CN105832744B - A kind of Alprostadil freeze-dried emulsion composition of injection - Google Patents
A kind of Alprostadil freeze-dried emulsion composition of injection Download PDFInfo
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- CN105832744B CN105832744B CN201610326584.0A CN201610326584A CN105832744B CN 105832744 B CN105832744 B CN 105832744B CN 201610326584 A CN201610326584 A CN 201610326584A CN 105832744 B CN105832744 B CN 105832744B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Abstract
The invention belongs to pharmaceutical technology fields, disclose a kind of Alprostadil freeze-dried emulsion composition of injection, including Alprostadil, oil phase, water phase and emulsifier, wherein the oil phase is soybean oil and safflower seed oil with 11:1~6:1 weight ratio composition, further includes the DHA of 1~3 parts by weight.Alprostadil freeze-dried emulsion composition of the present invention reduces non-active ingredient addition, and has uniform particle diameter, and encapsulation rate is high, and stability is good, the few feature of injection adverse reaction.
Description
Technical field
The present invention relates to a kind of Alprostadil freeze-dried emulsion compositions of injection, belong to pharmaceutical technology field.
Background technology
Alprostadil is also known as prostaglandin E1, and its chemical name is (1R, 2R, 3R) -3- hydroxyls -2- [(E)-(3S) -3- hydroxyls
Base -1- octenyls] -5- oxo-cyclopentane enanthic acid is a kind of endogenous physiological substance that activity is extremely strong, in each histocyte of human body
Interior equal energy synthesis.
Alprostadil has multiple pharmacological effect, has significant effect and effect in terms for the treatment of a variety of diseases, because
And there are the research about Alprostadil important medical applications to be worth.
Alprostadil poorly water-soluble, chemical stability is also poor, to water, thermally labile, it is easy to degrade.In stomach and intestine
Dao Neiyi metabolic inactivations should not be administered orally, and the mode of generally use intravenous drip is administered.The Alprostadil freeze-dried powder needle of injection
Agent mostly uses cyclodextrin inclusion technique, and dosage is big, and side effect is apparent, and Alprostadil inactivates very soon in vivo.Forefront
You list in Japan injection at first on ground, use Fat Emulsion drug delivery technologies, by drug, soybean oil, exquisite egg yolk lecithin, oil
Acid, glycerine and pH adjusting agent composition.It has the following advantages：(1) targeting：To the affinity higher of inflammation part vascular wall,
It can be deposited on atherosclerotic blood vessel, hypertensive vascular wall, curative effect is played for diseased region, and to the shadow of normal blood vessels
It rings seldom, substantially reduces rate of side effects, be known as " drug guided missile ".(2) long-term effect：The body of the common powder-injection of Alprostadil
Only 3~5 minutes interior half-life period after being made into lipid microspheres, can maintain 12~24 hours release drugs, and play drug effect.(3) high
Imitate safety：Prostadil fatty breast quantity is only the 1/5~1/10 of traditional powder injection formulation, you can reaches better treatment
Effect；Alprostadil adverse reaction rate is only the 1/10 of traditional powder injection formulation.It can be seen that Alprostadil emulsions relative to
Other form of administration have the advantages that the important directions notable, necessarily Alprostadil is studied.
CN201310506901.3 discloses a kind of Alprostadil composition, including Alprostadil, oil for injection, phosphatide,
Water for injection, a concentration of 6-11 μ g/ml of Alprostadil in prescription, preferably 7-9 μ g/ml, oil for injection it is a concentration of
100mg/ml, phospholipid concentration 18mg/ml.It is not under the premise of increasing emulsifier, by improving preparation process by encapsulation rate
It is increased to 95% or more.
CN201010168597.2 discloses a kind of freeze-dried emulsion using cyclodextrin substance and polysaccharose substance as freeze-drying
Protective agent is made a kind of Alprostadil freeze-dried emulsion for injection of high stability, improves the chemical stability of Alprostadil
And physiological activity, avoid the red and swollen adverse reaction with pain in part in injection process.
