures according to forint phenol algoscopy.
Forint phenol algoscopy
Sodium hydroxide 10g got by reagent alkaline copper test solution, sodium carbonate 50g, and the 400ml that adds water makes dissolving, as first liquid; Get Soluble tartar. 0.5g, the 50ml that adds water makes dissolving, separately gets copper sulfate 0.25g, and the 30ml that adds water makes dissolving, by two liquid mixing, as second liquid.
Before use, merge first, second two liquid, and add water to 500ml.
Bovine serum albumin reference substance is got in the preparation of maneuver reference substance solution, and add water the solution made containing 0.3mg in every 1ml.
The method preparation prepared according to specifying under each kind item of need testing solution.
The preparation precision of standard curve measures reference substance solution 0.0ml, 0.1ml, 0.3ml, 0.5ml, 0.7ml, 0.9ml, put in tool plug test tube respectively, respectively add water to 1.0ml, add alkaline copper test solution 1.0ml more respectively, shake up, respectively add forint phenol test solution (getting the stock solution 1 → 16 in forint test solution) 4.0ml, mix immediately, to put in 55 DEG C of water-baths accurate response 5 minutes, put psychrolusia 10 minutes, according to ultraviolet visible spectrophotometry (China's coastal port two annex IVA), measure trap at the wavelength place of 650nm; Using No. 0 pipe as blank.Regression equation is calculated with reference substance solution concentration and corresponding trap.
Algoscopy precision measures need testing solution 1.0ml, the method under the preparation of sighting target directrix curve, from " adding alkaline copper test solution ", measures in accordance with the law, from the content of regression equation calculation polypeptide, and is multiplied by extension rate, obtains final product.
Preparation embodiment
Embodiment 1
Pharmaceutical composition Os Cervi 3000g, Semen Melo 1000g
(1) get Os Cervi and remove bone marrow, get 3000g to pulverize, add the water for injection of 2 times of Os Cervi weight, 125 DEG C are extracted 3 times, each 3 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 2.5, 5 DEG C leave standstill 12 hours, filter, filtrate adjusts pH9.0 with sodium citrate, 5 DEG C leave standstill 12 hours, filter, filtrate is with citric acid adjust pH 6.5, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1.5mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo 100g is got, pulverize, add the water for injection of 2 times of Semen Melo weight, 125 DEG C are extracted 3 times, each 3 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 5 DEG C leave standstill 12 hours, filter, filtrate adjusts pH9.0 with sodium citrate, 5 DEG C leave standstill 24 hours, filter, filtrate is with citric acid adjust pH 6.5, at 15000r/min centrifugal 5 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1.5mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 3.5mg/ml, and fill obtains injection 1000.The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 4.85% of polypeptide weight.
Embodiment 2
Pharmaceutical composition Os Cervi 4000g, Semen Melo 2000g
(1) get Os Cervi and remove bone marrow, get 4000g to pulverize, add the water for injection of 2.5 times of Os Cervi weight, 122 DEG C are extracted 3 times, each 4.5 hours, merge extractive liquid, filter, filtrate lactic acid adjust pH is 3.3, 3 DEG C leave standstill 20 hours, filter, filtrate adjusts pH10.5 with sodium acetate, 3 DEG C leave standstill 20 hours, filter, filtrate is with lactic acid adjust pH 7.3, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2.5mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo 2000g is got, pulverize, add the water for injection of 2.5 times of Semen Melo weight, 124 DEG C are extracted 3 times, each 3.5 hours, merge extractive liquid, filter, filtrate lactic acid adjust pH is 3.0, 3 DEG C leave standstill 22 hours, filter, filtrate adjusts pH10.5 with sodium acetate, 3 DEG C leave standstill 22 hours, filter, filtrate is with lactic acid adjust pH 7.2, at 15500r/min centrifugal 6 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2.5mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 5mg/ml, and fill obtains injection 1000; The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 4.25% of polypeptide weight.
Embodiment 3
Pharmaceutical composition Os Cervi 1000g, Semen Melo 3000g
(1) get Os Cervi and remove bone marrow, get 1000g to pulverize, add the water for injection of 3.5 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, when 0 DEG C standing 16, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, 0 DEG C leaves standstill 16 hours, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 2: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 3.80mg/ml, and fill obtains injection 1000; The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 3.45% of polypeptide weight.
