CN103301076A - Alprostadil frozen-drying lipid emulsion and preparation method thereof - Google Patents
Alprostadil frozen-drying lipid emulsion and preparation method thereof Download PDFInfo
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- CN103301076A CN103301076A CN2012100651412A CN201210065141A CN103301076A CN 103301076 A CN103301076 A CN 103301076A CN 2012100651412 A CN2012100651412 A CN 2012100651412A CN 201210065141 A CN201210065141 A CN 201210065141A CN 103301076 A CN103301076 A CN 103301076A
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- Prior art keywords
- alprostadil
- freeze
- oil
- dried
- injection
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- 230000003578 releasing effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides an alprostadil frozen-drying lipid emulsion and a preparation method thereof. The emulsion comprises the following compositions in percentage by mass: 0.0005-0.01% of alprostadil, 1-10% of oil for injection, 0.01-5% of an emulsifier, 0.02-2% of a stabilizer, 0-0.5% of an antioxidant, 1-20% of a freeze-drying protecting agent, and proper pH regulator and water for injection; the preparation method comprises the steps of: stirring alprostadil and oil for injection, and evenly mixing to obtain an oil phase; stirring freeze-drying protecting agent and water for injection to obtain a water phase; respectively the emulsifier, antioxidant and stabilizer into the water phase or the oil phase according to the solubility; mixing the water phase and the oil phase, carrying out high-speed stirring and dispersion, carrying out constant volume on the water for injection, regulating the pH value to obtain initial emulsion; transferring the initial emulsion into a high-pressure homogenizer for homogenizing for many times, then filtering, subpackaging, freeze-drying to obtain the alprostadil frozen-drying lipid emulsion. The alprostadil frozen-drying lipid emulsion is more stable and more uniform, the preparation technology and method can be simplified, and the economic efficiency can be improved.
Description
Technical field
The invention belongs to medical technical field, relate to particularly a kind of Alprostadil freeze-dried liplid emulsions and preparation method thereof.
Background technology
Alprostadil claims again prostaglandin (Prostaglandins, PG).Alprostadil is that PGE1 (PGE1) is the extremely strong biological active substances of a kind of activity wherein; effect with anticoagulant, thromboxane A2 generation, atherosclerosis, Lipid Plaque formation and immune complex; can expand peripheral blood vessel and coronary vasodilator; reduce Peripheral resistance and blood pressure; the protection ischemic myocardial is arranged; the effects such as capable of reducing myocardial infarction area; arrange in addition sodium, diuresis and liver, kidney, lung, gastropathy are all had treatment, protective effect, especially the treatment of geriatric cardiovascular disease had unique curative effect.Yet, PGE
1Metabolism is very fast in vivo, and under pulmonary's oxidase effect, the per pass pulmonary circulation namely has 60%～90% inactivation, in order to keep drug effect, usually adopts the method for the above during continuous intravenous infusion administration of heavy dose of 5h.But the side effect that therefore produces, particularly blood vessel pain makes patient's endurable.
Existing Alprostadil lipid Emulsion injection because Alprostadil is very unstable in aqueous solution, degrades medicine very soon, the shortcoming such as have that medicine stability is poor, content poor controllability, effect duration are short.
The Alprostadil freeze-dried injectable powder of common injection has extremely strong blood vessel irritation and relatively poor chemical stability.
In the existing disclosed alprostadil injection type of the patent freeze-dried emulsion preparation method; freeze drying protectant adding method is to add after the Emulsion molding; be unfavorable for the dissolving of freeze drying protectant and the uniformity in the emulsion before lyophilizing; affect the front emulsion state of lyophilizing, make the product that redissolves after the lyophilizing unstable, it is large that particle diameter becomes; easy breakdown of emulsion; producing macroparticle affects the safety of product, and simultaneously technological operation is unfavorable for sterile production repeatedly.And the novel freeze drying protectant adding method that the present invention proposes; its water before the Emulsion molding is added; the emulsion that still can guarantee to form homogeneous before the lyophilizing, stablize, particle diameter is little; not only make freeze drying protectant Uniform Dispersion in product; and guaranteed that the product cut size that redissolves after the lyophilizing changes little; improve product stability, and simplified technology difficulty, improved production efficiency.
