CN1314401C - Polyenic phosphatide acylcholine freeze-dried powder injecta medicine - Google Patents

Polyenic phosphatide acylcholine freeze-dried powder injecta medicine Download PDF

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Publication number
CN1314401C
CN1314401C CNB2005100216365A CN200510021636A CN1314401C CN 1314401 C CN1314401 C CN 1314401C CN B2005100216365 A CNB2005100216365 A CN B2005100216365A CN 200510021636 A CN200510021636 A CN 200510021636A CN 1314401 C CN1314401 C CN 1314401C
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freeze
acylcholine
polyenic
phosphatide
dried powder
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CN1742740A (en
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郁东梅
欧苏
梁隆
程志鹏
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Sichuan Kelun Pharmaceutical Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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Sichuan Kelun Pharmaceutical Co Ltd
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Abstract

The present invention relates to a polyene phosphatidyl choline freeze-drying powder injection which is composed of polyene phosphatidyl choline as an effective medicine ingredient and auxiliary ingredients comprising a necessary solubilizing agent and a freeze-drying protective agent. The weight of the ingredients comprises that the polyene phosphatidyl choline weighs 0.1 to 1.5 parts, the weight ratio of the solubilizing agent to the polyene phosphatidyl choline is 0.1 to 2.5: 1, and the weight ratio of the freeze-drying protective agent to the polyene phosphatidyl choline is 0.1 to 10: 1. As required, other auxiliary ingredients including pharmaceutically acceptable vitamin can also be added to the ingredients. The medicine solves the problem of the stability of effective medicine ingredients under normal conditions including storage and transportation and reduces transportation cost and transportation difficulty. The curative effects of the medicine are enhanced, potential safety hazards caused by phenylmethanol are eliminated, and the safety of medication is improved.

