WO2015165373A1 - 一种注射用前列地尔脂肪乳及其制备方法 - Google Patents

一种注射用前列地尔脂肪乳及其制备方法 Download PDF

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WO2015165373A1
WO2015165373A1 PCT/CN2015/077642 CN2015077642W WO2015165373A1 WO 2015165373 A1 WO2015165373 A1 WO 2015165373A1 CN 2015077642 W CN2015077642 W CN 2015077642W WO 2015165373 A1 WO2015165373 A1 WO 2015165373A1
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weight
oil
alprostadil
injection
phosphatidylglycerol
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PCT/CN2015/077642
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English (en)
French (fr)
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林金平
宋华先
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北京蓝丹医药科技有限公司
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Publication of WO2015165373A1 publication Critical patent/WO2015165373A1/zh

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a prostaglandin fat emulsion for injection and a preparation method thereof.
  • Alprostadil injection was first marketed in Japan, using fat-loaded drug technology, consisting of drugs, soybean oil, refined egg yolk lecithin, oleic acid, glycerin and pH adjuster.
  • the preparation method is to dissolve the drug in fatty oil.
  • refined lecithin is used as emulsifier
  • oleic acid is used as auxiliary emulsifier
  • O/W type drug-loaded fat emulsion is prepared by high pressure homogenization, and the average particle diameter of the milk particles is 200 nm.
  • Prostaglandin injection is a drug-loaded method of fat emulsion, which encapsulates the drug in the oil phase, greatly reducing the occurrence of irritation.
  • Targeting It has higher affinity to the blood vessel wall of the inflammation site, can deposit on the atherosclerotic blood vessel and the blood vessel wall of hypertension, and exerts curative effect on the lesion, but has a great influence on normal blood vessels. Less, greatly reducing the incidence of side effects, known as "drug missiles.”
  • Long-acting The in vivo half-life of alprostadil is only 3 to 5 minutes. After it is made into lipid microspheres, it can be sustained for 12 to 24 hours to release the drug.
  • Efficient safety the clinical dosage of alprostadil fat emulsion is only 1/5 to 1/10 of the traditional powder injection preparation, which can achieve better therapeutic effect; the incidence of alprostadil adverse reaction is only traditional powder needle 1/10 of the preparation.
  • alprostadil injection is in the form of an emulsion, some of the drugs will be degraded by water, resulting in the following quality problems: (1) The content of the degradation product PAL 1 of alprostadil injection is as high as 60% (national drug standard) WS1-(X-041)-2002Z-2008); (2) The validity period is short, only 12 months (0-5 °C).
  • CN1562041A discloses a alprostadil freeze-dried emulsion containing alprostadil, an injectable oil, an emulsifier, a stabilizer, a glycerin, a preservative, and a preparation method thereof, wherein the pH ranges from 4 to 9.
  • the emulsifier used in addition to phospholipids, poloxamers and HS15 Tweens which are nonionic surfactants can be used.
  • CN1903206A discloses a alprostadil freeze-dried emulsion and a preparation method thereof, wherein the weight percentage of the medicinal excipient is 0.01-1% (g/mL) of the injection oil per 1000 ml of the emulsion.
  • Emulsifier 0.01 ⁇ 5% (g / mL), stabilizer 1 ⁇ 6% (g / mL), lyoprotectant 1% ⁇ 20% (g / mL); pH range 4 ⁇ 9 (pH range in the examples) 4.21 ⁇ 5.43).
  • CN101843594A discloses a linquid lyophilized emulsion for injection and a preparation method thereof, wherein in order to solve the problem of protection of alprostadil in the invention, a cyclodextrin substance and a saccharide substance are used together as a lyoprotectant.
  • the stability of the drug is increased by the principle that the cyclodextrin encapsulates the drug to increase stability.
  • cyclodextrin itself has certain nephrotoxicity and hemolysis for intravenous injection, and cyclodextrin increases the water solubility after wrapping the drug, and the drug will be distributed in a larger proportion in the aqueous phase than in the oil phase. There are hidden dangers in the safety of the preparation.
  • the object of the present invention is to overcome the defects that the pharmaceutical excipients used in the prior alprostadil freeze-dried emulsions have low safety when ensuring stability, and provide a safety and stability combination of prostaglandin for injection. Fatty milk and its preparation method.
  • the present invention provides an alprostadil emulsion for injection, which comprises alprostadil, Phosphatidylcholine, phosphatidylglycerol, an injectable oil, and a lyoprotectant, wherein the phosphatidylcholine is contained in an amount of 1200 to 4000 parts by weight based on 1 part by weight of alprostadil, and the phosphatidylglycerol The content is 12-120 parts by weight, the injection oil is 2,000-20,000 parts by weight, and the lyoprotectant is 16,000-60,000 parts by weight.
  • the present invention also provides a method for preparing the above-described alprostadil emulsion for injection, the method comprising:
  • the colostrum is homogenized to form a fine emulsion, and is sterilized and freeze-dried.
  • the alprostadil fat emulsion for injection provided by the present invention has good stability and improves the medicinal safety of the defrostil emulsion for injection; and at the same time, the synergy of each component in the lyophilized emulsion of the present invention The effect effectively controls the particle size and particle size distribution of the fat emulsion before and after lyophilization.