Summary of the invention
The purpose of this invention is to provide a kind of Alprostadil freeze-dried liplid emulsions and preparation method thereof, the Alprostadil freeze-dried liplid emulsions of the method preparation is stable uniform more, and has simplified its process of preparing, has improved business efficiency.
The invention provides a kind of Alprostadil freeze-dried liplid emulsions, this Emulsion is comprised of following material, and the quality percentage composition of each composition is respectively: Alprostadil 0.0005～0.01%, oil for injection 1～10%, emulsifying agent 0.01～5%, stabilizing agent 0.02～2%, antioxidant 0-0.5%, freeze drying protectant 1～20%, pH adjusting agent are an amount of, water for injection;
Described oil for injection is selected from one or more mixture in soybean oil, olive oil, fish oil, Petiolus Trachycarpi oil, Oleum sesami, safflower oil, Oleum Camelliae, Oleum Cocois, Oleum Gossypii semen, medium chain monoglyceride, medium chain glycerol dibasic acid esters, the medium chain triglyceride;
Described emulsifying agent is selected from one or more mixture in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, the poloxamer (F68);
Described stabilizing agent is selected from one or more mixture in oleic acid, enuatrol, cholic acid, sodium cholate, deoxycholic acid, the NaTDC;
Described antioxidant is selected from one or more mixture in vitamin E, vitamin C, the sulphite;
Described freeze drying protectant is selected from one or more mixture in glucose, lactose, galactose, fructose, dextran, mannitol, glycine, sorbitol, xylose, xylitol, sucrose, trehalose, maltose, the polyvinylpyrrolidone (PVP);
Described pH adjusting agent is selected from one or more mixture in sodium hydroxide, hydrochloric acid, acetic acid, citric acid, sodium citrate, the phosphate.
Alprostadil freeze-dried liplid emulsions provided by the invention, described emulsifying agent is preferably from Ovum Gallus domesticus Flavus lecithin.
Alprostadil freeze-dried liplid emulsions provided by the invention, when described emulsifying agent was selected from Ovum Gallus domesticus Flavus lecithin, during the quality percentage composition of phosphatidylcholine in the Ovum Gallus domesticus Flavus lecithin (PC) 〉=98%, the lyophilizing liplid emulsions effect that makes was more excellent.
Alprostadil freeze-dried liplid emulsions provided by the invention, the ratio of described emulsifier and oil for injection consumption is 1: 1～1: 5.
Alprostadil freeze-dried liplid emulsions provided by the invention, described freeze drying protectant is preferably from maltose.
The present invention also provides the preparation method of described Alprostadil freeze-dried liplid emulsions, and whole preparation process is carried out under nitrogen protection, and detailed process is as follows:
1. with Alprostadil, oil for injection, at 50-80 ℃ of stirring, mixing, get oil phase;
2. with freeze drying protectant, water for injection, be heated to 50-80 ℃, stir, get water;
3. emulsifying agent, antioxidant and stabilizing agent add respectively in water or the oil phase according to its dissolubility;
4. water and oil phase are mixed, through high-speed stirred, dispersion, the water for injection standardize solution is regulated pH value in the 4-7 scope, gets colostrum;
5. colostrum is changed over to the high pressure homogenizer homogenizing for several times, then through filtering with microporous membrane, the packing of 0.2 μ m, lyophilizing namely gets Alprostadil freeze-dried liplid emulsions.
The preparation method of Alprostadil freeze-dried liplid emulsions provided by the invention, described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin.
The preparation method of Alprostadil freeze-dried liplid emulsions provided by the invention, when described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin, the quality percentage composition of phosphatidylcholine in the Ovum Gallus domesticus Flavus lecithin (PC) 〉=98%.
The preparation method of Alprostadil freeze-dried liplid emulsions provided by the invention, the ratio of described emulsifier and oil for injection consumption is 1: 1～1: 5.
The preparation method of Alprostadil freeze-dried liplid emulsions provided by the invention, described freeze drying protectant is preferably from maltose.
