CN104622804A - Preparation method of alprostadil injection emulsion and prepared alprostadil injection emulsion - Google Patents
Preparation method of alprostadil injection emulsion and prepared alprostadil injection emulsion Download PDFInfo
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- CN104622804A CN104622804A CN201410838493.6A CN201410838493A CN104622804A CN 104622804 A CN104622804 A CN 104622804A CN 201410838493 A CN201410838493 A CN 201410838493A CN 104622804 A CN104622804 A CN 104622804A
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Abstract
The invention discloses a preparation method of alprostadil injection emulsion and the prepared alprostadil injection emulsion. The method comprises the following steps: preparing an oil phase and a water phase in the presence of nitrogen; preparing a pre-emulsifying liquid by using a shear machine in the presence of nitrogen at the same time; testing the pH of the pre-emulsifying liquid; calculating the amount of 0.1 mol/L hydrochloric acid solution or 0.1 mol/l sodium hydroxide solution, of which the pH is regulated between 5.5 and 6.0, which is required to be added according to an equation that the pH is equal to -1g[H<+>]; continuously introducing nitrogen for protecting under a stirring condition; adding a 0.1 mol/L hydrochloric acid solution or a 0.1 mol/l sodium hydroxide solution through a charging hole and regulating pH; fully dissolving and regulating a pH value to be 5.5-6.0; and adding injection water to meet prescription quantity through a tank-bottom weighing system. The alprostadil injection emulsion prepared by using the method can be out of expiration date for 24 months at the storage temperature of 4 DEG C.
Description
Technical field:
The present invention relates to a kind of preparation method of alprostadil injection emulsion and the alprostadil injection emulsion of preparation.
Background technology:
In alprostadil injection emulsion listing many years, have many Patents, but the effect duration of the alprostadil injection emulsion prepared by them is 1 year.And the patent being absorbed in 2 years alprostadil injection emulsion effect duration has CN10126909B and CN101511367B, the prescription mentioned in its Patent CN10126909B is median chain triglyceride oil, Alprostadil, water for injection, glycerol, polyoxyethylene sorbitol acid anhydride ester 80, think in this patent that adding appropriate polyoxyethylene sorbitol acid anhydride ester 80 is the stable key factors of alprostadil injection, but the applicant studies discovery, pH5.5 ~ 6.0 and the protection of logical nitrogen is all ignored on the stable impact of alprostadil injection in the embodiment of this prescription, in fact, this prescription is in the situation not having suitable first emulsion pH regulator and nitrogen protection, to ensure the effect duration of storage about 4 DEG C more than 24 months that this patent is claimed.
Summary of the invention:
One of technical problem to be solved by this invention is for the deficiency existing for existing alprostadil injection emulsion preparation technology and provides a kind of effect duration to reach the alprostadil injection emulsion preparation method of 2 years.
Two of technical problem to be solved by this invention is to provide the alprostadil injection emulsion prepared according to described method.
Technical problem to be solved by this invention can be come to be realize by the following technical programs:
A preparation method for alprostadil injection emulsion, specifically comprises the steps:
(1) preparation of colostrum
1. the air in nitrogen displacement oil phase tank and aqueous phase tank tank is used, then the Alprostadil oil phase containing median chain triglyceride oil and Alprostadil is injected into for subsequent use in described oil phase tank and maintaining nitrogen purge protection, will containing water for injection, glycerol, the Alprostadil aqueous phase of Tween 80 is injected into for subsequent use in described aqueous phase tank and maintaining nitrogen purge protection;
2. logical nitrogen pressurization, Alprostadil aqueous phase in Alprostadil oil phase in described oil phase tank and described aqueous phase tank is added in wire shearing with certain flow rate separately, Alprostadil oil phase and Alprostadil aqueous phase pass back into colostrum tank after shearing, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour, to emulsifying completely, liquid level without floating oil, obtained first emulsion;
3. use pH meter to test the original ph of this first emulsion, and according to pH=-lg [H+], calculate the amount regulating and need 0.1mol/L hydrochloric acid solution or the 0.1mol/l sodium hydroxide solution added between pH to 5.5 ~ 6.0; Under agitation, and maintaining nitrogen purge protection, 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH is added by charge door, abundant dissolving just emulsion adjust ph 5.5 ~ 6.0, adding water for injection to recipe quantity by tank bottoms weighing system keeps pH between 5.5 ~ 6.0, obtains colostrum and prepares liquid;
(2) preparation of essence breast
Storage tank all uses air in nitrogen displacement tank; and maintaining nitrogen purge protection; logical nitrogen pressurization, colostrum prepared by step (1) is prepared liquid and is added in high pressure homogenizer, makes particle diameter between 0.12 μm ~ 0.28 μm stored in also maintaining nitrogen purge protection in storage tank after several homogenizing.