CN201110195802.9 discloses a kind of Alprostadil lipid nanosphere freeze-drying injection, it is by following raw materials
It is prepared by ratio of weight and the number of copies：Alprostadil 0.0005~0.1, midchain oil 15~60, emulsifier 3.0~35, polyethylene glycol
Ten dihydroxystearic acid esters 8.5~48, glycerine 22, trehalose 20~200, cyclodextrin 20~300.The ring of above patent addition
Dextrin substance is likely to renal toxicity, and drug safety is worth considering.
CN201310054314.5 discloses a kind of Alprostadil injection, consisting of：Alprostadil 0.001-
0.05mg/mL；Oil phase 0.01-100mg/mL；Phosphatidase 1 0-500mg/mL；Remaining is organic solvent.Although the patent is in certain journey
Stability is improved on degree, but is added to larger amount of absolute ethyl alcohol, absolute ethyl alcohol can generate undesirable stimulation to blood vessel,
It can cause to inject adverse reaction.
CN201310638539.5 discloses a kind of Alprostadil liposome microsphere preparation, consisting of：Alprostadil and/or its
0.001~5g/L of salt, 50~500g/L of oil for injection, 6~36g/L of emulsifier, 0.1~5g/L of assistant for emulsifying agent, osmotic pressure are adjusted
10~30g/L of agent, 0.01~5g/L of metal chelating agent, 0.01~30g/L of antioxidant, wherein pH adjusting agent add to preparation pH value
It is 5.5~6.0.Although the patent increases the stability of emulsion to a certain extent, it is added to metal chelating agent, such as grass
Acid etc. may be decreased the bioavilability of mineral ion.
CN200910058187.X discloses a kind of alprostadil injection emulsion of stabilization, it is characterised in that：Before it is
You are active constituent on row ground, in addition the emulsion liquid preparation that pharmaceutically acceptable auxiliary material is prepared, per in 1000mL lotions
5mg containing Alprostadil~500mg, oil for injection are 50g~100g, emulsifier is 4g~36g, glycerol for injection be 20g~
25g, remaining is water for injection；Wherein, 3g containing PLURONICS F87~30g and injection lecithin 1g in the emulsifier~
The weight ratio of 6g, wherein PLURONICS F87 and injection lecithin is in the range of 3~10.What the method in the patent was added
Emulsifier and assistant for emulsifying agent are more.
For presently disclosed Alprostadil emulsions in preparation, used oil phase is all kinds of vegetable oil that people can obtain
Or animal oil, the combination of single oil product or several oil products may be used.When preparing Alprostadil emulsions in order to promote oil phase and
Water phase can form relatively stable phase system, be usually required for adding more emulsifier, help emulsion；In order to improving forefront
The chemical stability of your emulsion, and need additional addition preservative, stabilizer, antioxidant etc., the non-active ingredient of introducing is got over
More, uncertain factor when medication is more, does not meet the security requirement of pharmaceutical production more.Meanwhile in order to improve Alprostadil
The encapsulation rate of emulsion reduces harm of the degradation material to human body, needs high-frequency shearing and high pressure mostly in preparation process
It is homogeneous, the energy consumption in preparing is increased, pharmacy cost is increased, is unfavorable for drug and is promoted the use of to ordinary populace.In particular, at present
Alprostadil emulsions usually will appear more bad hair in use and answer, clinical compliance is poor.
Invention content
In order to overcome above-described defect, present inventor has performed a large amount of research work.It is an object of the invention to
A kind of Alprostadil freeze-dried emulsion composition is provided, reduces the introducing of non-active ingredient substance, and encapsulation rate is high, stability
Good, injection almost has no adverse reaction.
The present invention obtains the Alprostadil freeze-dried emulsion composition by the following technical programs：
A kind of Alprostadil freeze-dried emulsion composition of injection, including Alprostadil, oil phase, water phase and emulsifier,
Wherein, the oil phase is soybean oil and safflower seed oil with 11:1~6:1 weight ratio composition, further includes 1~3 parts by weight
DHA。
DHA, docosahexaenoic acid are commonly called as docosapentaenoic acid, are a kind of to the very important unsaturated fatty acid of human body, have
Anti-inflammatory reduces fat, prevents the effects that cardiovascular disease.
