CN1742778A - Cervus and cucumis polypeptide injection composition and preparing method - Google Patents

Cervus and cucumis polypeptide injection composition and preparing method Download PDF

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Publication number
CN1742778A
CN1742778A CNA2005101081577A CN200510108157A CN1742778A CN 1742778 A CN1742778 A CN 1742778A CN A2005101081577 A CNA2005101081577 A CN A2005101081577A CN 200510108157 A CN200510108157 A CN 200510108157A CN 1742778 A CN1742778 A CN 1742778A
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cervi
semen melo
polypeptide
solution
injection
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CN100363019C (en
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王金富
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HEILONGJIANG DILONG PHARMACEUTIC CO Ltd
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HEILONGJIANG DILONG PHARMACEUTIC CO Ltd
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Abstract

The present invention discloses a deer's bone melon seed polypeptide medicine composite. It is made up by using deer's bone extract, melon seed extract and one or several excipients, in which the weight ratio of deer's bone polypeptide and melon seed polypeptide is 2:1 to 6:1. Said polypeptide medicine composite can be used as injection preparation.

Description

Injection cervus and cucumis polypeptide pharmaceutical composition and preparation method thereof
Technical field
The present invention relates to injection cervus and cucumis polypeptide pharmaceutical composition and preparation method thereof.More specifically, the present invention relates to contain the injection cervus and cucumis polypeptide pharmaceutical composition of Os Cervi polypeptide and Semen Melo polypeptide.The invention still further relates to injection cervus and cucumis polypeptide preparation of drug combination method.
Background technology
Cervus and cucumis polypeptide is formulated with the extract of Os Cervi and Semen Melo, motherland's medical science is thought, Os Cervi sweet in the mouth, slight fever, have tonify deficiency win, bone and muscle strengthening, the effect of dispelling the wind and dampness pathogens limbs pain and the cold numbness of muscles and bones, and Semen Melo has eliminating stagnation, effects such as pain disappear, both preparations are used for cold expelling, wind-damp dispelling, analgesia, thereby rheumatic arthritis or rheumatoid arthritis are had therapeutical effect.
Some relevant cervus and cucumis polypeptide extract or its preparation technologies are disclosed in the prior art.For example, CN1470256A discloses and has promoted pharmaceutical composition that union of fracture and osteoarticular injury are repaired and its production and application.The pharmaceutical composition that the disclosed compositions of this patent application is made up of Os Cervi extract and Semen Melo extract and one or more carriers of pharmaceutically accepting or excipient; Os Cervi extract and Semen Melo extract are respectively that Os Cervi and Semen Melo crude drug raw material obtain through extracting, and the weight ratio of Os Cervi and Semen Melo crude drug raw material is 1: 4 to 4: 1.
This patent application also discloses the preparation of drug combination method, it comprise (1) with fresh Os Cervi after pretreatment, the water of weight such as in Os Cervi (400-100Kg), add, heating extraction is 3 times under 121 ℃ temperature; The water that merges gained is carried solution, is transferred to 3.2 extracting solution that obtain after the Acid precipitation with 2M hydrochloric acid adjusting pH value; Extracting solution after the heated and boiled Acid precipitation removes by filter impurity and the centrifugal Acid precipitation of removing; After collecting filtrate and centrifugal supernatant, add sodium hydroxide solution PH is transferred to 8.5, thereby obtain required Os Cervi extracting solution; (2) in rustless steel container, the water of weight such as in cleaning back Semen Melo (100-400Kg), add, heating extraction is 3 times under 121 ℃ temperature; Merge water and carry solution, regulate pH value with 2M hydrochloric acid and be transferred to 3.2; Extracting solution after the heated and boiled Acid precipitation, the centrifugal acid deposit of removing; After collecting centrifugal supernatant, add caustic lye of soda PH and be transferred to 8.3, thereby obtain required Semen Melo extracting solution; (3) the Os Cervi extracting solution and the Semen Melo extracting solution that obtain of blend step (1) and (2), heating is concentrated into 1/3 of original volume.After the PH of this concentrated solution was transferred to 7.2, using the molecular weight that dams successively was that 10,000 and 8,000 hollow fiber column carries out hyperfiltration treatment, and carrier or excipient that the mixed liquor that obtains and one or more are pharmaceutically accepted are made pharmaceutical composition.
In addition, CN1579542A discloses a kind of cervus and cucumis polypeptide for injection and its prepration technology.This cervus and cucumis polypeptide comprises polypeptides matter and excipient, wherein polypeptides matter is to extract to form from animal in deer family skeleton and cucurbitaceous plant muskmelon seeds, its parts by weight are polypeptides matter 5-100, excipient 20-90, the polypeptides matter molecular weight is 3000-10000 dalton, and pH value is 3.5-9.0.