  • the present invention provides a prostaglandin fat emulsion for injection, which comprises alprostadil, phosphatidylcholine, phosphatidylglycerol, an injection oil and a lyoprotectant, wherein, relative to 1 part by weight of the former Diltiaze, the content of the phosphatidylcholine is 1200-4000 parts by weight, the content of the phosphatidylglycerol is 12-120 parts by weight, and the content of the injection oil is 2000-20000 parts by weight, the frozen
  • the content of the dry protective agent is from 16,000 to 60,000 parts by weight.
  • the prostaglandin fat emulsion for injection is a conventional meaning in the art, that is, a fat emulsion formed by lyophilizing an emulsion containing alprostadil, which can be redispersed in water to form an injectable emulsion.
  • alprostadil fat emulsion for injection contains the alprostadil, phosphatidylcholine, phosphatidylglycerol, injectable oil and lyoprotectant in the above content range, good safety and stability can be obtained.
  • the content of the phosphatidylcholine is 2400-3000 parts by weight
  • the content of the phosphatidylglycerol is 24-48 parts by weight
  • the content of the injection oil is 4000-12000 parts by weight
  • the content of the lyoprotectant It is 20,000-30,000 parts by weight.
  • the phosphatidylcholine is contained in an amount of 2400 to 3000 parts by weight, and the phosphatidylglycerol is contained in an amount of 30 to 120 parts by weight, based on 1 part by weight of alprostadil.
  • the injection oil is contained in an amount of 10,000 to 12,000 parts by weight, and the lyoprotectant is contained in an amount of 20,000 to 30,000 parts by weight.
  • the phosphatidylcholine can be combined with other components in the fat emulsion, particularly phosphatidylglycerol, to stabilize alprostadil and reduce the degree of degradation of alprostadil in water, thereby reducing the resulting fat emulsion.
  • the degradation by-product of alprostadil in the middle, while phosphatidylcholine is an injectable substance, and therefore has high medicinal safety.
  • the phosphatidylcholine may be phosphatidylcholine (egg phosphatidylcholine) extracted from egg yolk, synthetic phosphatidylcholine or any combination thereof.
  • the phosphatidylcholine extracted from the egg yolk is generally 96% by weight or more, and such phosphatidylcholine is also safely usable.
  • the synthetic phosphatidylcholine is preferably distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristam Acylphosphatidylcholine (DMPC), didecanoylphosphatidylcholine (DDPC), dilauroylphosphatidylcholine (DLPC), di-erucylphosphatidylcholine (DEPC), 1-stearoyl-2- Oleoylphosphatidylcholine (SOPC), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), 1-myristoyl-2-oleoylphosphatidylcholine (MOPC), 1-stearoyl -2-palmitoylphosphatidylcholine (SPPC), 1-stearoyl-2-myristoyl phosphatidylcholine (SMPC), 1-palmit
  • the phosphatidylcholine is egg yolk phosphatidylcholine, distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or any combination thereof.
  • DSPC distearoylphosphatidylcholine
  • DMPC dimyristoylphosphatidylcholine
  • the phosphatidylglycerol can stabilize alprostadil together with other components in the fat emulsion, and reduce the degree of degradation of alprostadil in water, thereby reducing the forefront of the obtained fat emulsion. It is a by-product of degradation, and phosphatidylglycerol is an injectable substance, so it has high medicinal safety.
  • the phosphatidylglycerol may be egg yolk phosphatidylglycerol (EPG) extracted from egg yolk and a salt thereof, synthetic phosphatidylglycerol and salts thereof, or any combination thereof.
  • the "salt" herein may be egg phosphatidylglycerol or a sodium salt or a potassium salt of synthetic phosphatidylglycerol.
  • the synthetic phosphatidylglycerol is preferably distearoylphosphatidylglycerol (DSPG) and a salt thereof, dioleoylphosphatidylglycerol (DOPG) and a salt thereof, dipalmitoylphosphatidylglycerol (DPPG) and salts thereof , dimyristoyl phosphatidylglycerol (DMPG) and its salt, 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) and its salt, di-erucylphosphatidylglycerol (DEPG) and its salt, dilauroyl Phosphatidylglycerol (DLPG) and salts thereof or any combination thereof.
  • DSPG distearoylphosphatidylglycerol
  • DOPG dioleoylphosphatidylglycerol
  • DPPG dipalmitoylphosphatidylglycerol
  • the phosphatidylglycerol is egg yolk phosphatidylglycerol and its sodium salt, distearoyl phosphatidylglycerol and sodium salt thereof, dimyristoyl phosphatidylglycerol and sodium salts thereof, or any combination thereof.
  • the injectable oil may be an injection oil conventional in the art, as long as it can improve the safety and stability of the fat emulsion together with other components of the fat emulsion of the present invention.
  • the injection oil is soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil, fish oil, medium chain monoglyceride, medium chain diglyceride, medium chain triglyceride, oil Ethyl acetate, acetylated monoglyceride, propylene glycol diester, glyceryl linoleate, polyethylene glycol laurate or any combination thereof, preferably olive oil and/or medium chain triglyceride.
  • the above-exemplified injection oils are more preferably a refined oil.
  • the oil for injection is a combination of olive oil and medium chain triglyceride, wherein the weight ratio of olive oil to medium chain triglyceride is 1:0.5-2, preferably It is 1:1.