Alprostadil injection emulsion of the present invention is prepared according to said method.
The alprostadil injection emulsion adopting said method to prepare can when storage temperature be 4 DEG C, and effect duration was more than 24 months.
Detailed description of the invention:
Comparative example 1:
(1) preparation of colostrum
1. oil phase tank, will containing Alprostadil oil phase (median chain triglyceride oil, Alprostadil) and aqueous phase (water for injection, glycerol, Tween 80) be separately added in wire shearing with certain flow rate pass back into colostrum tank after shearing, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour, to emulsifying completely, liquid level without floating oil, obtained first emulsion.
2. pH meter must be used to test the original ph of this first emulsion.
3. water for injection is added to recipe quantity by tank bottoms weighing system.
(2) preparation of essence breast
1. making colostrum prepare liquid adds in high pressure homogenizer, makes particle diameter after several homogenizing between 0.12 μm ~ 0.28 μm.
Record this alprostadil injection emulsion pH and 4.450 be less than 5.0, do not meet the requirement of national Alprostadil standard.The content measured is: 107.36%, 25 DEG C of labelled amount were accelerated placement after 30 days, and pH is reduced to 3.311, and content is reduced to: 39.78% of labelled amount, and cannot be up to state standards requirement.
Comparative example 2:
(1) preparation of colostrum
1. oil phase tank; aqueous phase tank all must use air in nitrogen displacement tank; and maintaining nitrogen purge protection, logical nitrogen pressurization, will containing Alprostadil oil phase (median chain triglyceride oil; Alprostadil) and aqueous phase (water for injection; glycerol, Tween 80) be added in wire shearing with certain flow rate separately pass back into colostrum tank, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour after shearing; to emulsifying completely, liquid level without floating oil, obtained first emulsion.
2. pH meter must be used to test the original ph of this first emulsion.
3. according to pH=-lg [H+], the amount regulating and need 0.1mol/L hydrochloric acid solution or the 0.1mol/l sodium hydroxide solution added between pH to 5.5 ~ 6.0 is calculated
4. under agitation, and maintaining nitrogen purge protection, add 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH by charge door, fully dissolve and adjust ph 5.2, add water for injection to recipe quantity by tank bottoms weighing system.
(2) preparation of essence breast
1. storage tank all uses air in nitrogen displacement tank, and maintaining nitrogen purge protection, logical nitrogen pressurization, makes colostrum prepare liquid and adds in high pressure homogenizer, make particle diameter after several homogenizing between 0.12 μm ~ 0.28 μm.
Record this alprostadil injection emulsion pH and 4.826 be less than 5.0, do not meet the requirement of national Alprostadil standard.Assay is: 99.36%, 25 DEG C of labelled amount were accelerated placement after 30 days, and pH is reduced to 3.942, and content is reduced to: 42.73% of labelled amount, and cannot be up to state standards requirement.
Comparative example 3:
(1) preparation of colostrum
1. oil phase tank; aqueous phase tank all must use air in nitrogen displacement tank; and maintaining nitrogen purge protection, logical nitrogen pressurization, will containing Alprostadil oil phase (median chain triglyceride oil; Alprostadil) and aqueous phase (water for injection; glycerol, Tween 80) be added in wire shearing with certain flow rate separately pass back into colostrum tank, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour after shearing; to emulsifying completely, liquid level without floating oil, obtained first emulsion.