This patent application also discloses the preparation technology of cervus and cucumis polypeptide, comprise (1) by weight mark get Os Cervi 17500-63000, add the water for injection that 3-8 doubly measures, hot pressing (80-120 ℃) is extracted 2-4 time.Merge extractive liquid, transfers pH value to 3.5-4.5, removes sediment, and supernatant transfers alkaline ph value to 8.5-9.0, removes sediment, and supernatant is used the ultrafilter membrane ultrafiltration after transferring neutral PH, and molecular cut off is 3000-10000 dalton relatively, from making the Os Cervi extracting solution; (2) mark is got Semen Melo 3000-10000 by weight, adds the water for injection that 3-8 doubly measures, and hot pressing (80-120 ℃) is extracted 2-4 time, and merge extractive liquid, removes sediment, ultrafiltration, and molecular cut off is 3000-10000 dalton relatively, makes the Semen Melo extracting solution; (3) Os Cervi and the Semen Melo extracting solution of step (1) and (2) are pressed 1-10: 1 mixed obtains cervus and cucumis polypeptide solution; (4) get cervus and cucumis polypeptide solution, add excipient (mannitol, Polyethylene Glycol, glucosan, lactose, glycine and colloidal substance) aqueous solution, lyophilization obtains off-white color block or amorphous powder.
Above-mentioned technology is than serving as extract of prescription composition and preparation method thereof with the crude drug raw material weight, because crude drug raw material Os Cervi and Semen Melo exist the place of production and the difference on the collection phase, the active ingredient that is contained differs greatly, liken prescription to the crude drug raw material weight, the effective component content unanimity of every batch of cervus and cucumis polypeptide extracting solution be difficult to guarantee producing, thus the drug quality produced can't be guaranteed.
Simultaneously, owing to be difficult to accomplish the in full accord of every batch of extraction conditions, even therefore the same place of production, the active ingredient that crude drug is carried of collection phase also there are differences, serve as that prescription is formed with crude drug raw material weight ratio, be difficult to guarantee the content of peptides unanimity of every batch of preparation of cervus and cucumis polypeptide.
Above-mentioned technology adopts 8 respectively, 000 hollow fiber column carries out hyperfiltration technique or adopts 10,000 ultrafilter membrane hyperfiltration techniques, can not effectively remove high molecular weight material in the extracting solution (in pharmaceutical production, molecular weight is called high molecular weight material greater than 5800 material), very easily cause allergy.
Os Cervi and Semen Melo extract contain multiple free amino acid, and it is supplied raw materials for the synthetic BMPs of osteocyte, bone source property biotic factors such as TGF-β, FGF, promotes the synthetic of bone source property biotic factor.But most of aminoacid are easily separated out in alkaline solution, and above-mentioned technology all adopts the pH value of alkalescence in leaching process, all be not inconsistent with the national drug standards.
Therefore, pressing in the prior art provides the stable injection cervus and cucumis polypeptide of a kind of active ingredient maintenance and the production technology of corresponding simplification, the injection cervus and cucumis polypeptide can be a raw material by the different places of production and the Os Cervi of different acquisition phase and Semen Melo, and product quality is not subjected to the extraction process condition influence, safe and effective, meet the relevant pharmaceutical production standard of country.
Summary of the invention
The present invention has solved the demand through making great efforts research for many years and exploring, and has finished the present invention.
The invention provides a kind of injection cervus and cucumis polypeptide pharmaceutical composition, it contains Os Cervi extract, Semen Melo extract and one or more excipient, and wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
The present invention also provides a kind of injection cervus and cucumis polypeptide pharmaceutical composition, and it is by being prepared as follows the method preparation, and this method comprises the steps:
A) preparation of Os Cervi extract solution:
(1) Os Cervi pretreatment;
(2) pretreated clean Os Cervi is pulverized;
(3) add 2 times of waters for injection more than the weight in broken Os Cervi, 121 ℃ of hot pressing are extracted to leach and are obtained an Os Cervi extracting solution;
(4) add weight water for injection more than 2 times in the Os Cervi slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach and obtain secondary Os Cervi extracting solution, an Os Cervi extracting solution that obtains with step (3) merges makes the Os Cervi extracting solution;
(5) the Os Cervi extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution, make Os Cervi extract solution;
B) preparation of Semen Melo extract solution:
(1) rinsing of drying and ripening Semen Melo is clean;
(2) water for injection of adding weight more than 2 times in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate is extracted 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add weight water for injection more than 2 times in the Semen Melo slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) the Semen Melo extracting solution is centrifugal, collect supernatant centrifugal liquid
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution, make Semen Melo extract solution;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
The present invention also provides a kind of injection cervus and cucumis polypeptide preparation of drug combination method, and it comprises the steps:
A) preparation of Os Cervi extract solution:
(1) Os Cervi pretreatment;
(2) pretreated clean Os Cervi is pulverized;
(3) add the water for injection of weight more than 2 times in broken Os Cervi, 121 ℃ of hot pressing are extracted to leach and are obtained an Os Cervi extracting solution;
(4) add weight water for injection more than 2 times in the Os Cervi slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach and obtain secondary Os Cervi extracting solution, an Os Cervi extracting solution that obtains with step (3) merges makes the Os Cervi extracting solution;
(5) the Os Cervi extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution, make Os Cervi extract solution;
B) preparation of Semen Melo extract solution:
(1) rinsing of drying and ripening Semen Melo is clean;
(2) water for injection of adding weight more than 2 times in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate is extracted 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add weight water for injection more than 2 times in the Semen Melo slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) the Semen Melo extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution, make Semen Melo extract solution;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
As the raw material that is used for pharmaceutical composition Os Cervi extract of the present invention and Semen Melo extract, use animal in deer family, especially the dry mature seed of skeleton of Cervus nippon Temminck (Cervus nippon Temmick) and cucurbitaceous plant Fructus Melo (Cucumis melo L.), after extracting respectively, mix, and make pharmaceutical composition of the present invention with one or more mixed with excipients.