Based on the Alprostadil freeze-dried powder pin of tradition, the comparatively serious vascular stimulation phenomenon that occurs during intravenous drip, the present invention can reduce free Alprostadil greatly to the zest of blood vessel after utilizing Alprostadil and the specific affinity of phospholipid that Alprostadil is scattered in liplid emulsions, again with liplid emulsions by suitable means lyophilization, obtain redissolving the liplid emulsions of rear particle diameter at 50nm-200nm, can adopt the aseptic filtration mode to sterilize, avoid the negative effect of high temperature sterilize to Alprostadil stability.By aseptic filtration and hypothermic lyophilization technology, make impurity obtain more efficiently control.The present invention adopts special freeze drying protectant addition method to prepare efficient, stable targeted drug preparation take liplid emulsions as carrier.Therefore the injection Alprostadil dry emulsion of the present invention difficult problem that not only will solve the Alprostadil poor chemical stability has improved product stability, but also will improve the compliance of patient in the clinical use procedure.
The lyophilizing liplid emulsions that the present invention obtains more is conducive to non-RES tissue distribution in the Alprostadil body because the rear particle diameter of redissolution is appropriate, reduces pulmonary's circulation deactivation and blood and removes, and is conducive to the interior for a long time circulation of body, is suitable for the treatment of corresponding disease.
The method that the present invention has adopted water to add freeze drying protectant is dispersed in the Alprostadil freeze-dried liplid emulsions system freeze drying protectant; obtained the more Alprostadil freeze-dried liplid emulsions of stable uniform; and simplified the process of preparing of lyophilizing liplid emulsions, improved business efficiency.But the present invention's room temperature storage and transport, stability can reach 2 years; The low-temperature freeze drying process is breakdown of emulsion not, and indices all met the ejection preparation requirement after lyophilizing was redissolved.
The lyophilizing liplid emulsions that the present invention obtains has certain targeting, strengthens medicine in the concentration of disease sites, and the release medicine that slowly continues is better brought into play curative effect; Can also improve drug solubility, reduce use amount, improve bioavailability, reduce local irritation, reduce side effect etc.Thereby for extensive patients provides safer, efficient, stable Alprostadil preparation.
The present invention adopts a kind of novel freeze drying protectant addition method to prepare Alprostadil freeze-dried liplid emulsions, makes it compared with prior art, has following advantage and good effect:
1, the present invention has solved the unsettled problem of prostadil fatty emulsion injection because the component that Alprostadil freeze-dried breast reaches cooperates and effective preparation method.
2, the present invention has adopted novel freeze drying protectant addition method; soon freeze drying protectant directly joins the aqueous phase in the preparation process; freeze drying protectant is dispersed in the Alprostadil freeze-dried liplid emulsions system; obtained the more Alprostadil freeze-dried liplid emulsions of stable uniform; and simplified the process of preparing of lyophilizing liplid emulsions, improved business efficiency.But and the room temperature storage and transport, reduced the cost of transportation of medicine;
3, the present invention has been owing to having adopted the Alprostadil freeze-dried liplid emulsions of the drying that novel freeze drying protectant addition method obtains, and thus not only at low-temperature freeze drying process breakdown of emulsion not, and the indices of lyophilizing after redissolving all meets the ejection preparation requirement.
4, the present invention select human toxicity little, stable chemical nature, the mixture of independent a kind of or lecithin and poloxamer in not labile Ovum Gallus domesticus Flavus lecithin, soybean lecithin, the poloxamer prepares Emulsion as emulsifying agent respectively and investigates.Find by test of many times, particle diameter is relevant with emulsifying agent PC content after redissolving.The phosphatidylcholine of emulsifying agent (PC) content has obtained the rear better Alprostadil freeze-dried liplid emulsions of particle diameter of redissolution greater than 98% Ovum Gallus domesticus Flavus lecithin.
5, a kind of novel freeze drying protectant addition method of the present invention prepares in the Alprostadil freeze-dried liplid emulsions, and emulsifying agent is selected relevant.If consumption very little, the film density on the emulsion droplet interface is too small even not to be enough to wrap up emulsion droplet; Consumption is too much, and emulsifying agent can not dissolve fully, makes that the Emulsion particle diameter is excessive can not to adopt aseptic filtration sterilization.The present invention selects emulsifiability good, little to human toxicity, stable chemical nature, the mixture of independent a kind of or lecithin and poloxamer in not labile Ovum Gallus domesticus Flavus lecithin, soybean lecithin, the poloxamer prepares Emulsion as emulsifying agent respectively and investigates.Find by test of many times, the consumption of emulsifying agent and the ratio of oil mass are 1: 1～1: 5 o'clock, and indices was better after the lyophilizing liplid emulsions of preparing redissolved.