Description

Polyenic phosphatide acylcholine freeze-dried powder injecta medicine
Technical field
What the present invention relates to is a kind of polyenic phosphatide acylcholine freeze-dried powder injecta medicine that the liver plasma membrane protective agent uses that can be used as.
Background technology
Polyene phosphatidylcholine is as a kind of liver plasma membrane protection composition, in the various types of acute and chronic hepatopathys of treatment, is employed at present, and be a most sure hepatic of present curative effect.In hepatic disease, regardless of the cause of disease, the damage of hepatic parenchymal cells and organelle takes place inevitably all, simultaneously losing with phospholipid.Polyene phosphatidylcholine can replenish the exogenous phospholipid of human body, and be attached in cell membrane or the organelle film, hepatocellular regeneration and reconstruct had important effect, and can obviously improve nutrient substance and the electrolytical membrane process of striding, increase the activity of phospholipid dependent enzyme, make impaired membrane structure obtain repairing.
The main component of polyene phosphatidylcholine is linoleic acid (accounting for 70%), linolenic acid and oleic acid, is a kind of high-purity soybean oil phospholipid that extracts from soybean phospholipid, is " essential " phospholipid of human body.Owing to be rich in the phosphatidylcholine of polyunsaturated fatty acid, so be called polyene phosphatidylcholine again.At present, this medicine has two kinds of oral and injections, can have only Polyene Phosphatidylcholine injection liquid for the dosage form of injection use.The open defect of this injection products, the one, principal agent instability in the aqueous solution, easily degraded in storage, effect duration is short, needs in storage below 8 ℃, so must protect with ice bag in transportation, transport difficulty and cost of transportation have been increased, also increase patient's financial burden, also can cause the decline of drug content simultaneously inevitably, influenced the curative effect of this product; The 2nd, in the aqueous solution of its hydro-acupuncture preparation, need be added with benzyl alcohol as antiseptic, therefore these product also can make patient produce anaphylaxis except can not being used for neonate and premature infant.
Summary of the invention
The objective of the invention is provides a kind of safe, stable, effective polyenic phosphatide acylcholine freeze-dried powder injecta to extensive patients, its preparation technology is simple, solve active drug composition polyene phosphatidylcholine and under normal condition, (comprised and having preserved and transportation) a stable difficult problem, cost of transportation and transport difficulty have been reduced, when having improved curative effect of medication, also eliminate the potential safety hazard of bringing because of benzyl alcohol, improved the safety of medication.
Polyenic phosphatide acylcholine freeze-dried powder injecta medicine of the present invention is the active drug composition with the polyene phosphatidylcholine, forms jointly with comprising the necessary solubilizing agent and the auxiliary element of freeze drying protectant, and its weight consists of:
Polyene phosphatidylcholine 0.1-1.5 part,
Solubilizing agent/polyene phosphatidylcholine 0.1-2.5: 1,
Freeze drying protectant/polyene phosphatidylcholine 0.1-10: 1,
Wherein, said solubilizing agent can be selected cholanic acid or its esters, and a kind of as in cholic acid, glycocholic acid, cholyltaurine or its esters etc. wherein is preferably glycocholic acid or its esters; Or deoxycholic acid or its esters, a kind of as in chenodeoxy cholic acid, glycodesoxycholic acid, Calculus Bovis deoxycholic acid and its esters etc., wherein preferred deoxycholic acid or its esters; Can also be in the compositions such as poloxamer, tween a kind of.Because polyene phosphatidylcholine is water insoluble, use this type of solubilizing agent can increase its water solublity.Can exchange use between these heterogeneities and there is no the significant adverse influence.
Said freeze drying protectant can be in sodium chloride, aminoacid, glucose, mannitol sugar, Sionit, sucrose, trehalose, lactose, low molecular dextran, cyclodextrin, soluble starch, the cellulose family a kind of, they all can protect micelle not to be destroyed in freeze-drying process.
Test shows that in the above-mentioned polyenic phosphatide acylcholine freeze-dried powder injecta medicine, said polyene phosphatidylcholine is preferably 0.1-0.8 part.The preferred proportion of said polyene phosphatidylcholine and solubilizing agent is 0.5-2.0: 1.The usage ratio of freeze drying protectant/polyene phosphatidylcholine is preferably 0.1-5: 1.
On the basis of above-mentioned composition, can also add the auxiliary element that comprises one or more vitamin ingredients of acceptable in the medicine as required.Said vitamin ingredients can comprise as vitamin A, C, H, E, K, vitamin D family, the vitamin B same clan and derivant etc.During use, the cholic usage ratio of vitamin ingredients/polyene phosphatidyl can be 0.0005-0.05: 1.