According to the preferred embodiments of the invention, in injection cervus and cucumis polypeptide pharmaceutical composition, the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1.
Excipient as pharmaceutical composition of the present invention can be Dextran 40, glucose, lactose, Polyethylene Glycol, glucosan, glycine etc., consider the influence that content of peptides in the final products is detected, wherein preferred excipient is Dextran 40, glucose or lactose.Polypeptide total amount and excipient weight ratio should be 1: 5~and 30.
Injection cervus and cucumis polypeptide pharmaceutical composition of the present invention can be used for treating disease or symptoms such as rheumatism, rheumatoid arthritis, ankylosing spondylitis, all kinds fracture, repair in trauma and lumbago and skelalgia.
Though do not plan to be so limited, but we think, Os Cervi polypeptide in the pharmaceutical composition of the present invention is extracted by Os Cervi, bone wherein induces polypeptide class biotic factor can effectively promote influence 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., thus 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 factor 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 a 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 composition also, and by inducing new bone formation better with TGF-β and FGF coordinative role each other, makes osseous tissue more ripe.TGF-β then is the protein polypeptide that gang has multiple function, osteoblast and chondroblast there are the dual regulation effect that promotes that differentiation or reduction are broken up, regulate somatomedin with the multiple factor such as extracellular matrix with other differentiation and work in coordination with the adjusting that the participation pair cell breaks up; TGF-β can promote extracellular matrix synthetic, can directly stimulate the synthetic of fibroblast epimatrix, and its new synthetic substrate degradation is had remarkable inhibitory action; For osteoblast, TGF-β can promote its synthetic type i collagen, bone conglutination element and osteopontin; Simultaneously, TGF-β shows that to the effect of lymphocyte and macrophage it can alleviate the destructiveness of inflammatory reaction, can assist some macrophage derived cytokine to play a role in the cell tissue reparation again.FGF is that one group of heparin binds polypeptide, but the trend of irritation cell move, increment and differentiation increase the quantity of rubber polymer archeocyte, promote the synthetic of bone collagen and noncollagen protein, increase the synthetic of Bone Gla protein.
Semen Melo polypeptide extract in the pharmaceutical composition of the present invention is that the ripe exsiccant seed from the cucurbitaceous plant Fructus Melo extracts, and can reduce the local capillary permeability of fracture, and the minimizing inflammatory exudation promotes local blood to transport the recovery of obstacle; Simultaneously can also reduce whole blood viscosity and erythrocyte aggregation degree, improve the partial blood circulation of callus, for osteocyte provides a good blood supply environment; Can also suppress the release of prostaglandin in addition, reach analgesic effect; In promoting fracture heals in early days, Semen Melo extract induces the polypeptide biotic factor to have synergism with the bone that replenishes, and promotes the synthetic of bdgf.
In addition, injection Os Cervi polypeptide pharmaceutical composition of the present invention is rich in multiple free amino acid, supply raw materials for the synthetic BMPs of osteocyte, bone source property biotic factors such as TGF-β, FGF, promote the synthetic of bone source property biotic factor, organic calcium, phosphonium ion can participate in alcium and phosphor metabolization, keep bone volume.Thereby can effectively treat disease or symptoms such as rheumatism, rheumatoid arthritis, ankylosing spondylitis, all kinds fracture, repair in trauma and lumbago and skelalgia.
The dosage of injection cervus and cucumis polypeptide pharmaceutical composition of the present invention is: when being used for intramuscular injection, a 4-8mg, daily dose are 8-16mg, with intramuscular injection behind an amount of water for injection dissolved dilution; When being used for intravenous injection, every day, 16-24mg instiled with 5% glucose injection or 0.9% sodium chloride injection 250-500ml dissolved dilution posterior vein.Accurately dosage will be determined according to factors such as patient's age, body weight, the symptom of being treated, patient body situations by the clinician, and general 10-15 day is a course of treatment.The packing specification of cervus and cucumis polypeptide pharmaceutical composition of the present invention has 4mg, 8mg, 16mg, 24mg.