6, a kind of novel freeze drying protectant addition method of the present invention prepares in the Alprostadil freeze-dried liplid emulsions, and effect is selected relevant with freeze drying protectant.Freeze drying protectant of the present invention is selected from one or more mixture in glucose, lactose, galactose, fructose, dextran, mannitol, glycine, sorbitol, xylose, xylitol, sucrose, trehalose, maltose, the polyvinylpyrrolidone (PVP) etc.Find by test of many times, when freeze drying protectant was selected maltose, indices was more excellent after the lyophilizing liplid emulsions of preparing redissolved.
7, a kind of novel freeze drying protectant addition method of the present invention prepares in the Alprostadil freeze-dried liplid emulsions, and whole preparation process is all carried out under nitrogen protection.In order to confirm nitrogen to the impact of emulsion stability, respectively in nitrogen protection with do not have under the nitrogen protection, prepare the Alprostadil freeze-dried liplid emulsions of same prescription.The long-term test results demonstration, both compare, and at the lyophilizing liplid emulsions that does not have to prepare under the nitrogen protection, its medicament contg and pH value all have obvious decline, and free fatty acid level raises to some extent, and the long-time stability of lyophilizing liplid emulsions are bad.In order effectively to prevent or delay oxidation, the hydrolysis of the compositions such as medicine, oil for injection, emulsifying agent, so select whole preparation process under nitrogen protection, to carry out, guaranteed the quality of lyophilizing liplid emulsions long term store.
8, in addition, the present invention can add an amount of antioxidant as one sees fit, but when not adding antioxidant, also can prepare qualified product.
9, a kind of novel freeze drying protectant addition method of the present invention prepares in the Alprostadil freeze-dried liplid emulsions, freeze drying protectant water addition cooperate phosphatidylcholine (PC) content to be higher than 98% egg yolk lecithin to make lyophilizing liplid emulsions effect as emulsifying agent and maltose as freeze drying protectant more excellent.Traditional Emulsion and conventional freeze dry preparation zest and product stability have been improved.Obtained reliable and stable high-quality lyophilizing lipid emulsion formulation, simplified technology difficulty and reduced industrial cost, for suitability for industrialized production provides more easily production thinking.
The specific embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1
Under nitrogen protection, Alprostadil 20mg, 15g soybean lecithin, 2g oleic acid, 0.5g vitamin E are added respectively in the 30g soybean oil, be heated to 60 ℃, stirring, mix homogeneously get oil phase; 2g F68,100g sucrose add in the 500ml water for injection, are heated to 60 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 2
Under nitrogen protection, Alprostadil 20mg, 15g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 2g oleic acid, 0.5g vitamin E are added respectively in the 30g soybean oil, be heated to 60 ℃, stirring, mix homogeneously get oil phase; 2gF68,100g sucrose add in the 500ml water for injection, are heated to 60 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 3
Under nitrogen protection, Alprostadil 20mg, 15g Ovum Gallus domesticus Flavus lecithin (PC content 80%), 2g oleic acid, 0.5g vitamin E are added respectively in the 30g soybean oil, be heated to 60 ℃, stirring, mix homogeneously get oil phase; 2gF68,100g sucrose add in the 500ml water for injection, are heated to 60 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 4
Under nitrogen protection, Alprostadil 50mg, 20g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 0.2g oleic acid, 5g vitamin E are added respectively in the 20g soybean oil, be heated to 70 ℃, stirring, mix homogeneously get oil phase; 5g F68,200g maltose add in the 500ml water for injection, are heated to 70 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 5
Under nitrogen protection, Alprostadil 50mg, 20g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 0.2g oleic acid, 5g vitamin E are added respectively in the 20g soybean oil, be heated to 70 ℃, stirring, mix homogeneously get oil phase; 5gF68,200g sucrose add in the 500ml water for injection, are heated to 70 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 6