  • the lyoprotectant may be a lyoprotectant conventionally used in the art as long as the medicinal requirements for the safety and stability of the fat emulsion of the present invention can be attained, preferably, the lyophilization protection
  • the agent is lactose, sucrose, trehalose, dextran or any combination thereof.
  • the alprostadil fat emulsion for injection has an average particle diameter of 150-230 nm and a particle size distribution of less than 0.2.
  • the average particle diameter of the emulsion for the emulsion before lyophilization is preferably from 150 to 230 nm, and the particle size distribution is less than 0.2.
  • the fat emulsion contains alprostadil, phosphatidylcholine, phosphatidylglycerol, an injectable oil, and a lyoprotectant, and further, it may contain some conventional excipients as long as the fat emulsion is not damaged. It is sufficient for safety and stability, such as glycerin, a pH adjuster (such as sodium hydroxide, hydrochloric acid), and the like.
  • the total weight of alprostadil, the phosphatidylcholine, the phosphatidylglycerol, the injectable oil, and the lyoprotectant as its main component may be It accounts for 80% by weight or more of the lyophilized fat emulsion, more preferably 80 to 100% by weight, still more preferably 90 to 100% by weight, still more preferably 95 to 100% by weight, particularly preferably 100% by weight. It should be understood by those skilled in the art that when the fat emulsion further contains other minor components, these minor components do not affect the effects of the main components of the present invention, and do not employ the safety of destroying the fat emulsion of the present invention. And stable material composition.
  • the content of 100% by weight means that the fat emulsion is composed of alprostadil, phosphatidylcholine, phosphatidylglycerol, an injection oil, and a lyoprotectant.
  • the fat emulsion composed of the acylglycerol, the oil for injection, and the lyoprotectant, the phosphatidylcholine is 1200-4000 parts by weight based on 1 part by weight of alprostadil
  • the phosphatidylglycerol content is
  • the oil for injection is contained in an amount of from 2,000 to 20,000 parts by weight
  • the lyophilized protective agent is contained in an amount of from 16,000 to 60,000 parts by weight.
  • the content of the phosphatidylcholine is 2400-3000 parts by weight
  • the content of the phosphatidylglycerol is 24-48 parts by weight
  • the content of the injectable oil is 1 part by weight of alprostadil.
  • the lyoprotectant is contained in an amount of 20,000 to 30,000 parts by weight.
  • the proalilide fat emulsion for injection contains alprostadil, phosphatidylcholine, phosphatidylglycerol, injectable oil, lyoprotectant, and glycerin, wherein 1 part by weight of alprostadil, the content of the phosphatidylcholine is 1200-4000 parts by weight, the content of the phosphatidylglycerol is 12-120 parts by weight, and the content of the injection oil is 2000-20000 parts by weight.
  • the lyoprotectant is contained in an amount of 16,000 to 60,000 parts by weight, and the glycerin is contained in an amount of 500 to 1,500 parts by weight.
  • the content of the phosphatidylglycerol is more than 60 parts by weight, so that the particle size and distribution of the obtained fat emulsion can be better controlled in the presence of glycerin.
  • the alprostadil fat emulsion for injection does not contain glycerin, which is more advantageous for controlling the particle size of the obtained fat milk and reducing the particle size distribution.
  • the present invention provides a method for preparing the above-described alprostadil emulsion for injection, the method comprising:
  • the colostrum is homogenized to form a fine emulsion, and is sterilized and freeze-dried.
  • preferred contents and types of the phosphatidylcholine, the phosphatidylglycerol, the injectable oil, and the lyoprotectant are as defined above, and are not described herein again.
  • steps (1) and (2) may be adjusted, and may be carried out simultaneously or in stages, as long as the oil phase and the water phase can be obtained.
  • dissolution is preferably carried out at 50 to 70 °C.
  • mixing is preferably carried out at 50 to 70 °C.
  • the shear dispersion described in the step (3) can be reasonably adjusted according to the desired milk particle size.
  • the shear dispersion conditions include: a dispersion time of 10 to 60 minutes, and shearing. The speed is 3000-10000 rpm and the temperature is 50-70 °C. More preferably, the conditions of the shear dispersion include a dispersion time of 10 to 60 minutes, a shear rate of 3,000 to 10,000 rpm, and a temperature of 55 to 70 °C.
  • the conditions for shear dispersion include a dispersion time of 10-30 minutes, a shear rate of 3000-10000 rpm, and a temperature of 55-70 °C.
  • the conditions of the shear dispersion include a dispersion time of 10 to 30 minutes, a shear rate of 8,000 to 10,000 rpm, and a temperature of 55 to 70 °C.
  • the high-pressure homogenization described in the step (4) can also be reasonably adjusted according to the desired milk particle size.
  • the high-pressure homogenization conditions include: the pressure is 600-2000 bar, and the number of times of homogenization It is 3-6 times and the temperature is 15-30 °C. More preferably, the conditions for the high pressure homogenization include a pressure of 800 to 1200 bar, a number of times of homogenization of 3-5 times, and a temperature of 15 to 30 °C.
  • the temperature here refers to the temperature of the effluent controlled after high pressure homogenization.
  • the high pressure homogenization can be accomplished using a microfluidizer as is conventional in the art.
  • the sterilization in the step (4) can be carried out by a conventional emulsion sterilization method in the art, for example, filtration using a membrane filter for sterilization, for example, using a 0.45-0.8 ⁇ m filter for initial filtration, and then adopting Filter through a 0.2-0.3 ⁇ m microporous membrane.