2. pH meter must be used to test the original ph of this first emulsion.
4. under agitation, and maintaining nitrogen purge protection, add 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH by charge door, fully dissolve and adjust ph 9.7, add water for injection to recipe quantity by tank bottoms weighing system.
(2) preparation of essence breast
1. storage tank all uses air in nitrogen displacement tank, and maintaining nitrogen purge protection, logical nitrogen pressurization, makes colostrum prepare liquid and adds in high pressure homogenizer, make particle diameter after several homogenizing between 0.12 μm ~ 0.28 μm.
Recording this alprostadil injection emulsion pH value is 9.547 be greater than 6.0, does not meet the requirement of national Alprostadil standard.Assay is: 61.76% of labelled amount, and cannot be up to state standards requirement.
Comparative example 4:
(1) preparation of colostrum
1. oil phase tank; aqueous phase tank all must use air in nitrogen displacement tank; and maintaining nitrogen purge protection, logical nitrogen pressurization, will containing Alprostadil oil phase (median chain triglyceride oil; Alprostadil) and aqueous phase (water for injection; glycerol, Tween 80) be added in wire shearing with certain flow rate separately pass back into colostrum tank, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour after shearing; to emulsifying completely, liquid level without floating oil, obtained first emulsion.
2. pH meter must be used to test the original ph of this first emulsion.
4. under agitation, and maintaining nitrogen purge protection, add 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH by charge door, fully dissolve and adjust ph 10.2, add water for injection to recipe quantity by tank bottoms weighing system.
(2) preparation of essence breast
1. storage tank all uses air in nitrogen displacement tank, and maintaining nitrogen purge protection, logical nitrogen pressurization, makes colostrum prepare liquid and adds in high pressure homogenizer, make particle diameter after several homogenizing between 0.12 μm ~ 0.28 μm.
Recording this alprostadil injection emulsion pH value is 9.990 be greater than 6.0, does not meet the requirement of national Alprostadil standard.Assay is: 41.94%, and cannot be up to state standards requirement.
Embodiment 1:
(1) preparation of colostrum
1. oil phase tank; aqueous phase tank all must use air in nitrogen displacement tank; and maintaining nitrogen purge protection, logical nitrogen pressurization, will containing Alprostadil oil phase (median chain triglyceride oil; Alprostadil) and aqueous phase (water for injection; glycerol, Tween 80) be added in wire shearing with certain flow rate separately pass back into colostrum tank, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour after shearing; to emulsifying completely, liquid level without floating oil, obtained first emulsion.
2. pH meter must be used to test the original ph of this first emulsion.
3. according to pH=-lg [H+]; calculate to regulate between pH to 5.5 ~ 6.0 and need the amount of 0.1mol/L hydrochloric acid solution or the 0.1mol/l sodium hydroxide solution added 4. under agitation; and maintaining nitrogen purge protection; 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH is added by charge door; abundant dissolving adjust ph 5.7, add water for injection to recipe quantity by tank bottoms weighing system.
(2) preparation of essence breast
1. storage tank all uses air in nitrogen displacement tank, and maintaining nitrogen purge protection, logical nitrogen pressurization, makes colostrum prepare liquid and adds in high pressure homogenizer, make particle diameter after several homogenizing between 0.12 μm ~ 0.28 μm.
Record this alprostadil injection emulsion pH and 5.370 be less than 5.5, do not meet the requirement of national Alprostadil standard.Assay is: 99.29%, 25 DEG C of labelled amount were accelerated placement after 30 days, and pH is reduced to 5.173, and content is reduced to: 98.89%, complies with the national standard requirements.
Table 1: the stability synopsis of embodiment and comparative example
Be the embodiment to some experimental data in table 1, because comparative example 3 and comparative example 4 are because undesirable after having prepared, so there is no provide 25 DEG C of results accelerated after 30 days.