Under nitrogen protection, Alprostadil 50mg, 20g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 0.2g oleic acid, 5g vitamin E are added respectively in the 20g soybean oil, be heated to 70 ℃, stirring, mix homogeneously get oil phase; 5gF68,200g lactose add in the 500ml water for injection, are heated to 70 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 7
Under nitrogen protection, Alprostadil 5mg, 20g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 20g oleic acid are added respectively in the 20g soybean oil, be heated to 50 ℃, stirring, mix homogeneously get oil phase; 200g maltose, 5g vitamin C add in the 500ml water for injection, are heated to 50 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 8
Under nitrogen protection, Alprostadil 10mg, 15g Ovum Gallus domesticus Flavus lecithin (PC content is higher than 98%), 5g oleic acid are added respectively in the 30g soybean oil, be heated to 80 ℃, stirring, mix homogeneously get oil phase; 2g F68,100g maltose add in the 500ml water for injection, are heated to 80 ℃, and stirring, mixing get water; Slowly pour above-mentioned oil phase into aqueous phase, stirred 10 minutes under the 12000rmp/min condition, be settled to 1000ml, regulate pH value in the 4-7 scope, get colostrum.Change colostrum over to high pressure homogenizer, the homogenizing several, then through the microporous filter membrane of 0.2 μ m, filtration sterilization, packing, lyophilizing namely get the lyophilizing liplid emulsions.The lyophilizing liplid emulsions that makes measured on demand add water, after the hydration vibration, be recovered to and carry out intravenous liplid emulsions.
Embodiment 9
Test particle diameter after change of size situation before and after the Emulsion lyophilizing, lyophilized formulations are redissolved with water for injection.As shown in table 1:
Change of size situation before and after table 1 lyophilizing
| Particle diameter (nm) before the lyophilizing | Particle diameter after the lyophilizing (nm) | |
| Embodiment 1 | 135 | 152 |
| Embodiment 2 | 118 | 129 |
| Embodiment 3 | 120 | 159 |
| Embodiment 4 | 105 | 130 |
| Embodiment 5 | 110 | 150 |
| Embodiment 6 | 108 | 159 |
| Embodiment 7 | 125 | 146 |
| Embodiment 8 | 136 | 149 |
According to embodiment in the table 11,2,3 Data Comparisons as can be known, change of size is relevant with emulsifying agent PC content before and after this liplid emulsions lyophilizing.The PC content of emulsifying agent has obtained the rear better Alprostadil freeze-dried liplid emulsions of particle diameter of redissolution greater than 98% Ovum Gallus domesticus Flavus lecithin.
According to embodiment in the table 14,5,6 Data Comparisons as can be known, when freeze drying protectant was selected maltose in this lyophilizing liplid emulsions preparation process, indices was more excellent after the lyophilizing liplid emulsions of preparing redissolved.
In sum, advantage of the present invention is that particle diameter can adopt the aseptic filtration mode to sterilize at 50nm-200nm after redissolving, and has solved the sterilization stability problem of Alprostadil thermally labile medicine, has improved product stability.The lyophilizing liplid emulsions that the present invention obtains more is conducive to non-RES tissue distribution in the Alprostadil body because the rear particle diameter of redissolution is appropriate, reduces pulmonary's circulation deactivation and blood and removes, and is conducive to the interior for a long time circulation of body, is suitable for the treatment of corresponding disease.And the method that the present invention has adopted water to add freeze drying protectant is dispersed in the Alprostadil freeze-dried liplid emulsions system freeze drying protectant; obtained the more Alprostadil freeze-dried liplid emulsions of stable uniform; not only effectively improve the dissolubility of Alprostadil, the targeting that has strengthened medicine and slowly releasing effect, improved the bioavailability of medicine; and; reduced the clinical using dosage of medicine; greatly reduce the zest to blood vessel, significantly improved the stability of Alprostadil.And simplified the process of preparing of lyophilizing liplid emulsions, improved business efficiency.But the present invention's room temperature storage and transport, stability can reach 2 years; The low-temperature freeze drying process is breakdown of emulsion not, and indices all met the ejection preparation requirement after lyophilizing was redissolved, and for extensive patients provides safer, effective, stable preparation, had very wide potential applicability in clinical practice.
