CN1318085C - Ossotide injection and preparation method thereof - Google Patents
Ossotide injection and preparation method thereof Download PDFInfo
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- CN1318085C CN1318085C CNB2005100769128A CN200510076912A CN1318085C CN 1318085 C CN1318085 C CN 1318085C CN B2005100769128 A CNB2005100769128 A CN B2005100769128A CN 200510076912 A CN200510076912 A CN 200510076912A CN 1318085 C CN1318085 C CN 1318085C
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Abstract
The present invention discloses a new ossotide injection preparation method and a product obtained by the method. The preparation method comprises the following steps: 1) hot pressing and boiling extraction are carried out to a mammal bone by salt water, centrifugal filtration is carried out, boiling extracting solutions are merged and placed under a low temperature for 1 to40 hours, heating and centrifugal filtration are carried out to the merged extracting solution, and filter liquor is collected to be used; 2) vacuum concentration is carried out to the filter liquor, ethanol is added, standing and precipitation are carried out to the mixture, the upper layer of alcohol liquid is sucked out, and ethanol is recovered in a metered volume mode to obtain aqueous extraction liquid; 3) distilled water with the same volume with that of the aqueous extraction liquid is added to the aqueous extraction liquid, and the mixture orderly passes through a subacidity cationic resin column, a weak base anion resin column, a bead-shaped chitosan column and a chitosan modified activated carbon column, is decontaminated and is purified to obtain purified thin physic liquor; 4) the purified thin physic liquor is condensed, is pressurized and passes through a microporous filtering film, and filling, seal by fusing, hot pressing sterilization are carried out to the filter liquor, or freeze-drying is carried out to the physic liquor to obtain a freeze-dried injection. The ossotide injection of the present invention contains high ossotide ingredients and has the advantages of simple and direct preparation process, and short production period.
Description
Technical field
The present invention relates to a kind of preparation method of injection, relate in particular to a kind of preparation method of bone peptide injection and, belong to drug world by the product that this preparation method obtains.
Background technology
Bone peptide injection (GUNING ZHUSHEYE) extracts from the mammal bones of limbs of pig or cattle for example, after biochemical pharmaceutical factory develops, is used nearly 30 years clinical by Nanjing from 1976, is mainly used in the various arthritis of treatment, can anti-inflammatory analgetic, and determined curative effect.In recent years, the therapeutic domain of the bone peptide injection of being found is more and more wider, as is used for the treatment of osteoporosis (Liu Weirun etc., Binzhou Medical College's journal, the 26th the 6th phase of volume, 2003, pp395), also be used for the treatment of long bone of limbs nonunion (Xue Yunfeng, Henan surgery's magazine, the 10th the 2nd phase of volume, 2004, pp16～17).Along with going deep into of molecular pharmacology research in recent years, discovery for example contains the various active peptide material the bones of limbs extracting solution of pig or cattle from mammal, these active polypeptide can be regulated bone metabolism, stimulating osteoblast propagation, promote new bone formation and regulate calcium, phosphorus metabolism, increase bone calcium deposition, so also can prevent and treat osteoporosis and fracture, its clinical application constantly enlarges.
The traditional preparation process method of bone peptide injection except that having defectives such as complex process, step be loaded down with trivial details (referring to " animal biochemical pharmacy " P283, the People's Health Publisher publishes, version in 1981), and its effective ingredient bone peptide content is lower, impurity is more, has limited its effective application.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of new bone peptide injection is provided, and this bone peptide injection is with short production cycle, preparation technology is simple and direct, effective ingredient bone peptide content height, and impurity content is few.
Technical problem to be solved by this invention realizes by following technological approaches:
Bone peptide injection of the present invention can be prepared from by following method:
1, with the mammalian bone of fresh or freezing preservation, clean to smash and weigh, broken bone boils with saline hot pressing and carries one or many, and centrifugal filtration merges leach cooking liquid, puts to room temperature; Leach cooking liquid placing 1～40 hour, is removed external fat then under-4～8 ℃ low temperature,, collect filtrate for later use the warm back centrifugal filtration of extracting solution;
2, with the filtrate vacuum concentration, stir 95% ethanol that is incorporated as 1～5 times of filtrate weight down, staticly settle fully after, siphon goes out upper strata alcohol liquid, standardize solution reclaims ethanol, the water extract is continued to employ;
3, directly or add the equal-volume distilled water with the water extract, successively by acidulous cation resin post, weak anion resin post, pearl chitosan post and chitin modified activated-charcoal column, the roguing purification, pure rare medicinal liquid;
4, pure rare medicinal liquid is concentrated after, the microporous filter membrane that pressurizeed, with filtrate fill, sealing by fusing, pressure sterilizing promptly, perhaps, in order to prepare lyophilized injectable powder, can be with pure rare medicinal liquid through the conventional method lyophilization, obtain lyophilized powder, make the bone peptide injection lyophilized injectable powder.