Embodiment 4
Pharmaceutical composition Os Cervi 2500g, Semen Melo 1500g
(1) get Os Cervi and remove bone marrow, get 2500g to pulverize, add the water for injection of 3 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4.5 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 20 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 20 hours, filter, filtrate is with citric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 22 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 22 hours, filter, filtrate is with citric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Semen Melo extracting solution,
(3) Os Cervi extracting solution and Semen Melo extracting solution is mixed according to content of peptides weight ratio 1: 1, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 3.5mg/ml, and fill, obtains injection; The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 3.0% of polypeptide weight.
Embodiment 5
Pharmaceutical composition Os Cervi 3000g, Semen Melo 3000g
(1) get Os Cervi and remove bone marrow, get 1000g to pulverize, add the water for injection of 3.5 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, when 0 DEG C standing 16, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate tartaric acid adjust pH is 3.0, 0 DEG C leaves standstill 16 hours, filter, filtrate adjusts pH10.0 with ethylenediamine, 0 DEG C leaves standstill 16 hours, filter, filtrate is with tartaric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Semen Melo extracting solution,
(3) content of peptides weight ratio 2.5: 0.8 mixes Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate using intercepts the ultrafilter membrane ultrafiltration of molecular weight 8000, retain permeate, permeate is through 0.22 μm of filter element filtering, and being concentrated into content of peptides is 6mg/ml, fill, lyophilization, obtains lyophilized injectable powder 1000; The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 3.10% of polypeptide weight.
Embodiment 6
Pharmaceutical composition Os Cervi 4000g, Semen Melo 1500g
(1) get Os Cervi and remove bone marrow, get 4000g to pulverize, add the water for injection of 3 times of Os Cervi weight, 121 DEG C are extracted 3 times, each 4.5 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 20 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 20 hours, filter, filtrate is with citric acid adjust pH 7.0, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 2mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the water for injection of 3 times of Semen Melo weight, 121 DEG C are extracted 3 times, each 4 hours, merge extractive liquid, filter, filtrate citric acid adjust pH is 3.0, 2 DEG C leave standstill 22 hours, filter, filtrate adjusts pH10.0 with sodium citrate, 2 DEG C leave standstill 22 hours, filter, filtrate is with citric acid adjust pH 7.0, at 16000r/min centrifugal 8 minutes, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Semen Melo extracting solution,
(3) content of peptides weight ratio 2.0: 1.0 mixes Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate using intercepts the ultrafilter membrane ultrafiltration of molecular weight 8000, retain permeate, permeate is through 0.22 μm of filter element filtering, and being concentrated into content of peptides is 6mg/ml, fill, lyophilization, obtains lyophilized injectable powder 1000; The material that injection middle-molecular-weihydroxyethyl is greater than 10000 accounts for 0.75% of polypeptide weight.
Claims (8)
1. a raw material is the pharmaceutical composition of Os Cervi and Semen Melo, drug regimen raw material is ejection preparation prepared by Os Cervi and Semen Melo, it is characterized in that material that preparation middle-molecular-weihydroxyethyl that this pharmaceutical composition is prepared into is greater than 10000 accounts for polypeptide weight and is less than or equal to 5.0%.
2. a kind of raw material according to claim 1 is the pharmaceutical composition of Os Cervi and Semen Melo, and the material that wherein preparation middle-molecular-weihydroxyethyl is greater than 10000 accounts for polypeptide weight and is less than or equal to 3.0%.
3. a kind of raw material according to claim 1 is the pharmaceutical composition of Os Cervi and Semen Melo, and the material that wherein preparation middle-molecular-weihydroxyethyl is greater than 10000 accounts for polypeptide weight and is less than or equal to 1.0%
4. a kind of raw material according to claim 1 is the pharmaceutical composition of Os Cervi and Semen Melo, and wherein the weight ratio of Os Cervi and Semen Melo is 1-4: 1-4.
5. a kind of raw material according to claim 1 is the pharmaceutical composition of Os Cervi and Semen Melo, and wherein ejection preparation comprises injection and injectable powder.
