CN1391899A - Aseptic freeze-dried prostaglandin injection and its preparing method and use - Google Patents
Aseptic freeze-dried prostaglandin injection and its preparing method and use Download PDFInfo
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- CN1391899A CN1391899A CN 02126054 CN02126054A CN1391899A CN 1391899 A CN1391899 A CN 1391899A CN 02126054 CN02126054 CN 02126054 CN 02126054 A CN02126054 A CN 02126054A CN 1391899 A CN1391899 A CN 1391899A
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- alprostadil
- cyclodextrin
- dried
- injection
- prostaglandin
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Abstract
The present invention relates to a kind of freeze-dried prostaglandin injection and its preparation process and use. It aims at solving the problems of unstable medicine performance and pain produced during injection. The freeze-dried prostaglandin injection consists of prostaglandin, alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin, Thymosin and Dextran. It has the function of bi-directional immunity regulation, produces less pain, stable quality and stable and high treating effect. It may be also delay released, controlling released and target released.
Description
Technical field
The present invention relates to a kind of lyophilized injection, particularly relate to a kind of aseptic freeze-dried prostaglandin injection and its production and use.
Technical background
Known Alprostadil (prostaglandin E
1, Alprostadil, PGE
1) be a kind of nontoxic endogenous substance of determined curative effect, be present in widely in human body fluid and the histiocyte, has physiological function widely, the adjusting body immunity is arranged, the effect of microcirculation improvement, can treat cardiovascular and cerebrovascular disease, first, second, the third three type hepatitis are outstanding medicines of high curative effect.But it is not dissolved in water, and performance is extremely unstable, causes medicament contg to descend easily, needs freezer storage and transportation, store and transport very inconvenient, cost height, and pain when injecting, patient is difficult to stand, and clinical practice is restricted.
Known thymosin has the effect of regulating body immunity, and its effect mainly is the activation of body immunity, and Alprostadil is the inhibitor of body immunity.Both are in conjunction with body immunity is had the two-ways regulation function.But, at present both independent separately preparations only being arranged, can only be used clinically, be inconvenient to use.
Known dextran-40 is the good excipient of sterile freeze-drying preparation.
Summary of the invention
The objective of the invention is to overcome the above-mentioned shortcoming of prior art, the aseptic freeze-dried prostaglandin injection that provides that a kind of stable in properties, dosage form are stable, has no side effect when stable curative effect, injection.
The present invention also aims to provide the preparation method and the purposes of this invention medicine.
For achieving the above object, aseptic freeze-dried prostaglandin injection of the present invention is made by following component:
Alprostadil, alpha-cyclodextrin, HP-or gamma-cyclodextrin, thymosin, dextran.
As optimization, the weight proportion of described raw material is:
Alprostadil 0.01-0.4;
Alpha-cyclodextrin is 1-1.5 a times of Alprostadil molal quantity;
HP-or gamma-cyclodextrin are 1-3 times of Alprostadil molal quantity;
Thymus peptide 1 0-100;
Dextran 40-100.
As optimization, the preferred 0.1-0.2 of the weight proportion of described Alprostadil.
As optimization, the purity of described Alprostadil 〉=99.5%.
The preparation method of medicine of the present invention comprises the following steps:
Use alpha-cyclodextrin, reach HP-or gamma-cyclodextrin and comprise Alprostadil, be dissolved in the sterile water for injection, the thymosin that adds ormal weight is again adjusted pH value, after membrane filtration, carry out fill after mensuration bacterial endotoxin clarity is qualified, the false add plug encapsulates after the lyophilization.
As optimization, the described step that comprises Alprostadil is: Alprostadil is dissolved in the dehydrated alcohol; Alpha-cyclodextrin is dissolved in the sterile water for injection, adds HP-or gamma-cyclodextrin again and be stirred to dissolving fully; The ethanol solution of Alprostadil is added drop-wise in the dextrin solution, continues to be stirred to complete miscibility.
As optimization, described pH value is 7.5-8.5; The used filter membrane of membrane filtration is 0.22um.
As optimization, described lyophilization step is: carrying out lyophilization under the vacuum pressure of 10Pa-15Pa and under-45 ℃-20 ℃, make water content≤2%.
The purposes of medicine of the present invention is the medicine that is used for preparation treatment cardiovascular and cerebrovascular disease and treatment first, second, the third three type hepatitis.
Medicine of the present invention adopts Alprostadil and the collaborative mode of thymosin, and body immunity is had the two-ways regulation function, and thymosin still is the ideal excipients of aseptic freeze-dried prostaglandin preparation simultaneously.
Alpha-cyclodextrin is used for comprising the pendant moiety of Alprostadil molecule, with the water solublity of increase Alprostadil, and makes its stable in properties be difficult for taking place qualitative change, the pain side effect when reducing alprostadil injection greatly simultaneously.HP-or gamma-cyclodextrin can comprise the five-membered ring part of Alprostadil molecule, to increase water solublity.It produces the collaborative effect that comprises with alpha-cyclodextrin, make the Alprostadil of a molecule be subjected to simultaneously α-, the effect that comprises of powder-beta-dextrin or gamma-cyclodextrin, can more effectively stablize Alprostadil than single with alpha-cyclodextrin and single beta-schardinger dextrin-of using, make it that qualitative change not take place, and the side effect can reduce alprostadil injection effectively the time.