When medicinal liquid was carried out the lyophilizing processing, freeze drying process can use conventional freeze drying technology, for example: freezing lyophilizing working system, solvent crystal working system without limits.
In the above-mentioned preparation method, the bones of limbs of preferred pig of the mammalian bone described in the step 1) or cattle wherein; Broken bone boils with saline hot pressing and carries twice; Used brinish concentration is 0.15～0.2M; Preferably placing 8 hour or more under-4～8 ℃ the low temperature leach cooking liquid; Step 2) preferred 95% ethanol that is incorporated as 2～3 times of filtrate weight down that stirs in; Preferably pure rare medicinal liquid is concentrated into 0.5～0.8 times that the collagen material feeds intake heavy, more preferably 0.67 times (V/W) in the step 4); After in the step 4) pure rare medicinal liquid being concentrated, the 0.2um microporous filter membrane pressurizeed.
Advantage of the present invention: its effective ingredient of bone peptide injection of the present invention-bone peptide content height, impurity is few, and its preparation technology is simple and direct, and is with short production cycle, is very beneficial for large-scale industrial production.
Further describe beneficial effect of the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
The specific embodiment
[embodiment 1]
Get the fresh pig bones of limbs, clean and smash, claim 50kg, add the NaCL solution of 100L 0.15mol, in 0.12 MPa, 2h is extracted in 123 ℃ of hot pressing, 100 order fine cloth centrifugal filtrations, and bone slag similarity condition extracts once again and filters, and merges filtrate twice, gets extracting solution 200L; The water extract is put earlier to room temperature, relays to deposit under 4 ℃ in cold room to spend the night, and eliminates upper strata fat next day, 100 order fine cloth centrifugal filtrations after the extracting solution tepor heat of bottom; Filtrate is gone into vacuum concentration pot, when being concentrated into 35L, emits cooling, stirs the ethanol that adds 70L95% down, stirs 10min, leaves standstill, treat that precipitation fully after, siphon goes out to go up pure liquid; Pure liquid is reclaimed ethanol to 70L, the about 34L of surplus water liquid; In water liquid, add the 34L distilled water, after stirring evenly, successively by acidulous cation resin post (7kg), weak anion resin post (10kg), pearl chitosan post (3kg), chitin modified activated-charcoal column (3kg) is all controlled flow velocity 5ml/min.cm
2To cross behind the post rare medicinal liquid vacuum concentration pot of packing into, and be concentrated into 33.5L, with the spray pump 0.2um microporous filter membrane that pressurizeed, with the filtrate fill, 2ml/ props up, sealing by fusing, 115 ℃ of pressure sterilizing 30min, 16750.
(detection method is with reference to national drug standards WS after testing
1Assay check under the-XG-035-2000 item), every milliliter bone peptide content is 8mg in the prepared injection of present embodiment; And adopt in the prepared bone peptide injection of prior art, bone peptide content is 6mg in every milliliter of injection.
[embodiment 2]
1, get the sheep extremity bone of freeze preservation, after thawing, clean, smash, claim 100kg, add the NaCL water of 200L 0.2mol, in 0.122 MPa, 1.5h is extracted in hot pressing under 125 ℃ of conditions, with 100 order filter cloth centrifugal filtrations.Bone slag similarity condition extracts once again, gets rid of filter, merges filtrate twice, gets extracting solution 400L.
2, the water extract is put to room temperature, transfers to deposit under-4 ℃ in the cold room and spends the night.Remove upper strata fat next day, after the extracting solution tepor heat of below, get rid of filter with 100 order filter clothes are centrifugal.
3, the filtrate vacuum concentration pot of packing into when being concentrated into 70L, is emitted the medicinal liquid cooling, in stirring the ethanol that adds 150L 95% down, stirs 10min, leaves standstill, treat that precipitation fully after, siphon goes out to go up pure liquid.
4, pure liquid is packed into alcohol distillation column reclaims ethanol to 150L, emits the about 67L of the surplus water liquid of institute.