Oil phase is using soybean oil of the present invention and safflower seed oil according to 11:1~6:1 weight ratio mixes, system
Standby Alprostadil freeze-dried emulsion composition has good milk particle stability, even if placing formation in one week in room temperature or 50 DEG C
Particle more than 1 μm is still less, is more in line with the quality requirement of injection medicament.
Further, the Alprostadil freeze-dried emulsion composition of a kind of injection, wherein by weight,
Alprostadil is 0.45~5 parts by weight, and emulsifier is 0.1~5 parts by weight, and oil phase is 8~15 parts by weight.
Further, the water phase is that glycerine and water for injection form.
Further, the glycerine is calculated as 0.15~2 parts by weight by weight.
Further, the emulsifier is soybean lecithin or egg yolk lecithin.
The HCl that the pH adjusting agent adjusted used in Alprostadil freeze-dried emulsion composition pH is 0.2~0.5mol/L,
It is more convenient, accurate that pH is adjusted using it.
Preferably, pH is adjusted with the HCl of 0.3mol/L.
Further, the Alprostadil freeze-dried emulsion composition pH to 5.0~6.5 of the injection is adjusted.
Another free-revving engine of the present invention is to provide a kind of side preparing the Alprostadil freeze-dried emulsion composition
Method is specifically implemented as follows：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. above-mentioned oil phase is mixed with water conjunction, stirs, adds the emulsifier of formula ratio, stirred, obtain colostrum；
D. obtained colostrum is adjusted into pH to 5.0~6.5, it is high-pressure homogenising, obtain smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Preferably, the step c is carried out in accordance with the following methods：
C. the oil phase and water phase 55~80 DEG C are warming up to mix, with 300~500rpm stirring 10~
25min adds the emulsifier of formula ratio, then with 1000~3000rpm, stirs 20~30min.
Preferably, the step d uses following method：
D. obtained colostrum is adjusted into pH to 5.0~6.5, the pressure of high pressure homogenization, homogenizer is 6000~18000psi
It repeats high-pressure homogeneous 4~6 times, obtains smart breast.
The present invention obtains under the premise of reducing the auxiliary additives such as introducing emulsifier, assistant for emulsifying agent, antioxidant, stabilizer
It is good to obtain a kind of stability, encapsulation rate is high, the few Alprostadil freeze-dried emulsion composition of injection pessimal stimulation.In addition ensureing emulsion
While quality, the preparation process of use is brief, saves energy consumption, belongs to a kind of environmentally friendly technique.
Specific implementation mode
With reference to some preferred specific embodiments, come the content further illustrated the present invention, in order to more preferable geographical
It is not limitation of the present invention to solve the intent of the present invention and advantageous effect, the specific embodiment.
Embodiment 1,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. above-mentioned oil phase is mixed with water conjunction, stirs, adds the soybean lecithin of formula ratio, stirred, obtain colostrum,
Colostrum injects water to 1000ml；
D. it is 5.0 obtained colostrum to be adjusted pH, high-pressure homogenising, obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 2,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 55 DEG C to mix, 25min is stirred with 300rpm, adds formula ratio
Egg yolk lecithin, then with 3000rpm, stir 30min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 5.2 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 18000psi, and it is equal to repeat high pressure
Matter 5 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 3,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 60 DEG C to mix, 20min is stirred with 400rpm, adds formula ratio
Soybean lecithin, then with 2500rpm, stir 25min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 5.5 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 16000psi, and it is equal to repeat high pressure
Matter 4 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 4,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 65 DEG C to mix, 25min is stirred with 450rpm, adds formula ratio
Soybean lecithin, then with 2800rpm, stir 20min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.0 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 14000psi, and it is equal to repeat high pressure
Matter 6 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 5,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 80 DEG C to mix, 15min is stirred with 450rpm, adds formula ratio
Soybean lecithin, then with 2000rpm, stir 20min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.5 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 10000psi, and it is equal to repeat high pressure
Matter 5 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 6,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 70 DEG C to mix, 15min is stirred with 480rpm, adds formula ratio
Soybean lecithin, then with 2000rpm, stir 20min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.2 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 8000psi, is repeated high-pressure homogeneous