6. a kind of raw material according to claim 1 is the pharmaceutical composition of Os Cervi and Semen Melo, and wherein the preparation method of ejection preparation is:
(1) get Os Cervi and remove bone marrow, pulverize, add the 2-4 water for injection doubly of Os Cervi weight, 120 DEG C-125 DEG C are extracted 3 times, each 3 hours-5 hours, merge extractive liquid, filter, filtrate is 2.5-3.5 with sour adjust pH, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate uses adjusting PH with base 9.0-11.0, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate is with sour adjust pH 6.5-7.5, filtrate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Os Cervi extracting solution,
(2) Semen Melo is got, pulverize, add the 2-4 water for injection doubly of Semen Melo weight, 120 DEG C-125 DEG C are extracted 3 times, each 3 hours-5 hours, merge extractive liquid, filter, filtrate is 2.5-3.5 with sour adjust pH, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate uses adjusting PH with base 9.0-11.0, 0 DEG C of-5 DEG C of standing 12-24 hour, filter, filtrate is with sour adjust pH 6.5-7.5, at the centrifugal 5-10 minute of 15000-17000r/min, get the ultrafilter membrane ultrafiltration that supernatant intercepting molecular weight is 100,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 10,000, retain permeate, permeate intercepting molecular weight is the ultrafilter membrane ultrafiltration of 8000, retain permeate, be concentrated into containing content of peptides 1-3mg/ml, obtain Semen Melo extracting solution,
(3) according to content of peptides weight ratio 1-3: 0.5-1 mixing Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate, with the ultrafilter membrane ultrafiltration intercepting molecular weight 8000, retains permeate, permeate is through 0.22 μm of filter element filtering, being concentrated into content of peptides is 3-6mg/ml, and fill, obtains injection;
Or according to content of peptides weight ratio 1-3: 0.5-1 mixing Os Cervi extracting solution and Semen Melo extracting solution, mixing completely, add active carbon, filter, filtrate using intercepts the ultrafilter membrane ultrafiltration of molecular weight 8000, retain permeate, permeate is through 0.22 μm of filter element filtering, and being concentrated into content of peptides is 3-6mg/ml, fill, lyophilization, obtains lyophilized injectable powder.
7. a kind of raw material according to claim 6 is the pharmaceutical composition of Os Cervi and Semen Melo, and in the preparation method of wherein injection, acid is acetic acid, citric acid, maleic acid, lactic acid or tartaric acid.
8. a kind of raw material according to claim 6 is the pharmaceutical composition of Os Cervi and Semen Melo, and in the preparation method of wherein injection, alkali is sodium citrate, sodium acetate, diethanolamine or ethylenediamine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106820158A (en) * | 2016-12-30 | 2017-06-13 | 江苏天美健大自然生物工程有限公司 | Calcium can be drawn to the marrow and multiple agent and preparation method thereof of replenishing the calcium of bone calcium loss is prevented |
| CN107595924A (en) * | 2017-09-21 | 2018-01-19 | 哈尔滨松鹤制药有限公司 | A kind of bone-melon extract injection preparation and corresponding pharmaceutical composition |
| CN107897943A (en) * | 2017-11-28 | 2018-04-13 | 苏洁 | A kind of method that deer bone native peptides are extracted in the bone from deer |
| CN109142580A (en) * | 2018-09-12 | 2019-01-04 | 南京康舟医药科技有限公司 | Measure method of the atosiban acetate in relation to substance |
| CN110339335A (en) * | 2019-07-01 | 2019-10-18 | 哈尔滨誉衡制药有限公司 | A kind of cervus and cucumis polypeptide ejection preparation |
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| CN101628025A (en) * | 2009-05-12 | 2010-01-20 | 哈尔滨誉衡药业股份有限公司 | Pharmaceutical composition containing deer bone extractive and melon seed extract |
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| CN1742778A (en) * | 2005-10-09 | 2006-03-08 | 黑龙江迪龙制药有限公司 | Cervus and cucumis polypeptide injection composition and preparing method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106820158A (en) * | 2016-12-30 | 2017-06-13 | 江苏天美健大自然生物工程有限公司 | Calcium can be drawn to the marrow and multiple agent and preparation method thereof of replenishing the calcium of bone calcium loss is prevented |
| CN106820158B (en) * | 2016-12-30 | 2020-09-11 | 江苏天美健大自然生物工程有限公司 | Calcium supplementing compound preparation capable of introducing calcium into bone and preventing bone calcium loss and preparation method thereof |
| CN107595924A (en) * | 2017-09-21 | 2018-01-19 | 哈尔滨松鹤制药有限公司 | A kind of bone-melon extract injection preparation and corresponding pharmaceutical composition |
| CN107897943A (en) * | 2017-11-28 | 2018-04-13 | 苏洁 | A kind of method that deer bone native peptides are extracted in the bone from deer |
| CN109142580A (en) * | 2018-09-12 | 2019-01-04 | 南京康舟医药科技有限公司 | Measure method of the atosiban acetate in relation to substance |
| CN110339335A (en) * | 2019-07-01 | 2019-10-18 | 哈尔滨誉衡制药有限公司 | A kind of cervus and cucumis polypeptide ejection preparation |
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