  • a conventional emulsion sterilization method in the art for example, filtration using a membrane filter for sterilization, for example, using a 0.45-0.8 ⁇ m filter for initial filtration, and then adopting Filter through a 0.2-0.3 ⁇ m microporous membrane.
  • the freeze-drying described in the step (4) may be a method of freeze-drying the emulsion conventionally used in the art, for example, the method of freeze-drying may include: rapidly freezing the sample to a temperature of -50 to -45 ° C, maintaining 1-3 Hour; further drying is carried out at a temperature of -35 to -30 ° C for a period of 24-48 hours; then a second drying is carried out at a temperature of 25-40 ° C for a period of 2-6 hours.
  • the method may further comprise adjusting the pH of the colostrum with a pH adjusting agent prior to the high pressure homogenization of step (4), for example adjusting the pH to 5-8, such a pH adjusting agent as before As defined in the text.
  • the alprostadil fat emulsion for injection provided by the invention is effective through the mutual cooperation between the components containing a specific content of alprostadil, phosphatidylcholine, phosphatidylglycerol, injectable oil and lyoprotectant.
  • the pharmaceutical active ingredient alprostadil is stabilized, and the medicinal safety of the fat emulsion is ensured.
  • the fat emulsion of the present invention can better control the particle size and particle size distribution of the obtained fat milk by the mutual blending of the respective components of the above specific content, and can obtain the better quality of the predileil for injection. Fatty milk products.
  • This example is intended to illustrate the prostaglandin fat emulsion for injection of the present invention and a method for preparing the same.
  • the colostrum obtained in the step (3) is adjusted to pH 6.9 with sodium hydroxide, and homogenized three times by a microfluidizer (M-110P model microfluidizer of the United States), the pressure is 1000 to 1200 bar, and the flow is performed.
  • the temperature of the liquid is 20 ° C to obtain a fine emulsion; the obtained fine milk is filtered through a 0.45 ⁇ m filter, and then filtered through a 0.22 ⁇ m microporous filter;
  • the filtrate obtained in the step (4) is freeze-dried, first rapidly frozen to -45 ° C, and then heated to -35 ° C for 3 hours; once again dried: temperature -30 ° C, time 24 hours; and then secondary drying: At a temperature of 30 ° C for 6 hours, the prostaglandin fat emulsion A1 was injected.
  • This example is intended to illustrate the prostaglandin fat emulsion for injection of the present invention and a method for preparing the same.
  • the colostrum obtained in the step (3) is adjusted to pH 7.1 with sodium hydroxide, and homogenized three times by a microfluidizer (M-110P model microfluidizer of the United States), the pressure is 1000 to 1200 bar, and the flow is performed.
  • the temperature of the liquid is 30 ° C to obtain a fine emulsion; the obtained fine milk is initially filtered through a 0.45 ⁇ m filter membrane, and then filtered and sterilized by a 0.22 ⁇ m microporous membrane;
  • the filtrate obtained in the step (4) is freeze-dried, first rapidly frozen to -45 ° C, and then heated to -35 ° C for 3 hours; once again dried: temperature -30 ° C, time 24 hours; and then secondary drying: The temperature was 30 ° C for 6 hours, and the alprostadil A2 was injected for injection.
  • This example is intended to illustrate the prostaglandin fat emulsion for injection of the present invention and a method for preparing the same.
  • the colostrum obtained in the step (3) is adjusted to pH 7.2 with sodium hydroxide, and homogenized three times by a microfluidizer (M-110P model microfluidizer of the United States MFIC) at a pressure of 1000 to 1200 bar.
  • the temperature of the liquid is 25 ° C to obtain a fine emulsion; the obtained fine milk is initially filtered through a 0.45 ⁇ m filter membrane, and then sterilized by filtration through a 0.22 ⁇ m microporous membrane;
  • the filtrate obtained in the step (4) is freeze-dried, first rapidly frozen to -45 ° C, and then heated to -35 ° C for 3 hours; once again dried: temperature -30 ° C, time 24 hours; and then secondary drying: The temperature was 30 ° C for 6 hours, and the alprostadil A3 was injected for injection.
  • This example is intended to illustrate the prostaglandin fat emulsion for injection of the present invention and a method for preparing the same.
  • the colostrum obtained in the step (3) is homogenized three times by a microfluidizer (M-110P model microfluidizer of the United States), the pressure is 800 to 1000 bar, and the temperature of the effluent is 25 ° C.
  • the refined milk was firstly filtered through a 0.45 ⁇ m filter and then sterilized by filtration through a 0.22 ⁇ m microporous membrane;
  • the filtrate obtained in the step (4) is freeze-dried, first rapidly frozen to -45 ° C, and then heated to -35 ° C for 3 hours; once again dried: temperature -30 ° C, time 24 hours; and then secondary drying: The temperature was 30 ° C for 6 hours, and the alprostadil A4 was injected for injection.
  • This example is intended to illustrate the prostaglandin fat emulsion for injection of the present invention and a method for preparing the same.