6 times, obtain smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 7,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 75 DEG C to mix, 10min is stirred with 500rpm, adds formula ratio
Egg yolk lecithin, then with 2400rpm, stir 20min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.4 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 13000psi, and it is equal to repeat high pressure
Matter 5 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 8,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 80 DEG C to mix, 10min is stirred with 350rpm, adds formula ratio
Egg yolk lecithin, then with 2800rpm, stir 22min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.5 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 16000psi, and it is equal to repeat high pressure
Matter 4 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 9,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 68 DEG C to mix, 10min is stirred with 480rpm, adds formula ratio
Egg yolk lecithin, then with 1500rpm, stir 14min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 5.6 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 9000psi, is repeated high-pressure homogeneous
4 times, obtain smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 10,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 80 DEG C to mix, 10min is stirred with 350rpm, adds formula ratio
Soybean lecithin, then with 2800rpm, stir 22min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 5.3 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 16000psi, and it is equal to repeat high pressure
Matter 4 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 11,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 69 DEG C to mix, 18min is stirred with 450rpm, adds formula ratio
Soybean lecithin, then with 2800rpm, stir 22min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 5.8 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 16000psi, and it is equal to repeat high pressure
Matter 4 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Embodiment 12,
A kind of Alprostadil freeze-dried emulsion composition of injection, composition is as what follows：
The step of preparation is：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, is added
The Alprostadil and DHA of formula ratio, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in appropriate water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. the oil phase and water phase are warming up to 75 DEG C to mix, 15min is stirred with 440rpm, adds formula ratio
Egg yolk lecithin, then with 2600rpm, stir 25min, obtain colostrum, colostrum injects water to 1000ml；
D. it is 6.0 obtained colostrum to be adjusted pH, high pressure homogenization, and the pressure of homogenizer is 14000psi, and it is equal to repeat high pressure
Matter 4 times obtains smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
Test example 1,
The experiment focuses on investigating the milk particle property of Alprostadil freeze-dried emulsion composition.
Specific method is：Each Alprostadil freeze-dried emulsion composition 0.1mL made above is taken respectively, adds purified water (pre-
It is 0.22 μm of membrane filtration first to use aperture) 5000 times are diluted, mixing is placed one week at room temperature respectively, or at a temperature of 50 DEG C
It places one week, it is to be measured；Then, with Malvern laser particle analyzer (Zetasizer 3000HS, Malvem, UK) measure 25 DEG C when
The grain size of above-mentioned prepare liquid and distribution；
The content of the test that the test example carries out is as follows：
1, the milk particle property of Alprostadil freeze-dried composition emulsion prepared by the present invention
Method as described above, Alprostadil freeze-dried emulsion composition prepared by each embodiment of the present invention
Milk particle variation investigated, specific result is referring to table 1.
Table 1
| Detection project | 0 day | Room temperature one week | 50 DEG C one week |
| 1 | a | a | b |
| 2 | a | a | b |
| 3 | a | b | a |
| 4 | a | b | b |
| 5 | a | a | b |
| 6 | a | b | a |
| 7 | a | a | b |
| 8 | a | a | a |
| 9 | a | a | a |
| 10 | a | b | b |
| 11 | a | b | b |
| 12 | a | b | a |
The Alprostadil freeze-dried emulsion composition of the invention prepared is can be seen that at room temperature or 50 DEG C from the result of investigation
It places one week, the change of size of milk particle is smaller, and 1 μm or more of milk particle forms less.This illustrates Alprostadil prepared by the present invention
The milk particle property of freeze-dried emulsion composition is stablized, can to avoid in injection because milk particle size variation acutely causes human body bad anti-
It answers, improves the drug safety in injection process.
2, investigating the selection of oil phase influences the milk particle property of Alprostadil freeze-dried emulsion composition
(1) oil phase is only changed to soybean oil and olive oil, according to each embodiment method of the present invention, other factors are not
Become, correspondence prepares a series of Alprostadil freeze-dried emulsion compositions, investigates the milk particle property of each Alprostadil emulsions of preparation, has
Body the results are shown in Table 2.
