CN102178650B - Alprostadil injection and preparation method thereof - Google Patents
Alprostadil injection and preparation method thereof Download PDFInfo
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- CN102178650B CN102178650B CN201110104824A CN201110104824A CN102178650B CN 102178650 B CN102178650 B CN 102178650B CN 201110104824 A CN201110104824 A CN 201110104824A CN 201110104824 A CN201110104824 A CN 201110104824A CN 102178650 B CN102178650 B CN 102178650B
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Abstract
The invention relates to an alprostadil injection and a preparation method thereof. The alprostadil injection has a prescription as follows: a, a main drug is alprostadil with concentration of 5mu g-15mu g/ml; b, an oil phase is soybean oil with concentration of respectively 10.0-12.0 percent; c, soyabean lecithin and poloxamer 188 are selected as emulsifying agents and have concentrations of respectively 1.0-1.8 percent and 0.02-0.2 percent; d, citric acid is adopted as a pH regulating agent with concentration of 5nM to 50Mm and pH of 5.0-6.0; e, glycerol is adopted as an osmotic pressure regulating agent with concentration of respectively 2.0-2.5 percent; and f, the balance is injection water.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, particularly a kind of safe, stable alprostadil injection and preparation method thereof.
Background technology
Alprostadil has another name called PGE
1(Alprostadil), its chemical name is: and (1R, 2R, 3R)-3-hydroxyl 2-[(E)-(3S)-3-hydroxyl-1-octenyl]-5-oxo-cyclopentane enanthic acid, chemical structural formula:
Alprostadil is a kind of endogenous biological active substances, has multiple physiology, pharmacologically active.
Concrete indication is following:
1. the extremity tranquillization pain that causes of the extremity ulcer that causes of treatment CAO disease (thromboangiitis obliterans, Arteriosclerosis obliterans etc.) and tiny blood vessels circulatory disturbance.Improve cardiovascular and cerebrovascular microcirculation disturbance.
2. organ transplantation postoperative thromboembolism preventing treatment is in order to suppress to transplant the endovascular thrombosis in back.
3. ductus arteriosus dependent form congenital heart disease in order to alleviate hypoxemia, keeps the conduit blood flow with the operative treatment of awaiting a favorable opportunity.
4. the auxiliary treatment that is used for chronic hepatitis.
The morning of this drug development, in U.S.'s listing (lyophilized injectable powder), American Pharmacopeia began to record in 1985 as far back as 1981, in the listing of many countries.Because degraded is fast when getting into body-internal-circulation, dosage is bigger during use, and side effect is more.Japan in 1988 alprostadil injection (lipomul) that gone on the market has significantly reduced original dosage (for former dosage 1/10th), has enlarged the treatment indication, has improved curative effect.Domestic Initial Public Offering in 1998 alprostadil injection (lipomul), trade name: when triumphant.Alprostadil dry emulsion Initial Public Offering at home in 2010, trade name: excellent Supreme Being's that.
But; Because Alprostadil is met water unstable, existing both at home and abroad commercially available alprostadil injection product generally adopts remaining probabilistic method (sterilizing 8 minutes down as 121 ℃) terminal sterilization technology or sterile production technology (trade name: bud is smooth) in process of production; The aseptic guarantee value of product (SAL) is low; Even sterilization back drug degradation rate surpasses 15% like this, and need (0～5 ℃) storage under unconventional temperature, effect duration only has 12 months.Product transport, product storage and use are very inconvenient.Even (trade name: excellent Supreme Being's that) effect duration also is 12 months to the Alprostadil dry emulsion of domestic Initial Public Offering in 2010.The present invention is through discovering: make coemulsifier with a certain amount of poloxamer 188; Form compound emulsifying agent with soybean phospholipid (injection); Thereby the product chemical stability is significantly increased, can tolerate and excessively kill method, the aseptic guarantee value of product (SAL) height; And can preserve 18 months down in conventional refrigeration temperature (2～8 ℃), product quality still meets national drug standards WS1-(X-041)-2002Z-2008.
Summary of the invention
In order to overcome the shortcoming of existing commercially available prod, obtain safer, stable alprostadil injection prescription and method for preparing, we have carried out conscientiously research to alprostadil injection prescription and method for preparing.Adopt single factor design method, the compound use of the used emulsifying agent of alprostadil injection (soybean phospholipid and poloxamer 188) has been carried out investigating (and with commercial preparation prescription contrast).Alprostadil injection with the preparation of different composite emulsifier proportion adopts the character of excessively killing after method is sterilized; PH value and Alprostadil degradation rate are evaluation index; The preferred emulsifier compositely proportional is fortunately prepared the preparation that can achieve the above object, thereby accomplishes the present invention.
Below, the present invention is at length explained.