  • the colostrum obtained in the step (3) is subjected to high-pressure homogenization by a microfluidizer (M-110P model microfluidizer of the United States) three times, the pressure is 1000-1200 bar, and the temperature of the effluent is 15 ° C to obtain fine Milk; the obtained concentrate was initially filtered through a 0.45 ⁇ m filter, and then sterilized by filtration through a 0.22 ⁇ m microporous membrane;
  • the filtrate obtained in the step (4) is freeze-dried, first rapidly frozen to -45 ° C, and then heated to -35 ° C for 3 hours; once again dried: temperature -30 ° C, time 24 hours; and then secondary drying: The temperature was 30 ° C for 6 hours, and the alprostadil A5 was injected for injection.
  • alprostadil fat B1 was obtained.
  • alprostadil fat B2 was obtained.
  • alprostadil fat milk B3 was obtained.
  • alprostadil fat emulsion B4 was obtained.
  • proalidil fat milk B5 was obtained.
  • the egg phosphatidylglycerol used was 800 mg, and alprostadil milk B6 was obtained.
  • the sample prepared above was placed at 40 ° C, and the content of alprostadil was measured on the 10th and 30th days, and compared with the content of alprostadil at 0 days, and the percentage decrease of the alprostadil content (%) was calculated.
  • Percentage decrease in dilt content (prostaglandin content measured on day 0 - alprostadil content measured on day n) / alprostadil content measured on day 0 x 100%.
  • phosphate buffer pH 6.3-acetonitrile (3:1 by volume) (wherein the phosphate buffer was prepared by taking 9.07 g of potassium dihydrogen phosphate, adding water to dissolve, Make 1000ml, take another 9.46g of anhydrous sodium hydrogen phosphate, add water to dissolve, make 1000ml, add the latter to the former until the pH is 6.3, take 100ml of this solution and add water to 1000ml, shake it, that is) .
  • Injection volume 20 ⁇ l; flow rate: 1.0 ml/min; detection wavelength: 278 nm; column temperature: 60 ° C;
  • Post-column reaction solution 1 mol/L potassium hydroxide solution
  • the specific content ratio of alprostadil, phosphatidylcholine, phosphatidylglycerol, injectable oil and lyoprotectant of the present invention can achieve higher alprostadil for injection. Stability. According to the results of A1 and A2, the stability of fat emulsion using olive oil is slightly better than that of soybean oil.
  • Test Example 2 Test of particle size before and after lyophilization
  • the fat emulsions A1-A5 and B1-B6 obtained after lyophilization were first reconstituted with water for injection and then measured by the above operation, and the measurement results of the average particle diameter and the particle size distribution are shown in Table 2.
  • the average particle diameter refers to the average particle diameter specified in the USP729 method I of the United States Pharmacopoeia, which is calculated by a method of dynamic light scattering;
  • the particle size distribution is a particle size distribution value (P.I.) which is simultaneously calculated by measuring the average particle diameter by dynamic light scattering. The larger the value, the worse the particle size distribution and the worse the uniformity of the particle size.
  • the protoparipid for injection of the specific content ratio of alprostadil, phosphatidylcholine, phosphatidylglycerol, injectable oil and lyoprotectant of the present application relative to the comparative example Milk can obtain alprostadil milk for injection with an average particle size of 150-230 nm and a particle size distribution of less than 0.2; wherein, when other components are used instead of phosphatidylglycerol, the particle size of the obtained fat emulsion is different before and after lyophilization.
  • glycerin has a large influence on the particle size distribution before and after lyophilization, that is, even in the case where glycerol is not added, even if the amount of phosphatidylglycerol is decreased, the particle size distribution after lyophilization does not significantly change.
  • an average particle diameter of the milk particles of 150 to 190 nm, in particular, a particle diameter difference of 10 to 30 nm before and after lyophilization, and a particle size distribution of 0.1 or less.
  • Alprostadil fat emulsion for injection This preferred embodiment may be an embodiment in which glycerin is not used, or may be an embodiment in which the content of the phosphatidylglycerol is more than 60 parts by weight when glycerin is used.