In more particular embodiment of the present invention, it provides a kind of injection cervus and cucumis polypeptide preparation of drug combination method, and it comprises the steps:
A) preparation of Os Cervi extract solution:
(1) after Os Cervi boils 30 minutes in boiling water, removes fascia and residual meat, finish pretreatment;
(2) pretreated clean deer bone powder is broken to the following broken bone of 1cm;
(3) add the water for injection of 2 times of weight in broken Os Cervi, 121 ℃ of hot pressing were extracted 2 hours, leached and obtained an Os Cervi extracting solution;
(4) 2 times of weight waters for injection of adding in the Os Cervi slag after once extracting continue to extract 2 hours 121 ℃ of-123 ℃ of hot pressing, leach to obtain secondary Os Cervi extracting solution, make the Os Cervi extracting solution with the Os Cervi extracting solution merging that step (3) obtains, and placement is spent the night;
(5) with the Os Cervi extracting solution with 4000 rev/mins centrifugal 15 minutes, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution,, make Os Cervi extract solution with 0.22 μ m membrane filtration;
B) preparation of Semen Melo extract solution:
(1) with water for injection rinsing 3-4 time of drying and ripening Semen Melo;
(2) water for injection of 2 times of weight of adding in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate was extracted 2 hours 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add 2 times of weight waters for injection in the Semen Melo slag after once extracting, continue to extract 2 hours 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) with the Semen Melo extracting solution with 4000 rev/mins centrifugal 15 minutes, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution,, make Semen Melo extract solution with 0.22 μ m membrane filtration;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1, excipient is selected from Dextran 40, glucose or lactose, and polypeptide total amount and excipient weight ratio are 1: 5-30.
The method of pharmaceutical compositions step C) is a known method in the pharmaceutical technology field, and those skilled in the art will choose concrete accurately process and condition according to the excipient of prepared dosage form and selection.
As mentioned above, injection cervus and cucumis polypeptide pharmaceutical composition provided by the invention and preparation method thereof has following advantage:
(1) be unit of account with Os Cervi polypeptide and Semen Melo polypeptide, can guarantee every batch of preparation content of peptides unanimity, batch difference can be reduced to minimum, guarantees product quality;
(2) be unit of account with Os Cervi polypeptide and Semen Melo polypeptide, the final products content difference of having avoided the place of production, collection phase, extraction conditions difference to be occurred;
(3) pulverize Os Cervi and the homogenate of preparation Semen Melo in advance, improve the extraction ratio that Os Cervi polypeptide and Semen Melo polypeptide are extracted in hot pressing;
(4) adopt pure hot pressing extracting method, avoid acid or alkali treatment, improve the extraction ratio of active ingredient;
(5) adopt the method for classification ultrafiltration, can effectively remove the molecular weight that exists in the extract and surpass 5800 high molecular weight material, allergic probability is reduced to minimum, improved constant product quality;
(6) adopting Dextran 40, glucose or lactose is excipient, can avoid content of peptides is detected the influence that is brought.
Brief Description Of Drawings
Accompanying drawing 1 is the process flow diagram that the present invention prepares the cervus and cucumis polypeptide pharmaceutical composition.
The specific embodiment
The present invention will specify technical scheme of the present invention by following embodiment, it should be understood that specifying in context is not construed as limiting the invention.Protection scope of the present invention is illustrated by claim.
Embodiment
Embodiment 1: the preparation of Os Cervi extract solution
Place boiling water to boil 30min Os Cervi, take out, reject fascia and residual meat, get clean Os Cervi.Get clean Os Cervi, be crushed to less than the broken bone of 1cm standby.Get broken bone 30kg, add 60kg water for injection, extract 2h, leach extracting solution one time 121 ℃ of hot pressing; Add 60kg water for injection again, 2h is extracted in 121 ℃ of hot pressing, leaches secondary raffinate, merging filtrate, and placement is spent the night.Get the Os Cervi extracting solution, centrifugal (4000 rev/mins, 15 minutes) get supernatant, abandon precipitation.Get supernatant, carry out the classification ultrafiltration, 100KD, 10KD, 6KD get filtered solution at every turn, abandon concentrated solution.Get filtered solution, be evaporated to 10% of cumulative volume, collect concentrated solution, regulate pH value 6.0-6.5,0.22 μ m filter membrane aseptic filtration gets Os Cervi extract solution 10L.
Measure through high performance liquid chromatography, forint phenol method, have Os Cervi polypeptide, its content is 6.1mg/ml.