Claims (10)
1. Alprostadil freeze-dried liplid emulsions, it is characterized in that: this Emulsion is comprised of following material, and the quality percentage composition of each composition is respectively: Alprostadil 0.0005～0.01%, oil for injection 1～10%, emulsifying agent 0.01～5%, stabilizing agent 0.02～2%, antioxidant 0-0.5%, freeze drying protectant 1～20%, pH adjusting agent are an amount of, water for injection;
Described oil for injection is selected from one or more mixture in soybean oil, olive oil, fish oil, Petiolus Trachycarpi oil, Oleum sesami, safflower oil, Oleum Camelliae, Oleum Cocois, Oleum Gossypii semen, medium chain monoglyceride, medium chain glycerol dibasic acid esters, the medium chain triglyceride;
Described emulsifying agent is selected from one or more mixture among Ovum Gallus domesticus Flavus lecithin, soybean lecithin, the poloxamer F68;
Described stabilizing agent is selected from one or more mixture in oleic acid, enuatrol, cholic acid, sodium cholate, deoxycholic acid, the NaTDC;
Described antioxidant is selected from one or more mixture in vitamin E, vitamin C, the sulphite;
Described freeze drying protectant is selected from one or more mixture among glucose, lactose, galactose, fructose, dextran, mannitol, glycine, sorbitol, xylose, xylitol, sucrose, trehalose, maltose, the polyvinylpyrrolidone PVP;
Described pH adjusting agent is selected from one or more mixture in sodium hydroxide, hydrochloric acid, acetic acid, citric acid, sodium citrate, the phosphate.
2. according to Alprostadil freeze-dried liplid emulsions claimed in claim 1, it is characterized in that: described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin.
3. according to Alprostadil freeze-dried liplid emulsions claimed in claim 2, it is characterized in that: described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin, the quality percentage composition of phosphatidylcholine PC 〉=98% in the Ovum Gallus domesticus Flavus lecithin.
4. according to Alprostadil freeze-dried liplid emulsions claimed in claim 1, it is characterized in that: the ratio of described emulsifier and oil for injection consumption is 1: 1～1: 5.
5. according to Alprostadil freeze-dried liplid emulsions claimed in claim 1, it is characterized in that: described freeze drying protectant is selected from maltose.
6. the preparation method of Alprostadil freeze-dried liplid emulsions claimed in claim 1, it is characterized in that: whole preparation process is carried out under nitrogen protection, and detailed process is as follows:
1. with Alprostadil, oil for injection, at 50-80 ℃ of stirring, mixing, get oil phase;
2. with freeze drying protectant, water for injection, be heated to 50-80 ℃, stir, get water;
3. emulsifying agent, antioxidant and stabilizing agent add respectively in water or the oil phase according to its dissolubility;
4. water and oil phase are mixed, through high-speed stirred, dispersion, the water for injection standardize solution is regulated pH value in the 4-7 scope, gets colostrum;
5. colostrum is changed over to the high pressure homogenizer homogenizing for several times, then through filtering with microporous membrane, the packing of 0.2 μ m, lyophilizing namely gets Alprostadil freeze-dried liplid emulsions.
7. according to the preparation method of Alprostadil freeze-dried liplid emulsions claimed in claim 6, it is characterized in that: described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin.
8. according to the preparation method of claim 6 and 7 described Alprostadil freeze-dried liplid emulsions, it is characterized in that: when described emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin, the quality percentage composition of phosphatidylcholine PC 〉=98% in the Ovum Gallus domesticus Flavus lecithin.
9. according to the preparation method of Alprostadil freeze-dried liplid emulsions claimed in claim 6, it is characterized in that: the ratio of described emulsifier and oil for injection consumption is 1: 1～1: 5.