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Abstract

一种注射用前列地尔脂肪乳及其制备方法。所述脂肪乳含有前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂，其中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份。

Description

一种注射用前列地尔脂肪乳及其制备方法 技术领域
本发明涉及药物制剂领域，具体涉及一种注射用前列地尔脂肪乳及其制备方法。
背景技术
前列地尔注射液最先在日本上市，采用了脂肪乳载药技术，由药物、大豆油、精致蛋黄卵磷脂、油酸、甘油和pH调节剂组成，其制备方法是将药物溶于脂肪油中，以精制卵磷脂为乳化剂，油酸为辅助乳化剂，经高压均质制成O/W型载药脂肪乳，其乳粒平均粒径为200nm。前列地尔注射液采用脂肪乳的载药方式，将药物包封于油相中，大大减少了刺激性的发生。其具有以下优点：(1)靶向性：对炎症部位血管壁的亲和力更高，能在动脉粥样硬化血管、高血压血管壁上沉积，针对病变部位发挥疗效，而对正常血管的影响很少，大大降低副反应发生率，被誉为“药物导弹”。(2)长效性：前列地尔普通粉针剂的体内半衰期仅3～5分钟，将其制成脂微球后，可以维持12～24小时释放药物，发挥药效。(3)高效安全性：前列地尔脂肪乳临床用量仅为传统粉针制剂的1/5～1/10，即可达到更好的治疗效果；前列地尔不良反应发生率仅为传统粉针制剂的1/10。
由于前列地尔注射液以乳液的形式存在，仍有一部分药物会遇水而发生降解，产生以下质量问题：(1)前列地尔注射液的降解产物PGA1的含量高达60％(国家药品标准WS1-(X-041)-2002Z-2008)；(2)有效期短，只有12个月(0～5℃)。
为此，现有技术将前列地尔注射液做了进一步的改进，将其改剂型制成无菌冻干制剂，以此减少药物与水的接触，增加其稳定性。例如：
CN1562041A公开了一种前列地尔冻干乳剂及其制备方法，该冻干乳剂含有前列地尔、注射用油、乳化剂、稳定剂、甘油、防腐剂，其pH范围为4～9，其所采用的乳化剂除了使用磷脂之外，还可以使用作为非离子表面活性剂的泊洛沙姆和HS15吐温类。
CN1903206A公开了一种前列地尔冻干乳剂及其制备方法，该冻干乳剂中，相对于每1000毫升乳剂，药用辅料的重量百分比为：注射用油0.01～1％(g/mL)，乳化剂0.01～5％(g/mL)、稳定剂1～6％(g/mL)、冻干保护剂1％～20％(g/mL)；pH范围4～9(实施例中pH范围4.21～5.43)。其研究发现前列地尔乳液的稳定性非常差，不仅糖类物质不能保证在生产过程中不破乳，同时，糖类冻干保护剂的复乳效果未达到微乳注射剂的要求。其采用人血白蛋白与糖类物质合用解决了冻干乳剂的制备。尽管人血白蛋白可以解决在冻干乳剂中前列地尔的保护问题，但其来源有限，价格昂贵，不适于该产品的临床广泛应用。
CN101843594A公开了一种注射用前列地尔冻干乳剂及其制备方法，其中，在该发明中为了解决对前列地尔的保护问题，采用环糊精类物质和糖类物质一起做冻干保护剂增加药物的稳定性，其原理是环糊精将药物包裹而增加稳定性。然而环糊精自身用于静脉注射有一定的肾毒性和溶血性，而且环糊精将药物包裹后，增加了水溶性，药物将以更大的比例分布于水相而不是油相中，因此，在制剂安全性方面存在隐患。
发明内容
本发明的目的在于克服现有的前列地尔冻干乳剂中所采用的药用辅料在保证稳定性时导致安全性低的缺陷，提供一种安全性和稳定性兼具的注射用前列地尔脂肪乳及其制备方法。
为此，本发明提供一种注射用前列地尔脂肪乳，该脂肪乳含有前列地尔、 磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂，其中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份。
本发明还提供了上述注射用前列地尔脂肪乳的制备方法，该方法包括：
(1)将冻干保护剂溶解于水中得到水相；
(2)将注射用油、磷脂酰胆碱、磷脂酰甘油和前列地尔混合，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，剪切分散以形成初乳，其中，在该初乳中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份；
(4)将所述初乳高压匀化形成精乳，并除菌、冷冻干燥。
本发明提供的注射用前列地尔脂肪乳具有良好的稳定性，并且提高了注射用前列地尔冻干乳剂的药用安全性；同时，通过本发明的该冻干乳剂中的各个成分的协同作用，有效地控制了脂肪乳在冻干前后的乳粒粒径和粒径分布。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
本发明提供一种注射用前列地尔脂肪乳，该脂肪乳含有前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂，其中，相对于1重量份的前 列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份。
根据本发明，所述注射用前列地尔脂肪乳为本领域的常规的意义，即指将含有前列地尔的乳剂经过冻干而形成的脂肪乳，可以再分散于水中形成可注射的乳剂。尽管使得所述注射用前列地尔脂肪乳含有上述含量范围内的前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂即可获得较好的安全性和稳定性，但是出于获得更好的安全性和稳定性以及更好地控制该脂肪乳在冻干前和冻干后的粒径分布上考虑，优选情况下，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为2400-3000重量份，所述磷脂酰甘油的含量为24-48重量份，所述注射用油的含量为4000-12000重量份，所述冻干保护剂的含量为20000-30000重量份。