Embodiment 2: the preparation of Semen Melo extract solution
Get Semen Melo, put in the water for injection, rinsing is 3-4 time repeatedly, and empty solid carbon dioxide part is chosen foreign material, and it is standby to get clean Semen Melo.Get clean Semen Melo 15kg, add 30kg water for injection, grind to form Semen Melo homogenate with colloid mill.Get Semen Melo homogenate, 2h is extracted in 121 ℃ of hot pressing, leaches extracting solution one time; Add 30kg water for injection again, 121 ℃ of ℃ of hot pressing continue to extract 2h, leach secondary raffinate, merging filtrate, and placement is spent the night.Get the Semen Melo extracting solution, centrifugal (4000 rev/mins, 15 minutes) get supernatant, abandon precipitation.Get supernatant, carry out classification ultrafiltration: 100KD, 10KD, 6KD, get filtered solution at every turn, abandon concentrated solution.Get final filtered solution, be evaporated to 10% of cumulative volume, collect concentrated solution, regulate pH value 6.0-6.5,0.22 μ m filter membrane aseptic filtration gets the about 5L of Semen Melo extract solution.
Measure through spectrophotography, forint phenol method, have Semen Melo polypeptide, its content is 4.2mg/ml.
Embodiment 3: pharmaceutical composition 1
Preparation prescription:
The Os Cervi extract solution 26.7g (by Os Cervi polypeptide) of embodiment 1
The Semen Melo extract solution 13.3g (by Semen Melo polypeptide) of embodiment 2
20% excipient solution 5000ml
5%NaOH (or 5%HCl) is an amount of
Water for injection adds to 20000ml
The Os Cervi extract solution of embodiment 1 preparation and the Semen Melo extract solution of embodiment 2 preparations are pressed Os Cervi polypeptide and 2: 1 mixed of Semen Melo polypeptide weight ratio, add 5000ml excipient (Dextran 40, glucose or lactose) solution, transfer survey solution pH value to 5.5-7.0 with an amount of 5%NaOH or 5%HCl, benefit adds to the full amount of water for injection, by canned, lyophilizing, roll steps such as lid, make the preparation of every 4mg.
Embodiment 4: pharmaceutical composition 2
Preparation prescription:
The Os Cervi extract solution 30g (by Os Cervi polypeptide) of embodiment 1
The Semen Melo extract solution 10g (by Semen Melo polypeptide) of embodiment 2
20% excipient solution 5000ml
5%NaOH (or 5%HCl) is an amount of
Water for injection adds to 20000ml
Except that the consumption of Os Cervi extract and Semen Melo extract was different, pharmaceutical composition prepared as described in example 3 above, by canned, lyophilizing, roll steps such as lid, made the preparation of every 4mg.
Embodiment 5: pharmaceutical composition 3
Preparation prescription:
The Os Cervi extract solution 53.4g (by Os Cervi polypeptide) of embodiment 1
The Semen Melo extract solution 26.6g (by Semen Melo polypeptide) of embodiment 2
20% Dextran 40 solution 10000ml
5%NaOH (or 5%HCl) is an amount of
Water for injection adds to 40000ml
Except that the consumption of Os Cervi extract and Semen Melo extract was different, pharmaceutical composition prepared as described in example 3 above, by canned, lyophilizing, roll steps such as lid, made the preparation of every 8mg.
Embodiment 6: pharmaceutical composition 4
Preparation prescription:
The Os Cervi extract solution 64g (by Os Cervi polypeptide) of embodiment 1
The Semen Melo extract solution 16g (by Semen Melo polypeptide) of embodiment 2
20% Dextran 40 solution 10000ml
5%NaOH (or 5%HCl) is an amount of
Water for injection adds to 40000ml
Except that the consumption of Os Cervi extract and Semen Melo extract was different, pharmaceutical composition prepared as described in example 3 above, by canned, lyophilizing, roll steps such as lid, made every 8mg preparation.
Embodiment 7: the preparation active ingredient is measured
1, the polypeptide active ingredient is determined
(1) preparation of sampling embodiment 3 adds water and makes the solution that contains polypeptides matter 2mg among every 1ml, gets 2ml, adds indenes three bronze medal test solution 1ml, and heating should show bluish violet.
(2) according to the method described in " two appendix IVA of Chinese Pharmacopoeia version in 2000 ", add water with the preparation of embodiment 3 and make the solution that contains polypeptides matter 2mg among every 1ml, get 2ml, put in the 50ml measuring bottle, add water to scale, shake up,, absorption maximum is arranged at the wavelength place of 258nm according to spectrophotometry.
As above presentation of results, the absorption maximum of embodiment 3 preparations are differentiated and are set up.
2, high molecular weight material assay
High effective liquid chromatography for measuring according to regulation in " two appendix VD of Chinese Pharmacopoeia version in 2000 ".
Chromatographic condition and system suitability test: with gel chromatographic columns (TSKgelG2000SW 7.8mm * 300mm, 5 μ m); Mobile phase is trifluoracetic acid-acetonitrile-water (0.05: 10: 90); The detection wavelength is 214nm.Number of theoretical plate must not calculate by insulin spikes and is lower than 3000.
The preparation of reference substance solution: it is an amount of to get insulin reference substance (molecular weight 5800), adds mobile phase and makes the solution that contains 1mg among every 1ml, in contrast product solution.