Table 2
(2) oil phase is only changed to soybean oil and cottonseed oil, according to each embodiment method of the present invention, other factors are not
Become, correspondence prepares a series of Alprostadil freeze-dried emulsion compositions, investigates the milk particle property of each Alprostadil emulsions of preparation, has
Body the results are shown in Table 3.
Table 3
The result recorded from table 2 and table 3 can be seen that the Alprostadil prepared the when of selecting other oil phases to mix as oil phase
Freeze-dried emulsion composition is placed one week at room temperature or 50 DEG C, and the change of size of milk particle is larger, 1 μm or more of milk particle formed compared with
More, emulsion property is unstable.
The present invention is implemented to the oil phase that other oil products are mixed to get may be used to have made comparison, obtained Alprostadil
The milk particle property of freeze-dried emulsion composition is unstable, inconvenient all to list in view of the requirement of length.Pass through above-described examination
Testing result can obtain, only use scheme of the present invention, can just obtain the Alprostadil freeze-dried of uniform particle diameter stabilization
Emulsion composition.
Test example 2
The test example essentially consists in the milk particle property for investigating different oil phase ratios to Alprostadil freeze-dried emulsion composition
Influence.
It is 0 according to soybean oil and safflower seed oil weight ratio:1,1:1,2:1,3:1,4:1,5:1,12:1,13:1,14:1,
15:1 or 1:0, using method of the present invention, prepare Alprostadil freeze-dried emulsion composition.
Milk particle property detailed examination method is specifically shown in Table 4 referring to the method described in test example 1, each milk particle property result.
Table 4
Contrast table 1 and the test result of table 4 can be seen that soybean oil and safflower seed oil with 11:1~6:When 1 weight ratio
The milk particle variation of Alprostadil freeze-dried emulsion composition obtained is smaller, and property is more stablized, and injecting purposes are more suitable for.
The result of compbined test example 1 and test example 2 is it can be found that using the Alprostadil freeze-dried emulsion prepared by this programme
The milk particle stability of composition is more excellent, is more in line with the quality requirement safety of the drug in pharmacopeia 2010 editions for injection
Performance is more preferable, has significant superiority.
Test example 3, adverse reaction test
Commercially available Alprostadil freeze-dried emulsion used in the test example is：Excellent Supreme Being's that injection Alprostadil dried emulsifier (10 μ
G/ branch), Chongqing Yaoyou Pharmaceutical Co., Ltd.'s production.
The method that this experiment is compared using single factors control.
Test method：Cavy 18 is taken, three groups, the i.e. dry breast of group of the embodiment of the present invention, commercially available Alprostadil are randomly divided into
Agent injection group and the normal negative control group of health, every group 6.Forefront prepared by the next day that every cavy the is distinguished intraperitoneal injection present invention
Ground your freeze-dried emulsion composition, the injection of market sale and 0.9% sodium chloride injection 1ml, it is co-continuous three times, observe and record
Test the reaction symptom of cavy；Then, then by every group it is divided into two groups, per group three, one group after injecting tested material for the first time
The 14th day, another group of the 21st day after injecting for the first time is injected intravenously corresponding test solution 2ml per mouse, then observe and record dynamic respectively
Reaction symptom after object injection.
Test result：To in the hypersensitive test of cavy, after preceding intraperitoneal injection Alprostadil emulsions continuous three times, cavy is equal
Do not occur any abnormal response；After being administered with challenge dose, the injection Alprostadil freeze-dried emulsion composition of the invention prepared
Group, cavy have no apparent allergic reaction, and injecting commercially available Alprostadil emulsions has 2 adverse reaction symptom occur.
This test example is tested all embodiments of the present invention, does not find adverse reaction phenomenon, illustrates this
Alprostadil freeze-dried emulsion composition prepared by invention has good clinical compliance, it is possible to reduce or patient is avoided to use
Pain in the process.
Test example 4, emulsion stability test
By the Alprostadil freeze-dried emulsion composition prepared in the embodiment of the present invention and commercially available Alprostadil freeze-dried emulsion
(excellent Supreme Being's that injection Alprostadil dried emulsifier (10 μ g/ branch), Chongqing Yaoyou Pharmaceutical Co., Ltd.'s production) is placed on 0~10
DEG C environment, at times detect each sample encapsulation rate and Alprostadil degradation rate.