The freeze-dried powder injecta medicine that the present invention is above-mentioned is investigated with the long-time stability parallel test that the injection liquid drugs injection that uses at present carries out under 25 ± 2 ℃ of temperature conditions, leading indicator is as shown in table 1, principal agent wherein is the effective ingredient polyene phosphatidylcholine, and the principal agent analyte is the related substances that polyene phosphatidylcholine produces because of degraded, oxidation etc.
Table 1 stability test is investigated the result
Time (moon) Outward appearance PH value Principal agent analyte (%) Drug content (%) Aseptic Bacterial endotoxin
The liquid drugs injection injection 0 Yellow clear liquid 8.7 1.36 102.4 Qualified Qualified
3 Yellow clear liquid 8.0 2.56 97.5 Qualified Qualified
6 Yellow clear liquid 7.8 4.01 95.8 Qualified Qualified
9 Yellow clear liquid 7.5 5.66 94.6 Qualified Qualified
Freeze-dried powder of the present invention 0 Yellow block 8.7 1.02 102.4 Qualified Qualified
3 Yellow block 8.6 1.39 101.3 Qualified Qualified
6 Yellow block 8.5 2.01 100.6 Qualified Qualified
9 Yellow block 8.6 2.61 99.2 Qualified Qualified
Above-mentioned result of the test shows, freeze-dried powder injecta medicine of the present invention stores for a long time not using under composition such as benzyl alcohol and room temperature, the normal condition, its pH value variation, the increase of principal agent decomposed substance, the every index of the following degradation aspect of drug content, all obviously be better than the corresponding injection that uses at present, show and to improve stability of drug and clinical application safety, effectiveness effectively.
The general preparation method of the polyenic phosphatide acylcholine freeze-dried powder injecta medicine that the present invention is above-mentioned is; with polyene phosphatidylcholine, solubilizing agent and after optionally auxiliary element dissolves with water for injection; homogenizing becomes clear liquid under nitrogen current; add an amount of freeze drying protectant then; abundant homogenize; add to full dose with water for injection in case of necessity, with the microporous filter membrane filtration of 0.2 μ m, lyophilization promptly.
The specific embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
The specific embodiment
Embodiment 1
Form: polyene phosphatidylcholine 5.0g
NaGC 9g
Mannitol 4g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, in the polyene phosphatidylcholine 5.0g of recipe quantity, an amount of water for injection that NaGC 9g joins 60 ℃, stir clear liquid, add the mannitol dissolving again after, regulating pH with NaoH is 6.5~8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃~-40 ℃, is warming up to-20 ℃~-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 2
Form: polyene phosphatidylcholine 4.65g
NaTDC 10g
Vitamin E 0.05g
Sucrose 5g
Preparation method: under logical condition of nitrogen gas, in polyene phosphatidylcholine 4.65g, the NaTDC 10g of recipe quantity, an amount of water for injection that vitamin E 0.05g joins 60 ℃, stir clear liquid, after adding the dissolving of sugarcane alcohol again, regulating pH with NaoH is 6.5~8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃~-40 ℃, is warming up to-20 ℃~-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 3
Form: polyene phosphatidylcholine 4.65g
Poloxamer 2g
Vitamin E 0.05g
Sucrose 5g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, in polyene phosphatidylcholine 4.65g, the poloxamer 2g of recipe quantity, an amount of water for injection that biotin 0.05g joins 60 ℃, stir clear liquid, add sucrose dissolved again after, regulating pH with NaoH is 6.5~8.0, and adds water to 100ml.Solution filters with the microporous filter membrane of 0.2 μ m, is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃~-40 ℃, is warming up to-20 ℃~-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Embodiment 4
Form: polyene phosphatidylcholine 5.0g
NaTDC 10g
Vitamin B 120.02g
Trehalose 6g
Water for injection adds to 100ml
Preparation method: under logical condition of nitrogen gas, with polyene phosphatidylcholine 5.0g, NaTDC 10g, the vitamin B of recipe quantity 120.02g, biotin 0.05g joins in 60 ℃ an amount of water for injection, stir clear liquid, add the trehalose dissolving again after, regulating pH with NaoH is 6.5~8.0, and adds water to 100ml.Microporous filter membrane with 0.2 μ m filters, and is sub-packed in the cillin bottle, puts in the freeze dryer and is chilled to-35 ℃~-40 ℃, is warming up to-20 ℃~-5 ℃ then, vacuum (0.1-0.5kPa) drying.Be warming up to 30 ℃ hours by 5 ℃/hour, jump a queue, roll lid pack promptly.
Although described the present invention by concrete enforcement preparation method, but make some modification or carry out some replacement and equivalent process according to the inventor's method, for the technical staff who is proficient in this field is easily, and these variations are believed to comprise within the scope of the invention.