The preparation of test solution: in the preparation of embodiment 3, add mobile phase and make the solution that contains polypeptide 1mg among every 1ml, as test solution.
Algoscopy: get each 20 μ l of reference substance solution and test solution, inject chromatograph of liquid respectively, the record chromatogram, to be considered as high molecular weight material prior to the peak of insulin spikes retention time, calculate by area normalization method, the result shows that the polymer substance content of test solution is lower than 2.0%.
3, amino acid content is measured
With contained free amino acid in quantitative embodiment 5 preparations of high performance liquid chromatography difference discriminated union, the results are shown in Table A.
Table A: injection cervus and cucumis polypeptide free amino acid check result
Aminoacid μg/ml Aminoacid μg/ml
Aspartic Acid 229.3 Cystine 131.6
Serine 110.1 Tyrosine 7.9
Glutamic acid 419.6 Valine 185.5
Glycine 414.7 Methionine 29.0
Histidine 82.3 Lysine 171.9
Arginine 432.1 Isoleucine 90.2
Threonine 92.4 Leucine 196.1
Alanine 508.9 Phenylalanine 125.8
Proline 109.7 Tryptophan 35.3
Total amino acids 3.23mg/
As above the result shows, injection cervus and cucumis polypeptide preparation contains 18 kinds of free amino acids.
Embodiment 8: the difference of polypeptide total amount between each batch in the production injection cervus and cucumis polypeptide
Present embodiment explanation drops into identical crude drug raw material at every batch, when preparing polypeptide extract with identical process, and the difference of polypeptide total amount in the every batch of extract.
With the method for embodiment 1, drop into the Os Cervi of identical weight, the preparation Os Cervi extract, its Os Cervi polypeptide total amount is shown among the following form B.
Table B: the Os Cervi extract solution compolision is analyzed
Lot number Drop into clean Os Cervi Cumulative volume Os Cervi polypeptide content The polypeptide total amount
20040301 150Kg 56L 7.32mg/ml 409.9g
20040302 150Kg 53L 5.25mg/ml 278.3g
20040303 150Kg 62L 5.33mg/ml 330.5g
With the method for embodiment 2, drop into the Semen Melo of identical weight, the preparation Semen Melo extract, its Semen Melo polypeptide total amount is shown among the following form C.
Table C: the Semen Melo extract solution compolision is analyzed
Lot number Drop into Semen Melo Cumulative volume Os Cervi polypeptide content The polypeptide total amount
20040301 50Kg 19L 3.50mg/ml 66.5g
20040302 50Kg 22L 4.35mg/ml 95.7g
20040303 50Kg 23L 3.54mg/ml 81.4g
By table B result as can be known, every batch is dropped into the 150Kg Os Cervi, and Os Cervi polypeptide maximum extracted amount and minimum difference reach 131g; By table C result as can be known, every batch is dropped into the 50Kg Semen Melo, and Semen Melo polypeptide maximum extracted amount and minimum difference reach 29.2g.
This embodiment explanation, if produce with the crude drug weight ratio according to background technology, it is very big not only to criticize a content, and finally in the injection cervus and cucumis polypeptide product Os Cervi polypeptide and Semen Melo polypeptide do not have definite ratio yet.This is explanation just, has only with the Os Cervi polypeptide in the extract separately and the weight ratio control production injection cervus and cucumis polypeptide pharmaceutical composition of Semen Melo polypeptide active ingredient, can guarantee the content difference minimum of final preparation.Is that the difference that 8mg/ props up is criticized effective component content explanation between preparation as following table D explanation with the specification that the method for embodiment 5 prepares.
Table D: injection cervus and cucumis polypeptide
Lot number Appearance character Acidity Macromolecule Content mg/ props up
20040525 The off-white color block 5.85 Up to specification 8.11 8.08 8.14
20040526 The off-white color block 6.05 Up to specification 8.14 8.12 8.12
20040527 The off-white color block 5.94 Up to specification 8.08 8.10 8.10
As above show data as can be seen, method of the present invention can prepare the active ingredient stable formulation, has guaranteed product quality, meets the national drug standards.
Embodiment 9: the effect of preparation for treating rheumatism of the present invention, rheumatoid arthritis
From the inpatient, select rheumatic arthritis 21 examples, rheumatoid arthritis 8 examples at random; Leukocyte count, the rheumatoid factor in clinical examination erythrocyte sedimentation rate, anti-" 0 ", the blood.
Therapeutic Method: with the preparation of embodiment 6, dosage is to use injection cervus and cucumis polypeptide 16-24mg every day, instils with 0.9% sodium chloride injection 250-500ml dissolved dilution posterior vein, and 15 is a course of treatment, treat 2 courses of treatment altogether, stop using during the treatment other therapies and medicine.
Curative effect judging standard:
1. produce effects: arthralgia and swelling disappear, and motion does not have sense of discomfort freely, and every inspection all recovers normal person.