Used detection method is method commonly used in the art, and testing result is as shown in table 5.
Table 5
Obtained according to above-mentioned experiment, the present invention prepared by Alprostadil emulsions have high encapsulation rate, low decomposition ratio it is excellent
Benign matter, at 0~10 DEG C, storage has preferable stability, and encapsulation rate and degradation rate in 24 months are relative to before commercially available
Row ground that product, there is apparent advantage, stability to significantly improve.Alprostadil freeze-dried emulsion composition pair prepared by the present invention
Transport and preservation condition requirement be not harsh, transport storage cost is greatly reduced, to further decrease product price, convenient for pushing away
Extensively to ordinary populace, with the favorable to the people positive effect of Huimin.
Claims (10)
1. a kind of Alprostadil freeze-dried emulsion composition of injection, including Alprostadil, oil phase, water phase and emulsifier,
It is characterized in that, the oil phase is soybean oil and safflower seed oil with 11:1~6:1 weight ratio composition, further includes 1~3 parts by weight
DHA；
The pH value of the Alprostadil emulsions is 5.0~6.0.
2. a kind of Alprostadil freeze-dried emulsion composition of injection according to claim 1, which is characterized in that by weight
Part meter is measured, the Alprostadil is 0.45~5 parts by weight, and the emulsifier is 0.1~5 parts by weight, and the oil phase is 8
~15 parts by weight.
3. the Alprostadil freeze-dried emulsion composition of injection according to claim 1, which is characterized in that the water
Mutually it is made of glycerine and water for injection.
4. the Alprostadil freeze-dried emulsion composition of injection according to claim 3, which is characterized in that described is sweet
Oil is calculated as 0.15~2 parts by weight by weight.
5. the Alprostadil freeze-dried emulsion composition of the injection according to Claims 1 to 4 any one, feature exist
In the emulsifier is soybean lecithin or egg yolk lecithin.
6. the Alprostadil freeze-dried emulsion composition of injection according to claim 1, which is characterized in that adjust forefront
The HCl that pH adjusting agent used in the pH value of your emulsion of ground is 0.2~0.5mol/L.
7. the Alprostadil freeze-dried emulsion composition of injection according to claim 6, which is characterized in that adjust forefront
The HCl that pH adjusting agent used in the pH value of your emulsion of ground is 0.3mol/L.
8. a kind of preparation method of the Alprostadil freeze-dried emulsion composition of claim 1~7 any one of them injection,
It is characterized in that, implementing as follows：
A. the miscella that soybean oil and safflower seed oil are prepared according to the quality and ratio, is uniformly mixed, formula is added
The Alprostadil and DHA of amount, stirring make it fully dissolve, obtain oil phase；
B. the glycerol for injection of formula ratio is dissolved in water for injection, stirring makes it be sufficiently mixed, and obtains water phase；
C. above-mentioned oil phase is mixed with water conjunction, stirs, the emulsifier of formula ratio is added, high speed shear obtains colostrum；
D. obtained colostrum is adjusted into pH to 5.0~6.0, it is high-pressure homogenising, obtain smart breast；
E. the essence breast of gained is sterile filtered, it is filling, it is lyophilized to obtain the final product.
9. preparation method according to claim 8, which is characterized in that the step c is carried out in accordance with the following methods：By institute
The oil phase and water phase stated are warming up to 55~80 DEG C and are mixed, and stir 10~25min with 300~500rpm, add formula ratio
Emulsifier, then with 1000~3000rpm, stir 20~30min.
10. preparation method according to claim 8 or claim 9, which is characterized in that the step d uses following method：Will
The colostrum that arrives adjusts pH to 5.0~6.0, high pressure homogenization, the pressure of homogenizer be 6000~18000psi repeat high-pressure homogeneous 4~
6 times, obtain smart breast.
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Denomination of invention: Alprostadil lyophilized emulsion composition for injection Effective date of registration: 20210719 Granted publication date: 20181030 Pledgee: Changhe Branch of Hangzhou United Rural Commercial Bank Co.,Ltd. Pledgor: ZHEJIANG CHANGDIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000940 |
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