Dextran-40 more helps the desirable figuration of sterile freeze-drying preparation of the present invention.Itself and thymosin synergism make the sterile freeze-drying preparation molding better, and goods are monoblock and are not powdery.Cracking, the powdering that can produce medicine after single excipient or other two or more excipient cooperate have been overcome, the defective that medicine scatters at the bottle inwall.
In addition, highly purified Alprostadil helps removing and causes pain impurity.
Alprostadil comprises through the collaborative of alpha-cyclodextrin, HP-or gamma-cyclodextrin, and medicine is undergone no deterioration in producing transporting procedures, thereby realizes steady quality, and dosage is stable, stable curative effect, and do not need the refrigerator storing, effect duration is long, and stable.
Medicine of the present invention also has slow release, controlled release, and the targeting triple functions, good effect, side effect is not almost felt, and obviously is better than traditional cardiovascular drugs.
The specific embodiment
Be further described below, aseptic freeze-dried prostaglandin injection of the present invention is made by following components in portion by weight: (unit of weight gram)
Alprostadil 0.01,0.1 or 0.2,0.4;
Alpha-cyclodextrin is 1,1.2,1.5 times of Alprostadil molal quantity;
HP-or gamma-cyclodextrin are 1,2,3 times of Alprostadil molal quantity;
Thymus peptide 10,50,100;
Dextran 40,65,100.
The purity of described Alprostadil 〉=99.5%.
The preparation method of medicine of the present invention comprises the following steps:
The 100mg Alprostadil is dissolved in the 15ml dehydrated alcohol;
1.5 times of alpha-cyclodextrins to the Alprostadil molal quantity are dissolved in the 200ml sterile water for injection, add 3 times again in the HP-or gamma-cyclodextrin of Alprostadil molal quantity, and be stirred to dissolving fully.
Under agitation the ethanol solution with Alprostadil is added drop-wise in the dextrin in aqueous solution of step preparation, continues to stir 3 hours.
Above-mentioned mixed liquor is joined in the 10000ml sterile water for injection, stir and adjust pH value extremely to 7.5-8.5.
Add thymus peptide 1 00000mg and " dextran-40 " 800000mg again, stir.
Above-mentioned medicinal liquid is again through the 0.22um membrane filtration.
With the heat-resisting bottle of 3ml (sterilization removes thermal source), packing, every fill amount 1.2ml, and false add plug divide to take on 10000.
Carrying out lyophilization under the vacuum pressure of 10Pa-15Pa and under-45 ℃-20 ℃, make water content≤2%, lid is rolled in tamponade.
Pack after the assay was approved.Aforesaid operations all carries out under the aseptic condition of GMP standard and regulation.The GMP standard is country's " Good Manufacturing Practice and Quality Control of Drug ".
Another kind of example is: the 1000mg Alprostadil is dissolved in the 150ml dehydrated alcohol, and every fill amount is 1.35ml, and other step is the same.
Simultaneously, the component consumption of giving an example in the also applicable the said goods of preparation method.
Clinical case
(1) treatment angina pectoris:
30 examples are selected from the hospitalizing, and wherein day outbreak of 35 examples is 4-5 time, and 5 examples day outbreak 3-4 time can not be alleviated with conventional antianginal drug.
Conventional angina drugs treatment is accepted in the 30 examples back of being in hospital: used medicine is a sorbitrate, metoprolol, nifedipine, routine medication after 5 days remission not obvious, use medicine treatment of the present invention afterwards.Usage: medicine 100ug of the present invention adds 5% glucose injection 500ml intravenous drip, about 30/minute, every day 1 time.2 days symptoms of individual patients are not alleviated and are used 200ug-300ug instead.Usually one day symptom of medication obviously alleviates or disappears, and symptom was controlled in medication 7-10 days, discontinued medication.
The result:
A, angina rate produce effects are 86.86%, and effective percentage is 7.9%, and inefficiency is 5.3%.
B, electrocardiogram change: it is 34.2% that electrocardiogram recovers normal person fully, and it is 47.4% that the improver is arranged, and the no change person is 18.4%.
(1) treatment subacute severe hepatitis 22 examples;
The treatment group is at composite basis treatment (vitamin, inosine, winter propylhomoserin potassium magnesium, branched-chain amino acid, potenlin, KUHUANG ZHUSHEYE, blood product etc.) on the basis, add with medicine 100ug of the present invention, add 5% Glucose Liquid 500ml, intravenous drip, once a day, general 30 days is a course of treatment.
Matched group, except that medicine of the present invention useless, other treatment measure is identical with the treatment group.