5, in water liquid, add the 67L distilled water, after stirring evenly, pass through the faintly acid sun successively from resin column (loading amount 14kg), weak anion resin post (loading amount 20kg), pearl chitosan post (loading amount 6kg), chitin modified activated-charcoal column (loading amount 6kg), all controlling flow velocity is 5ml/min.cm
2
6, the rare medicinal liquid that will cross behind the post is transferred in the vacuum concentration pot, is concentrated into 67L, with the microporous filter membrane of spray pump pressurization by 0.2mm.
7, fill, 2ml/ props up, sealing by fusing, 115 ℃ of pressure sterilizing 30min get 33500 of products, content 2ml:12mg.
(detection method is with reference to national drug standards WS after testing
1Assay check under the-XG-035-2000 item), every milliliter bone peptide content is 8mg in the prepared injection of present embodiment; And adopt in the prepared bone peptide injection of prior art, bone peptide content is 6mg in every milliliter of injection.
[embodiment 3]
1, get the cattle limbs bone of freeze preservation, after thawing, clean, smash, claim 100kg, add the NaCL water of 200L 0.18mol, in 0.122 MPa, 1.5h is extracted in hot pressing under 125 ℃ of conditions, with 100 order filter cloth centrifugal filtrations.Bone slag similarity condition extracts once again, gets rid of filter, merges filtrate twice, gets extracting solution 400L.
2, the water extract is put to room temperature, transfers to deposit under 8 ℃ in the cold room and spends the night.Remove upper strata fat next day, after the extracting solution tepor heat of below, get rid of filter with 100 order filter clothes are centrifugal.
3, the filtrate vacuum concentration pot of packing into when being concentrated into 70L, is emitted the medicinal liquid cooling, in stirring the ethanol that adds 200L 95% down, stirs 10min, leaves standstill, treat that precipitation fully after, siphon goes out to go up pure liquid.
4, pure liquid is packed into alcohol distillation column reclaims ethanol to 200L, emits the about 67L of the surplus water liquid of institute.
5, in water liquid, add the 67L distilled water, after stirring evenly, pass through the faintly acid sun successively from resin column (loading amount 14kg), weak anion resin post (loading amount 20kg), pearl chitosan post (loading amount 6kg), chitin modified activated-charcoal column (loading amount 6kg), all controlling flow velocity is 5ml/min.cm
2
6, the rare medicinal liquid that will cross behind the post is transferred in the vacuum concentration pot, is concentrated into 67L, with the microporous filter membrane of spray pump pressurization by 0.2mm.
7, fill, 2ml/ props up, sealing by fusing, 115 ℃ of pressure sterilizing 30min get 33500 of products.
(detection method is with reference to national drug standards WS after testing
1Assay check under the-XG-035-2000 item), every milliliter bone peptide content is 8mg in the prepared injection of present embodiment; And adopt in the prepared bone peptide injection of prior art, bone peptide content is 6mg in every milliliter of injection.
The test of [test example] bone peptide injection treatment knee joint osseous arthritis of the present invention clinical observation on the therapeutic effect
32 routine knee joint bone joint patients are divided into two groups at random, and one group is the treatment group, 16 people; Another group is matched group, 16 people; Treatment group every day, 1 time weekly, matched group was injected commercially available bone peptide injection 4ml, 2 times weekly at the prepared bone peptide injection 3ml of the intraarticular injection embodiment of the invention 1.Treated one month, followed up a case by regular visits to 3 months, mark according to the knee joint osseous arthritis clinical assessment index submeter of Goidberg VM and Legnesne MG, then according to the integral difference before and after the treatment, the evaluation curative effect.Be divided into greater than 50 with skin difference before and after the treatment excellent, 30～49 be divided into good, 10～29 be divided into can, little 9 are divided into poorly, the results are shown in Table 1.
The result of table 1 treatment relatively
| Group | Excellent | Very | Can | Difference | Acceptance rate (%) |
| The treatment group | 8 | 7 | 1 | 0 | 93.75 |
| Matched group | 5 | 8 | 2 | 1 | 81.25％ |
By table 1 as seen, bone peptide injection of the present invention is compared with existing commercially available bone peptide injection, and under the less situation of consumption, curative effect is higher.