在本发明的一种优选实施方式中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为2400-3000重量份，所述磷脂酰甘油的含量为30-120重量份，所述注射用油的含量为10000-12000重量份，所述冻干保护剂的含量为20000-30000重量份。
根据本发明，所述磷脂酰胆碱能够配合所述脂肪乳中的其他成分，特别是磷脂酰甘油，一起稳定前列地尔，降低前列地尔遇水降解的程度，以此降低了所得脂肪乳中的前列地尔的降解副产物，同时磷脂酰胆碱是可静脉注射用的物质，因此具有很高的药用安全性。所述磷脂酰胆碱可以为由蛋黄中提取的磷脂酰胆碱(蛋黄磷脂酰胆碱)、合成的磷脂酰胆碱或它们的任意组合。
其中，由蛋黄中提取的磷脂酰胆碱其纯度一般在96重量％以上，这样的磷脂酰胆碱也是安全可采用的。
其中，所述合成的磷脂酰胆碱优选为二硬脂酰基磷脂酰胆碱(DSPC)、二油酰基磷脂酰胆碱(DOPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二肉豆蔻 酰基磷脂酰胆碱(DMPC)、二癸酰基磷脂酰胆碱(DDPC)、二月桂酰基磷脂酰胆碱(DLPC)、二芥酰基磷脂酰胆碱(DEPC)、1-硬脂酰基-2-油酰基磷脂酰胆碱(SOPC)、1-棕榈酰基-2-油酰基磷脂酰胆碱(POPC)、1-肉豆蔻酰基-2-油酰基磷脂酰胆碱(MOPC)、1-硬脂酰基-2-棕榈酰基磷脂酰胆碱(SPPC)、1-硬脂酰基-2-肉豆蔻酰基磷脂酰胆碱(SMPC)、1-棕榈酰基-2-硬脂酰基磷脂酰胆碱(PSPC)、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱(PMPC)、1-肉豆蔻酰基-2-硬脂酰基磷脂酰胆碱(MSPC)、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱(MPPC)或它们的任意组合。
更优选地，所述磷脂酰胆碱为蛋黄磷脂酰胆碱、二硬脂酰基磷脂酰胆碱(DSPC)、二肉豆蔻酰基磷脂酰胆碱(DMPC)或它们的任意组合。
根据本发明，所述的磷脂酰甘油(PG)能够配合所述脂肪乳中的其他成分一起稳定前列地尔，降低前列地尔遇水降解的程度，以此降低了所得脂肪乳中的前列地尔降解副产物，同时磷脂酰甘油是可静脉注射用的物质，因此具有很高的药用安全性。所述的磷脂酰甘油可以为由蛋黄中提取的蛋黄磷脂酰甘油(EPG)及其盐、合成的磷脂酰甘油及其盐或它们的任意组合。这里的“盐”可以是蛋黄磷脂酰甘油或合成的磷脂酰甘油的钠盐、钾盐等。
其中，所述合成的磷脂酰甘油优选为二硬脂酰基磷脂酰甘油(DSPG)及其盐、二油酰基磷脂酰甘油(DOPG)及其盐、二棕榈酰基磷脂酰甘油(DPPG)及其盐、二肉豆蔻酰基磷脂酰甘油(DMPG)及其盐、1-棕榈酰基-2-油酰基磷脂酰甘油(POPG)及其盐、二芥酰磷脂酰甘油(DEPG)及其盐、二月桂酰磷脂酰甘油(DLPG)及其盐或它们的任意组合。
更优选地，所述磷脂酰甘油为蛋黄磷脂酰甘油及其钠盐、二硬脂酰基磷脂酰甘油及其钠盐、二肉豆蔻酰基磷脂酰甘油及其钠盐或它们的任意组合。
根据本发明，所述注射用油可以采用本领域常规的注射用油，只要可以与本发明的脂肪乳的其他成分一起提高所述脂肪乳的安全性和稳定性即可， 优选地，所述注射用油为大豆油、花生油、红花油、棉籽油、橄榄油、椰子油、麻油、鱼油、中链甘油单酯、中链甘油双酯、中链甘油三酯、油酸乙酯、乙酰化单甘油酯、丙二醇双酯、亚油酸甘油酯、聚乙二醇月桂酸甘油酯或它们的任意组合，优选为橄榄油和/或中链甘油三酯。本领域技术人员应当理解的是，上述列举的注射用油更优选采用精制后的油。在本发明的一种优选的实施方式中，所述注射用油为橄榄油和中链甘油三酯的组合，其中，橄榄油和中链甘油三酯的重量比为1:0.5-2，优选为1:1。
根据本发明，所述冻干保护剂可以采用本领域常规的冻干保护剂，只要能够达到本发明的脂肪乳的安全性和稳定性的药用要求即可，优选地，所述冻干保护剂为乳糖、蔗糖、海藻糖、右旋糖酐或它们的任意组合。
根据本发明，所述注射用前列地尔脂肪乳的乳粒平均粒径为150-230nm，粒径分布小于0.2。对于冻干前的乳剂的乳粒平均粒径优选为150-230nm，粒径分布小于0.2。
根据本发明，所述脂肪乳含有前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂，此外，其还可以含有一些常规的辅料，只要不破坏所述脂肪乳的安全性和稳定性即可，例如甘油、pH调节剂(如氢氧化钠、盐酸)等。在本发明的一种优选的实施方式中，作为其主要成分的前列地尔、所述磷脂酰胆碱、所述磷脂酰甘油、所述注射用油和所述冻干保护剂的总重量可以占所述冻干后脂肪乳的80重量％以上，更优选为80-100重量％，更优选为90-100重量％，更优选为95-100重量％，特别优选为100重量％。本领域技术人员应当理解的是，当所述脂肪乳还含有其他次要成分时，这些次要成分并不会影响本发明的主要成分的效果，不会采用破坏本发明的脂肪乳的安全性和稳定性的物质成分。
其中，该100重量％的含量是指所述脂肪乳由前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂组成。在由列地尔、磷脂酰胆碱、磷脂 酰甘油、注射用油和冻干保护剂组成的该脂肪乳中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份。优选地，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为2400-3000重量份，所述磷脂酰甘油的含量为24-48重量份，所述注射用油的含量为4000-12000重量份，所述冻干保护剂的含量为20000-30000重量份。