Two groups of patient's hepatopathys contrast with case fatality rate by stages:
| By stages | Group | The example number | The survival number | Death toll | Mortality rate (%) | The P value |
| In early days | Treatment group matched group | ??9 ??8 | ????8 ????6 | ????1 ????2 | ????11.11 ????25 | ＜0.05 |
| Mid-term | Treatment group matched group | ??11 ??10 | ????7 ????4 | ????4 ????6 | ????36.36 ????60 | ＜0.05 |
| Late period | Treatment group matched group | ??2 ??2 | ????2 ????2 | ????2 ????2 | ????100 ????100 | ＞0.05 |
The result shows: two groups of inferior heavy hepatopathys are used two kinds of methods treatment indifference opposite sex during to late period.But heavy hepatopathy people uses medicine good effect of the present invention in early days in the Asia, and its case fatality rate has been compared significant difference (P＜0.05) with matched group.
Claims (9)
1, a kind of aseptic freeze-dried prostaglandin injection is characterized in that being made by following component:
Alprostadil, alpha-cyclodextrin, HP-or gamma-cyclodextrin, thymosin, dextran.
2, aseptic freeze-dried prostaglandin injection according to claim 1 is characterized in that the weight proportion of described raw material is:
Alprostadil 0.01-0.4;
Alpha-cyclodextrin is 1-1.5 a times of Alprostadil molal quantity;
HP-or gamma-cyclodextrin are 1-3 times of Alprostadil molal quantity;
Thymus peptide 1 0-100;
Dextran 40-100.
3, aseptic freeze-dried prostaglandin injection according to claim 2 is characterized in that the preferred 0.1-0.2 of weight proportion of described Alprostadil.
4,, it is characterized in that purity 〉=99.5% of described Alprostadil according to claim 1,2 or 3 described aseptic freeze-dried prostaglandin injections.
5, the preparation method of medicine of the present invention is characterized in that comprising the following steps:
Use alpha-cyclodextrin, reach HP-or gamma-cyclodextrin and comprise Alprostadil, be dissolved in the sterile water for injection, the thymosin that adds ormal weight is again adjusted pH value, after membrane filtration, carry out fill after mensuration bacterial endotoxin clarity is qualified, the false add plug encapsulates after the lyophilization.
6, method according to claim 5 is characterized in that the described step that comprises Alprostadil is: Alprostadil is dissolved in the dehydrated alcohol; Alpha-cyclodextrin is dissolved in the sterile water for injection, adds HP-or gamma-cyclodextrin again and be stirred to dissolving fully; The ethanol solution of Alprostadil is added drop-wise in the dextrin solution, continues to be stirred to complete miscibility.
7, method according to claim 5 is characterized in that described pH value is 7.5-8.5; The used filter membrane of membrane filtration is 0.22um.
8, method according to claim 5 is characterized in that described lyophilization step is: carrying out lyophilization under the vacuum pressure of 10Pa-15Pa and under-45 ℃-20 ℃, make water content≤2%.
9, the purposes of medicine of the present invention is characterized in that being used for the medicine of preparation treatment cardiovascular and cerebrovascular disease and treatment first, second, the third three type hepatitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021260540A CN1176658C (en) | 2002-08-12 | 2002-08-12 | Aseptic freeze-dried prostaglandin injection and its preparing method and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021260540A CN1176658C (en) | 2002-08-12 | 2002-08-12 | Aseptic freeze-dried prostaglandin injection and its preparing method and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1391899A true CN1391899A (en) | 2003-01-22 |
| CN1176658C CN1176658C (en) | 2004-11-24 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021260540A Expired - Fee Related CN1176658C (en) | 2002-08-12 | 2002-08-12 | Aseptic freeze-dried prostaglandin injection and its preparing method and use |
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| Country | Link |
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| CN (1) | CN1176658C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360134C (en) * | 2003-10-29 | 2008-01-09 | 蔡海德 | Injection liquid containing alprostadic and its production process |
| CN100542536C (en) * | 2004-07-27 | 2009-09-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Nasal powder |
| CN100542537C (en) * | 2004-07-27 | 2009-09-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Oral preparation |
| CN102335179A (en) * | 2011-06-03 | 2012-02-01 | 蔡海德 | Alprostadil composite medicine, preparation method thereof, quality controlling method thereof, and purpose thereof |
-
2002
- 2002-08-12 CN CNB021260540A patent/CN1176658C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360134C (en) * | 2003-10-29 | 2008-01-09 | 蔡海德 | Injection liquid containing alprostadic and its production process |
| CN100542536C (en) * | 2004-07-27 | 2009-09-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Nasal powder |
| CN100542537C (en) * | 2004-07-27 | 2009-09-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Oral preparation |
| CN102335179A (en) * | 2011-06-03 | 2012-02-01 | 蔡海德 | Alprostadil composite medicine, preparation method thereof, quality controlling method thereof, and purpose thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1176658C (en) | 2004-11-24 |
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| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Hunan Kangyuan Pharmacy Co., Ltd. Assignor: Cai Haide Contract record no.: 2011430000206 Denomination of invention: Aseptic freeze-dried prostaglandin injection and its preparing method and use Granted publication date: 20041124 License type: Exclusive License Open date: 20030122 Record date: 20111008 |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20041124 Termination date: 20150812 |
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| EXPY | Termination of patent right or utility model |