Alprostadil injection provided by the invention is to be active component with the Alprostadil, adds that pharmaceutically acceptable soybean oil (injection), compound emulsifying agent, glycerol (injection), citric acid and water for injection are prepared from through emulsifying technology.
For this reason, the present invention provides a kind of alprostadil injection compositions, and its prescription is formed as follows:
(a) its concentration range of principal agent Alprostadil is 5 μ g～15 μ g/ml;
(b) oil phase is soybean oil (injection), and its concentration range is respectively 10.0～12.0% (g/ml);
(c) emulsifying agent is selected soybean phospholipid (injection) and poloxamer 188 for use, and its concentration range is respectively 1.0～1.8% (g/ml) and 0.02%～0.2% (g/ml);
(d) pH regulator agent citric acid, its concentration range is 5mM to 50mM, the scope of pH is 5.0 to 6.0;
(d) osmotic pressure regulator glycerol (injection), its concentration range is respectively 2.0～2.5% (g/ml);
All the other are water for injection.
Most preferred alprostadil injection compositions, its prescription is formed as follows:
(a) its concentration range of principal agent Alprostadil is 5-15 μ g/ml;
(b) oil phase is soybean oil (injection), and its concentration is 10.0% (g/ml);
(c) emulsifying agent is selected soybean phospholipid (injection) and poloxamer 188 for use, and its concentration is respectively 1.2% (g/ml) and 0.08% (g/ml);
(d) pH regulator agent citric acid, its concentration is 25mM, pH value is 5.5;
(d) osmotic pressure regulator glycerol (injection), its concentration are 2.2% (g/ml);
All the other are water for injection.
On the other hand, the present invention also provides the method for preparing of a kind of safe, stable alprostadil injection (lipomul), comprises the steps:
(a) it is subsequent use to take by weighing Alprostadil, soybean oil (injection), soybean phospholipid (injection), glycerol (injection), poloxamer 188 and the citric acid of recipe quantity respectively;
(b) respectively with Alprostadil, soybean phospholipid (injection) adds in the soybean oil (injection), and under high-shearing dispersion emulsifying machine, high speed shear was disperseed 10～20 minutes then, formed oil phase;
(c) respectively glycerol (injection), poloxamer 188, citric acid are added in an amount of water for injection, under high-shearing dispersion emulsifying machine, low velocity shear disperseed 3～5 minutes then, measured pH to 5.0～6.0, formed water;
(d) under high speed shear is disperseed, oil phase is slowly added aqueous phase, continue high speed shear then and disperseed 20～30 minutes, form colostrum;
(e) the colostrum benefit is added to the full amount of water for injection, move into high pressure microjet nano-dispersed appearance (trade name Microfluidizer) behind the mixing, homogenizing is 3 times under 18000～20000Psi pressure, fills the nitrogen fill to the 4ml cillin bottle;
(f) sample after the fill is put in the rotary water bath formula sterilization cabinet, adopted and excessively kill the method sterilization, sterilising conditions is selected from 121 ℃ of sterilizations 12 minutes down, 126 ℃ of a kind of in the sterilization 4 minutes down.After sterilization, promptly get alprostadil injection.
The alprostadil injection of technical scheme preparation of the present invention is compared with existing commercially available alprostadil injection product; Can tolerate and excessively kill the method sterilization; Can significantly strengthen its safety and stability, below further specify beneficial effect of the present invention through test data:
The test of Test Example 1 sterilization stability
Alprostadil injection sample after the sterilization of embodiment 1, embodiment 2 and comparative example 1 preparation is estimated, investigated its sterilization back preparation character, pH value and Alprostadil degradation rate (the degradation product PGA1 is than last Alprostadil inventory).The result sees table 1.
The sterilization stability of the different prescription of table 1 alprostadil injection
| Detect index | Embodiment 1 | Embodiment 2 | Comparative example 1 |
| Character | The white emulsion liquid | The white emulsion liquid | The white emulsion liquid |
| PH value | 5.5 | 5.2 | 5.5 |
| Degradation rate | 11.2％ | 12.0％ | 16.8％ |
Visible by table 1, the sample of the more commercially available prescription preparation of the alprostadil injection of the present invention's preparation can tolerate excessively kills the method sterilization process, can significantly strengthen its safety and stability.
The test of Test Example 2 storage-stables
The alprostadil injection sterilization back preparation of embodiment 1, embodiment 2 and comparative example 1 preparation was preserved 18 months down in conventional refrigeration temperature (2～8 ℃), served as to investigate index with the principal agent degradation rate, carried out long-time stability and investigated test.The result sees table 2.