2. effective: arthralgia and swelling disappear substantially, but motion sense still is uncomfortable, or have 1~2 inspection not recover normal person.
3. invalid: clinical symptoms and the preceding no obvious improver of treatment.
Therapeutic effect is shown in as among the following table E.
Table E: this product treatment rheumatism, rheumatoid arthritis clinical efficacy
Curative effect Classification Add up to
The rheumatic arthritis rheumatoid arthritis
Example number % example number % Example number %
The produce effects enabledisable 3 14.3 2 25.0 16 76.2 5 62.5 2 9.5 1 12.5 5 17.2 18 72.4 3 10.4
The result of table E shows that preparation of the present invention has significant therapeutical effect to treatment rheumatism, rheumatoid arthritis.
Embodiment 10: preparation of the present invention is to promoting the result of union of fracture
Select membra closure type bone fracture 57 examples at random, be divided into treatment at random and organize 42 examples, matched group 15 examples.
All adopt conventional methods such as drawing, reset, fix after the patient is admitted to hospital, and give antibiotic 3 days with prevention infection.Matched group gives routine administration simultaneously, and the treatment group gives the injection cervus and cucumis polypeptide 16-24mg of embodiment 5, instils with 0.9% sodium chloride injection 250-500ml dissolved dilution posterior vein, and 15 is a course of treatment.
Two groups of patient's swelling regression times, pain weaken time, callus formation time, healing time after observing medication.The results are shown among the table F.
The curative effect statistics:
Table F: preparation of the present invention is to the clinical effectiveness of the pain of subsiding a swelling, subtract, promotion union of fracture
Group pain weakens the time (h) swelling regression time (h) callus formation time (d) healing time (d)
Treatment group 50.4 ± 11.7 102.4 ± 32.3 28.5 ± 8.8 78.4 ± 22.4 matched groups 64.7 ± 13.1 136.2 ± 31.6 35.6 ± 10.2 91.2 ± 24.1
Table F shows that injection cervus and cucumis polypeptide preparation has the effect that slows down pain, elimination swelling significantly, promotes union of fracture.

Claims (10)

1, a kind of injection cervus and cucumis polypeptide pharmaceutical composition, it contains Os Cervi extract, Semen Melo extract and one or more excipient composition, and wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
2, the described injection cervus and cucumis polypeptide of claim 1 pharmaceutical composition, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1.
3, claim 1 or 2 described injection cervus and cucumis polypeptide pharmaceutical compositions, wherein said excipient is selected from Dextran 40, glucose or lactose.
4, a kind of injection cervus and cucumis polypeptide pharmaceutical composition, it is by being prepared as follows the method preparation, and this method comprises the steps:
A) preparation of Os Cervi extract solution:
(1) Os Cervi pretreatment;
(2) pretreated clean Os Cervi is pulverized;
(3) add 2 times of waters for injection more than the weight in broken Os Cervi, 121 ℃ of hot pressing are extracted to leach and are obtained an Os Cervi extracting solution;
(4) add weight water for injection more than 2 times in the Os Cervi slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach and obtain secondary Os Cervi extracting solution, an Os Cervi extracting solution that obtains with step (3) merges makes the Os Cervi extracting solution;
(5) the Os Cervi extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution, make Os Cervi extract solution;
B) preparation of Semen Melo extract solution:
(1) rinsing of drying and ripening Semen Melo is clean;
(2) water for injection of adding weight more than 2 times in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate is extracted 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add weight water for injection more than 2 times in the Semen Melo slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) the Semen Melo extracting solution is centrifugal, collect supernatant centrifugal liquid
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution, make Semen Melo extract solution;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
5, the described injection cervus and cucumis polypeptide of claim 4 pharmaceutical composition, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1.
6, claim 4 or 5 described injection cervus and cucumis polypeptide pharmaceutical compositions, wherein said excipient is selected from Dextran 40, glucose or lactose.
7, a kind of injection cervus and cucumis polypeptide preparation of drug combination method, it comprises the steps:
A) preparation of Os Cervi extract solution:
(1) Os Cervi pretreatment;
(2) pretreated clean Os Cervi is pulverized;
(3) add the water for injection of weight more than 2 times in broken Os Cervi, 121 ℃ of hot pressing are extracted to leach and are obtained an Os Cervi extracting solution;
(4) add weight water for injection more than 2 times in the Os Cervi slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach and obtain secondary Os Cervi extracting solution, an Os Cervi extracting solution that obtains with step (3) merges makes the Os Cervi extracting solution;
(5) the Os Cervi extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution, make Os Cervi extract solution;
B) preparation of Semen Melo extract solution:
(1) rinsing of drying and ripening Semen Melo is clean;
(2) water for injection of adding weight more than 2 times in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate is extracted 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add weight water for injection more than 2 times in the Semen Melo slag after once extracting, continue to extract 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) the Semen Melo extracting solution is centrifugal, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution, make Semen Melo extract solution;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 6: 1.