Claims (10)

1. polyenic phosphatide acylcholine freeze-dried powder injecta medicine is characterized in that with the polyene phosphatidylcholine being the active drug composition, forms jointly with comprising the necessary solubilizing agent and the auxiliary element of freeze drying protectant, and its weight consists of:
Polyene phosphatidylcholine 0.1-1.5 part,
Solubilizing agent/polyene phosphatidylcholine 0.1-2.5: 1,
Freeze drying protectant/polyene phosphatidylcholine 0.1-10: 1,
Solubilizing agent wherein is a kind of in cholanic acid or its esters, deoxycholic acid or its esters, poloxamer, the tween; Freeze drying protectant is a kind of in sodium chloride, aminoacid, glucose, mannitol sugar, Sionit, sucrose, trehalose, lactose, low molecular dextran, cyclodextrin, soluble starch, the cellulose family.
2. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that said polyene phosphatidylcholine is preferably 0.1-0.8 part.
3. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that cholanic acid or its esters in the said solubilizing agent is that one of cholic acid, glycocholic acid, cholyltaurine and their salt apoplexy due to endogenous wind are planted.
4. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 3 is characterized in that preferred glycocholic acid of said solubilizing agent or its esters.
5. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that deoxycholic acid in the said solubilizing agent or its esters are a kind of in chenodeoxy cholic acid, glycodesoxycholic acid, Calculus Bovis deoxycholic acid, deoxycholic acid or its esters.
6. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 5 is characterized in that preferred deoxycholic acid of said solubilizing agent or its esters.
7. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1, the preferred proportion that it is characterized in that said solubilizing agent and polyene phosphatidylcholine is 0.5-2.0: 1.
8. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 1 is characterized in that the usage ratio of said freeze drying protectant/polyene phosphatidylcholine is preferably 0.1-5: 1.
9. polyenic phosphatide acylcholine freeze-dried powder injecta medicine as claimed in claim 8 is characterized in that the preferred mannitol of said freeze drying protectant.
10. as the described polyenic phosphatide acylcholine freeze-dried powder injecta medicine of one of claim 1 to 9, it is characterized in that including in the said auxiliary element acceptable vitamin ingredients in the medicine, the cholic usage ratio of vitamin ingredients/polyene phosphatidyl is 0.0005-0.05: 1.
CNB2005100216365A 2005-09-08 2005-09-08 Polyenic phosphatide acylcholine freeze-dried powder injecta medicine Active CN1314401C (en)

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Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
CN100366238C (en) * 2005-10-25 2008-02-06 江苏正大天晴药业股份有限公司 Freeze dried polyene lecithin powder for injection and its prepn

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1602878A (en) * 2004-08-26 2005-04-06 北京瑞伊人科技发展有限公司 Preparation process of polyene phosphatidylcholine injection

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1602878A (en) * 2004-08-26 2005-04-06 北京瑞伊人科技发展有限公司 Preparation process of polyene phosphatidylcholine injection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
复方多烯磷脂酰胆碱治疗慢性乙型活动性肝炎的随机对照双盲临床试验 张孝秋等,药物流行病学杂志,第4卷第1期 1995 *

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Owner name: KELUN PHARM IND CO., LTD., SICHUAN; SICHUAN COLUM

Free format text: FORMER OWNER: KELUN PHARM IND CO., LTD., SICHUAN

Effective date: 20080822

C41 Transfer of patent application or patent right or utility model
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Effective date of registration: 20080822

Address after: South two road, Xindu Satellite Town Industrial Park, Sichuan, Chengdu Province, China: 610500

Co-patentee after: Sichuan Kelun Pharmaceutical Research Co.,Ltd.

Patentee after: Sichuan Kelun Pharmaceutical Co.,Ltd.

Address before: South two road, Xindu Industrial Park, Sichuan City, Chengdu Province: 610500

Patentee before: Sichuan Kelun Pharmaceutical Co.,Ltd.

C56 Change in the name or address of the patentee
CP01 Change in the name or title of a patent holder

Address after: 610500 south two road, Xindu Satellite Town Industrial Park, Sichuan, Chengdu

Patentee after: Sichuan Kelun Pharmaceutical Co.,Ltd.

Patentee after: SICHUAN KELUN PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd.

Address before: 610500 south two road, Xindu Satellite Town Industrial Park, Sichuan, Chengdu

Patentee before: Sichuan Kelun Pharmaceutical Co.,Ltd.

Patentee before: Sichuan Kelun Pharmaceutical Research Co.,Ltd.

C35 Partial or whole invalidation of patent or utility model
IP01 Partial invalidation of patent right

Commission number: 4W100491

Conclusion of examination: The patent rights continued to be valid on the basis of the modified claim 1-9, which was amended by the patent holder on 2011 01, 25.

Decision date of declaring invalidation: 20110301

Decision number of declaring invalidation: 16107

Denomination of invention: Polyenic phosphatide acylcholine freeze-dried powder injecta medicine

Granted publication date: 20070509

Patentee: Sichuan Kelun Pharmaceutical Co.,Ltd.|SICHUAN KELUN PHARMACEUTICAL RESEARCH INSTITUTE Co.,Ltd.