Table 2 different prescription alprostadil injection long-time stability under 2～8 ℃ of holding conditions
| Minute | Embodiment 1 | Embodiment 2 | Comparative example 1 |
| 0 month | 11.2％ | 12.0％ | 16.8％ |
| March | 14.2％ | 14.4％ | 21.6％ |
| June | 17.0％ | 17.9％ | 26.8％ |
| JIUYUE | 20.2％ | 20.0％ | 31.5％ |
| December | 23.2％ | 23.8％ | 42.2％ |
| 18 months | 29.2％ | 30.0％ | 55.2％ |
| 18 months content of drug | 96.3％ | 95.3％ | 72.1％ |
Visible by table 2, the sample of the more commercially available prescription preparation of the alprostadil injection of the present invention's preparation can be preserved 18 months down for 2～8 ℃ in the conventional refrigeration temperature, and product quality still meets national drug standards WS1-(X-041)-2002Z-2008.
What wherein comparative example 1 adopted is the method for preparing of traditional fat milk, and prescription derives from Japanese fuji pharmaceuticals industry Co., Ltd. should the article description.Method is following:
5mg Alprostadil, 18g soybean phospholipid (injection), 2.4g oleic acid and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol (injection) was added the back stirring at low speed 5 minutes, forms water; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum in 20 minutes, regulated aqueous pH values in 5.0～6.0 scopes with the 10mM sodium hydroxide, standardize solution 1000ml.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, promptly get in 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F0 value is greater than 12, for excessively killing method).
Prescription of the present invention obtains through screening, and screening process is following:
Adopt single factor design method commonly used in the pharmacy, the use amount of poloxamer 188 is investigated, and contrast with former prescription product.With the particle diameter after the alprostadil injection sterilization of different content poloxamer 188 preparations, pH value and Alprostadil content and degradation product prostaglandin A
1For investigating index, preferred secondary co-emulsifier poloxamer 188 consumptions are 0.08%.Screening most preferably simultaneously, pH value is 5.5.
The invention effect
As stated, through the present invention high-quality alprostadil injection can be provided.Injection of the present invention can be preserved 18 months down in conventional refrigeration temperature (2～8 ℃), and product quality still meets national drug standards WS1-(X-041)-2002Z-2008.
In sum, the invention provides a kind of new alprostadil injection prescription and method for preparing, production process is simple, has distinct creativeness and practicality, in clinical use, good prospects for application will be arranged.
The specific embodiment
Below the present invention will be described in more detail through embodiment, but the present invention is not limited to this.
Embodiment 1
5mg Alprostadil, 12g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol (injection), 0.8g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates ph value of aqueous phase 5.5 with the 25mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 2
5mg Alprostadil, 18g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol (injection), 2g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values 5.5 with the 25mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and 3 homogenizing of homogenizing are 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 3
10mg Alprostadil, 18g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol (injection), 2g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values in 5.5 scopes with the 10mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 4
10mg Alprostadil, 18g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol (injection), 2g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values in 5.0～6.0 scopes with the 10mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 5
10mg Alprostadil, 15g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 20g glycerol (injection), 1g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values 5.5 with the 25mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 6
5mg Alprostadil, 10g soybean phospholipid (injection) and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 20g glycerol (injection), 0.2g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values 5.0 with the 5mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Embodiment 7
15mg Alprostadil, 18g soybean phospholipid (injection) and 120g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 25g glycerol (injection), 2g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values 6.0 with the 50mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase, emulsifying formed colostrum, standardize solution 1000ml in 20 minutes.Colostrum is inserted high pressure microjet nano-dispersed appearance charging aperture, and homogenizing is 3 times under 18000～20000Psi pressure.Fill, the button plug rolls lid.To rotary water-bath sterilization cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F
0Value is greater than 12, for excessively killing method) promptly get.
Claims (1)
1. an alprostadil injection is characterized in that, it is formed as follows:
(a) Alprostadil, concentration are 5.0 μ g/ml;
(b) soybean oil, its concentration are 10.0%;
(c) soybean phospholipid and poloxamer 188, its concentration is respectively 1.2% and 0.08%;
(d) citric acid soln, its concentration is 25mM;
(e) glycerol, its concentration are 2.2%;
All the other are water for injection; The pH value of injection is 5.5;
This injection is made into 1000ml, and its preparation method is following:
5mg Alprostadil, 12g soybean phospholipid and 100g soybean oil are added in the container, and high shear disperses 15 minutes to dissolving, forms oil phase; Extracting container adds 850g water for injection in addition, and 22g glycerol, 0.8g poloxamer 188 were added the back stirring at low speed 5 minutes, forms water, regulates aqueous pH values 5.5 with the 25mM citric acid; Water is inserted under the high-shearing dispersion emulsifying machine working head, after running up, slowly add oil phase; Emulsifying formed colostrum in 20 minutes, and standardize solution 1000ml inserts high pressure microjet nano-dispersed appearance charging aperture with colostrum; Homogenizing is 3 times under 18000 ~ 20000psi pressure, fill, button plug; Roll lid, to rotary water-bath sterilization cabinet, promptly got in 4 minutes 126 ℃ of sterilizations.
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