Claims (9)
1, a kind of method for preparing bone peptide injection may further comprise the steps:
1), mammalian bone boiled with saline hot pressing carries one or many, centrifugal filtration merges leach cooking liquid, places under-4～8 ℃ low temperature 1～40 hour, removes external fat, with the warm back centrifugal filtration of extracting solution, collects filtrate for later use;
2), with the filtrate vacuum concentration, stir 95% ethanol that is incorporated as 1～5 times of filtrate weight down, staticly settle fully after, siphon goes out upper strata alcohol liquid, the water extract is continued to employ;
3), with the water extract successively by acidulous cation resin post, weak anion resin post, pearl chitosan post and chitin modified activated-charcoal column, pure rare medicinal liquid;
4), pure rare medicinal liquid concentrated after, the microporous filter membrane that pressurizeed obtains bone peptide injection with filtrate fill, sealing by fusing, pressure sterilizing; Perhaps with pure rare medicinal liquid through lyophilization, obtain lyophilized powder, the bone peptide freeze-drying injectable powder.
2,, it is characterized in that mammalian bone described in the step 1) is the bones of limbs of pig, cattle or sheep according to the preparation method of claim 1.
3,, it is characterized in that used brinish concentration is 0.15～0.2M in the step 1) according to the preparation method of claim 1.
4,, it is characterized in that in the step 1) mammalian bone boiled with saline hot pressing and carry 2 times according to the preparation method of claim 1.
5, according to the preparation method of claim 1, it is characterized in that step 2) in the filtrate vacuum concentration, stir 95% ethanol that is incorporated as 2～3 times of filtrate weight down.
6, according to the preparation method of claim 1, it is characterized in that in the step 4), in V/W, pure rare medicinal liquid is concentrated into 0.5～0.8 times that the collagen material feeds intake heavy.
7,, it is characterized in that in the step 4) pure rare medicinal liquid being concentrated into 0.67 times that the collagen material feeds intake heavy according to the preparation method of claim 6.
8, according to the preparation method of claim 1, after it is characterized in that in the step 4) pure rare medicinal liquid concentrated, the 0.2um microporous filter membrane pressurizeed.
9, a kind of bone peptide injection is characterized in that the product that is prepared by the arbitrary described method of claim 1～8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100769128A CN1318085C (en) | 2005-06-09 | 2005-06-09 | Ossotide injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100769128A CN1318085C (en) | 2005-06-09 | 2005-06-09 | Ossotide injection and preparation method thereof |
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| CN1698655A CN1698655A (en) | 2005-11-23 |
| CN1318085C true CN1318085C (en) | 2007-05-30 |
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| CNB2005100769128A Expired - Fee Related CN1318085C (en) | 2005-06-09 | 2005-06-09 | Ossotide injection and preparation method thereof |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015580B (en) * | 2006-12-12 | 2010-04-14 | 广东医学院 | PH-dependent composite bone peptide preparation, preparing method and use thereof |
| CN100457178C (en) * | 2007-05-25 | 2009-02-04 | 黑龙江省珍宝岛制药有限公司 | Process for preparing bone peptide injection |
| CN102675413A (en) * | 2012-05-27 | 2012-09-19 | 淮安麦德森制药有限公司 | Method for preparing lyophilized powder of polypeptide active substance |
| CN104127473B (en) * | 2014-07-31 | 2017-12-29 | 哈尔滨圣泰生物制药有限公司 | A kind of pharmaceutical composition for treating bone disease and its injection and preparation method |
| CN110898002B (en) * | 2019-12-06 | 2022-05-10 | 湖北威仕生物药业股份有限公司 | Bone peptide injection and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524573A (en) * | 2003-02-26 | 2004-09-01 | 江卫世 | Ossotide sodium chloride injection and its preparing process |
| CN1239201C (en) * | 2004-01-12 | 2006-02-01 | 江勇 | Bone peptide for injection and its preparation method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524573A (en) * | 2003-02-26 | 2004-09-01 | 江卫世 | Ossotide sodium chloride injection and its preparing process |
| CN1239201C (en) * | 2004-01-12 | 2006-02-01 | 江勇 | Bone peptide for injection and its preparation method |
Non-Patent Citations (4)
| Title |
|---|
| 生化药物和生化试剂 四川畜牧兽医，第28卷第129期 2001 * |
| 骨宁注射液治疗骨折的临床观察 孙振林，李琳，白欧，黑龙江医学，第26卷第1期 2002 * |
| 骨宁注射液治疗骨折的临床观察 孙振林，李琳，白欧，黑龙江医学，第26卷第1期 2002;骨肽注射液治疗骨质疏松症48例疗效观察 刘维润，孟爱贞，滨州医学院学报，第26卷第5期 2003;生化药物和生化试剂 四川畜牧兽医，第28卷第129期 2001 * |
| 骨肽注射液治疗骨质疏松症48例疗效观察 刘维润，孟爱贞，滨州医学院学报，第26卷第5期 2003 * |
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