8, the described preparation method of claim 7, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1.
9, claim 7 or 8 described preparation methoies, wherein excipient is selected from Dextran 40, glucose or lactose.
10, a kind of injection cervus and cucumis polypeptide preparation of drug combination method, it comprises the steps:
A) preparation of Os Cervi extract solution:
(1) after Os Cervi boils 30 minutes in boiling water, removes fascia and residual meat, finish pretreatment;
(2) pretreated clean deer bone powder is broken to the following broken bone of 1cm;
(3) add the water for injection of 2 times of weight in broken Os Cervi, 121 ℃ of hot pressing were extracted 2 hours, leached and obtained an Os Cervi extracting solution;
(4) 2 times of weight waters for injection of adding in the Os Cervi slag after once extracting continue to extract 2 hours 121 ℃ of-123 ℃ of hot pressing, leach to obtain secondary Os Cervi extracting solution, make the Os Cervi extracting solution with the Os Cervi extracting solution merging that step (3) obtains, and placement is spent the night;
(5) with the Os Cervi extracting solution with 4000 rev/mins centrifugal 15 minutes, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of cumulative volume, collect concentrated solution,, make Os Cervi extract solution with 0.22 μ m membrane filtration;
B) preparation of Semen Melo extract solution:
(1) with water for injection rinsing 3-4 time of drying and ripening Semen Melo;
(2) water for injection of 2 times of weight of adding in clean Semen Melo grinds to form Semen Melo homogenate with colloid mill;
(3) Semen Melo homogenate was extracted 2 hours 121 ℃ of hot pressing, leach the Semen Melo extracting solution one time;
(4) add 2 times of weight waters for injection in the Semen Melo slag after once extracting, continue to extract 2 hours 121 ℃ of-123 ℃ of hot pressing, leach secondary Semen Melo extracting solution, a Semen Melo extracting solution that obtains with step (3) merges makes the Semen Melo extracting solution;
(5) with the Semen Melo extracting solution with 4000 rev/mins centrifugal 15 minutes, collect supernatant centrifugal liquid;
(6) centrifugal liquid is carried out 100KD, 10KD, 6KD ultrafiltration respectively, collect filter liquor, be evaporated to 10% of original volume, collect concentrated solution,, make Semen Melo extract solution with 0.22 μ m membrane filtration;
C) injection cervus and cucumis polypeptide preparation of drug combination:
Blend step A) Zhi Bei Os Cervi extract solution and step B) preparation Semen Melo extract solution and one or more excipient pharmaceutical compositions, make freeze-dried powder by Freeze Drying Technique, wherein the weight ratio of Os Cervi polypeptide and Semen Melo polypeptide is 2: 1 to 4: 1, excipient is selected from Dextran 40, glucose or lactose, and the weight ratio of polypeptide total amount and excipient is 1: 5-30.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100382842C (en) * 2006-05-31 2008-04-23 哈尔滨吉尔生物科技有限公司 Orally administered cervus and cucumis polypeptide composition and preparation method thereof
CN101461834B (en) * 2009-01-09 2012-01-04 哈尔滨誉衡药业股份有限公司 Cervus and cucumis polypeptide medicament composition oral preparation and preparation method thereof
CN103070906A (en) * 2011-12-08 2013-05-01 赵联华 Quality control method of injection composition for treating orthopedic diseases
CN104248652A (en) * 2013-06-26 2014-12-31 哈尔滨誉衡药业股份有限公司 Preparation method of cervus and cucumis polypeptide injection preparation
CN104248651A (en) * 2013-06-26 2014-12-31 哈尔滨誉衡药业股份有限公司 Pharmaceutical composition prepared from deer bone and melon seed as raw materials
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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Publication number Priority date Publication date Assignee Title
CN100352496C (en) * 2004-03-04 2007-12-05 江卫世 Lugua polypeptides for injection and its preparing process

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100382842C (en) * 2006-05-31 2008-04-23 哈尔滨吉尔生物科技有限公司 Orally administered cervus and cucumis polypeptide composition and preparation method thereof
CN101461834B (en) * 2009-01-09 2012-01-04 哈尔滨誉衡药业股份有限公司 Cervus and cucumis polypeptide medicament composition oral preparation and preparation method thereof
CN103070906A (en) * 2011-12-08 2013-05-01 赵联华 Quality control method of injection composition for treating orthopedic diseases
CN104248652A (en) * 2013-06-26 2014-12-31 哈尔滨誉衡药业股份有限公司 Preparation method of cervus and cucumis polypeptide injection preparation
CN104248651A (en) * 2013-06-26 2014-12-31 哈尔滨誉衡药业股份有限公司 Pharmaceutical composition prepared from deer bone and melon seed as raw materials
CN104248652B (en) * 2013-06-26 2016-05-11 哈尔滨誉衡药业股份有限公司 A kind of preparation method of cervus and cucumis polypeptide ejection preparation
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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