10. according to the preparation method of Alprostadil freeze-dried liplid emulsions claimed in claim 6, it is characterized in that: described freeze drying protectant is selected from maltose.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103690484A (en) * | 2013-12-27 | 2014-04-02 | 哈药集团生物工程有限公司 | Medicine composition containing alprostadil and preparation method of medicine composition |
| CN104352503A (en) * | 2014-11-20 | 2015-02-18 | 北京蓝丹医药科技有限公司 | Alprostadil composition suitable for being used with contrast agent |
| CN105012248A (en) * | 2014-04-29 | 2015-11-04 | 北京蓝丹医药科技有限公司 | Injection alprostadil fat emulsion and preparing method thereof |
| CN105832744A (en) * | 2016-05-17 | 2016-08-10 | 海南合瑞制药股份有限公司 | Alprostadil freeze-dried emulsion composition for injection |
| CN106176600A (en) * | 2015-05-07 | 2016-12-07 | 上海现代药物制剂工程研究中心有限公司 | A kind of Alprostadil freeze-dried microemulsion, feedstock composition and preparation method thereof |
| CN106389328A (en) * | 2015-07-31 | 2017-02-15 | 北京蓝丹医药科技有限公司 | Alprostadil fat emulsion for injection |
| US20220008340A1 (en) * | 2018-11-27 | 2022-01-13 | Avignon Universite | Process for extracting substances of interest |
| JP2022509975A (en) * | 2018-11-27 | 2022-01-25 | シーアン リーバン ジャオシン バイオテクノロジー カンパニー リミテッド | Freeze-dried preparation for prostaglandin E1 methyl ester injection and its manufacture and use |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103690484B (en) * | 2013-12-27 | 2015-06-24 | 哈药集团生物工程有限公司 | Medicine composition containing alprostadil and preparation method of medicine composition |
| CN103690484A (en) * | 2013-12-27 | 2014-04-02 | 哈药集团生物工程有限公司 | Medicine composition containing alprostadil and preparation method of medicine composition |
| CN105012248B (en) * | 2014-04-29 | 2018-01-02 | 北京蓝丹医药科技有限公司 | A kind of injection prostadil fatty breast and preparation method thereof |
| WO2015165373A1 (en) * | 2014-04-29 | 2015-11-05 | 北京蓝丹医药科技有限公司 | Alprostadil lipid emulsion for injection and preparation method therefor |
| CN105012248A (en) * | 2014-04-29 | 2015-11-04 | 北京蓝丹医药科技有限公司 | Injection alprostadil fat emulsion and preparing method thereof |
| CN104352503A (en) * | 2014-11-20 | 2015-02-18 | 北京蓝丹医药科技有限公司 | Alprostadil composition suitable for being used with contrast agent |
| CN104352503B (en) * | 2014-11-20 | 2018-05-04 | 北京蓝丹医药科技有限公司 | A kind of Alprostadil composition for being adapted to be used in combination with contrast agent |
| CN106176600A (en) * | 2015-05-07 | 2016-12-07 | 上海现代药物制剂工程研究中心有限公司 | A kind of Alprostadil freeze-dried microemulsion, feedstock composition and preparation method thereof |
| CN106389328A (en) * | 2015-07-31 | 2017-02-15 | 北京蓝丹医药科技有限公司 | Alprostadil fat emulsion for injection |
| CN106389328B (en) * | 2015-07-31 | 2019-07-23 | 北京蓝丹医药科技有限公司 | A kind of injection prostadil fatty cream |
| CN105832744A (en) * | 2016-05-17 | 2016-08-10 | 海南合瑞制药股份有限公司 | Alprostadil freeze-dried emulsion composition for injection |
| CN105832744B (en) * | 2016-05-17 | 2018-10-30 | 浙江长典医药有限公司 | A kind of Alprostadil freeze-dried emulsion composition of injection |
| US20220008340A1 (en) * | 2018-11-27 | 2022-01-13 | Avignon Universite | Process for extracting substances of interest |
| JP2022509975A (en) * | 2018-11-27 | 2022-01-25 | シーアン リーバン ジャオシン バイオテクノロジー カンパニー リミテッド | Freeze-dried preparation for prostaglandin E1 methyl ester injection and its manufacture and use |
| JP7169024B2 (en) | 2018-11-27 | 2022-11-10 | シーアン リーバン ジャオシン バイオテクノロジー カンパニー リミテッド | Freeze-dried formulation for prostaglandin E1 methyl ester injection and its manufacture and use |
| US12016957B2 (en) * | 2018-11-27 | 2024-06-25 | Avignon Universite | Process for extracting substances of interest |
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