Claims (2)
1. a preparation method for alprostadil injection emulsion, is characterized in that, specifically comprises the steps:
(1) preparation of colostrum
1. the air in nitrogen displacement oil phase tank and aqueous phase tank tank is used, then the Alprostadil oil phase containing median chain triglyceride oil and Alprostadil is injected into for subsequent use in described oil phase tank and maintaining nitrogen purge protection, will containing water for injection, glycerol, the Alprostadil aqueous phase of Tween 80 is injected into for subsequent use in described aqueous phase tank and maintaining nitrogen purge protection;
2. logical nitrogen pressurization, Alprostadil aqueous phase in Alprostadil oil phase in described oil phase tank and described aqueous phase tank is added in wire shearing with certain flow rate separately, Alprostadil oil phase and Alprostadil aqueous phase pass back into colostrum tank after shearing, with the high-shear emulsion machine in colostrum tank and on-line shearing machine circulating emulsion certain hour, to emulsifying completely, liquid level without floating oil, obtained first emulsion;
3. use pH meter to test the original ph of this first emulsion, and according to pH=-lg [H+], calculate the amount regulating and need 0.1mol/L hydrochloric acid solution or the 0.1mol/l sodium hydroxide solution added between pH to 5.5 ~ 6.0; Under agitation, and maintaining nitrogen purge protection, 0.1mol/L hydrochloric acid solution or 0.1mol/l sodium hydroxide solution adjustment pH is added by charge door, abundant dissolving just emulsion adjust ph 5.5 ~ 6.0, adding water for injection to recipe quantity by tank bottoms weighing system keeps pH between 5.5 ~ 6.0, obtains colostrum and prepares liquid;
(2) preparation of essence breast
Storage tank all uses air in nitrogen displacement tank; and maintaining nitrogen purge protection; logical nitrogen pressurization, colostrum prepared by step (1) is prepared liquid and is added in high pressure homogenizer, makes particle diameter between 0.12 μm ~ 0.28 μm stored in also maintaining nitrogen purge protection in storage tank after several homogenizing.
2. alprostadil injection emulsion, is characterized in that, prepares according to method according to claim 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108927080A (en) * | 2018-10-11 | 2018-12-04 | 本溪恒康制药有限公司 | The equipment for preparing lipid microspheres |
| CN109261088A (en) * | 2018-10-11 | 2019-01-25 | 本溪恒康制药有限公司 | Prepare the equipment and preparation method of lipid microspheres |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872072A (en) * | 2006-03-14 | 2006-12-06 | 广州中大创新药物研究与开发中心有限公司 | Nano emulsion injection of alprostadil and preparation method |
| CN101627968A (en) * | 2009-08-14 | 2010-01-20 | 北京中海康医药科技发展有限公司 | Preparation method of alprostadil injection |
| CN102764240A (en) * | 2011-05-03 | 2012-11-07 | 上海现代药物制剂工程研究中心有限公司 | Alprostadil lyophilized microemulsion, and preparation method and application thereof |
-
2014
- 2014-12-25 CN CN201410838493.6A patent/CN104622804A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872072A (en) * | 2006-03-14 | 2006-12-06 | 广州中大创新药物研究与开发中心有限公司 | Nano emulsion injection of alprostadil and preparation method |
| CN101627968A (en) * | 2009-08-14 | 2010-01-20 | 北京中海康医药科技发展有限公司 | Preparation method of alprostadil injection |
| CN102764240A (en) * | 2011-05-03 | 2012-11-07 | 上海现代药物制剂工程研究中心有限公司 | Alprostadil lyophilized microemulsion, and preparation method and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108927080A (en) * | 2018-10-11 | 2018-12-04 | 本溪恒康制药有限公司 | The equipment for preparing lipid microspheres |
| CN109261088A (en) * | 2018-10-11 | 2019-01-25 | 本溪恒康制药有限公司 | Prepare the equipment and preparation method of lipid microspheres |
| CN108927080B (en) * | 2018-10-11 | 2024-04-05 | 本溪恒康制药有限公司 | Equipment for preparing lipid microsphere |
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