此外，在本发明的一种实施方式中，所述注射用前列地尔脂肪乳含有前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油、冻干保护剂和甘油，其中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份，甘油的含量为500-1500重量份。其中，更优选地，所述磷脂酰甘油的含量为大于60重量份，这样可以在甘油存在下，也能更好地对所得的脂肪乳的乳粒粒径及其分布进行控制。
在本发明的一种更为优选的实施方式中，所述注射用前列地尔脂肪乳中不含有甘油，这样更有利于对所得的脂肪乳的乳粒粒径的控制，降低粒径分布。
本发明提供一种上述注射用前列地尔脂肪乳的制备方法，该方法包括：
(1)将冻干保护剂溶解于水中得到水相；
(2)将注射用油、磷脂酰胆碱、磷脂酰甘油和前列地尔混合，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，剪切分散以形成初乳，其中，在该初乳中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份， 所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份；
(4)将所述初乳高压匀化形成精乳，并除菌、冷冻干燥。
根据本发明，所述磷脂酰胆碱、所述磷脂酰甘油、所述注射用油和所述冻干保护剂的优选含量和种类如前文中所定义的，在此不再赘述。
上述步骤(1)和步骤(2)的顺序可以调整，可以同时进行，也可分步进行，只要能够得到所述油相和水相即可。
为了促进步骤(1)的冻干保护剂的溶解，优选地在50-70℃下进行溶解。同理，为了促进步骤(2)的各个成分的混合，优选地在50-70℃下进行混合。
其中，步骤(3)中所述的剪切分散可以根据所需的乳剂的乳粒大小进行合理的调整，优选地，所述剪切分散的条件包括：分散时间为10-60分钟，剪切速度为3000-10000rpm，温度为50-70℃。更优选地，所述剪切分散的条件包括：分散时间为10-60分钟，剪切速度为3000-10000rpm，温度为55-70℃。
在本发明的一种实施方式中，所述剪切分散的条件包括：分散时间为10-30分钟，剪切速度为3000-10000rpm，温度为55-70℃。
在本发明的另一种实施方式中，所述剪切分散的条件包括：分散时间为10-30分钟，剪切速度为8000-10000rpm，温度为55-70℃。
其中，步骤(4)中所述的高压匀化也可以根据所需的乳剂的乳粒大小进行合理的调整，优选地，所述高压匀化的条件包括：压力为600-2000bar，匀化次数为3-6次，温度为15-30℃。更优选地，所述高压匀化的条件包括：压力为800-1200bar，匀化次数为3-5次，温度为15-30℃。这里的温度指的是高压匀化后控制的流出液的温度。所述高压匀化可以采用本领域常规的微射流仪完成。
其中，步骤(4)中所述的除菌可以采用本领域常规的乳剂除菌方法，例如采用滤膜过滤进行除菌，例如先采用0.45-0.8μm的滤膜初滤，再采用 0.2-0.3μm微孔滤膜过滤。
其中，步骤(4)中所述的冷冻干燥可以采用本领域常规的乳剂冷冻干燥的方法，例如该冷冻干燥的方法可以包括：将样品快速冷冻至温度-50至-45℃，维持1-3小时；再进行一次干燥，其温度为-35至-30℃，时间为24-48小时；然后进行二次干燥，其温度为25-40℃，时间为2-6小时。
根据本发明，该方法还可以包括在步骤(4)的高压匀化之前，采用pH调节剂对所述初乳的pH值进行调节，例如调节pH至5-8，这样的pH调节剂如前文中所定义的。
本发明提供的注射用前列地尔脂肪乳，有效地通过其含有特定含量的前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂成分间的相互配合作用，较好地稳定了药物活性成分前列地尔，同时又保证了所述脂肪乳的药用安全性。并且，本发明的脂肪乳还可以通过上述特定含量的各个成分间的相互配合，较好地控制了所得脂肪乳的乳粒粒径和粒径分布，能够获得品质更好的注射用前列地尔脂肪乳产品。
以下将通过实施例对本发明进行详细描述。
实施例1
本实施例用于说明本发明的注射用前列地尔脂肪乳及其制备方法。
配方：
Figure PCTCN2015077642-appb-000001
制备过程：
(1)将蔗糖和甘油加入到1000mL水中加热至65℃溶解得到水相备用；
(2)将精制大豆油加热至65℃，分别加入蛋黄磷脂酰胆碱(PC-98T，上海艾韦特医药科技有限公司)和蛋黄磷脂酰甘油(EPG，上海艾韦特医药科技有限公司)溶解后，加入前列地尔，搅拌使其溶解，得到油相；
(3)将步骤(2)所得的油相加入步骤(1)所得的水相中，在65℃下以10000rpm的剪切速度进行剪切分散15分钟，形成初乳；
(4)将步骤(3)所得的初乳用氢氧化钠调pH至6.9，经微射流仪(美国MFIC公司M-110P型号的微射流仪)高压匀化3次，压力1000～1200bar，流出液的温度为20℃，得到精乳；将所得的精乳经0.45μm滤膜初滤，再经0.22μm微孔滤膜过滤除菌；
将步骤(4)所得滤液进行冷冻干燥，先快速冷冻至-45℃，再升温至-35℃，维持3小时；再进行一次干燥：温度-30℃，时间24小时；而后进行二次干燥：温度30℃，时间6小时，即得注射用前列地尔脂肪乳A1。
实施例2
本实施例用于说明本发明的注射用前列地尔脂肪乳及其制备方法。
配方：
Figure PCTCN2015077642-appb-000002
制备过程：
(1)将蔗糖加入到1000mL水中加热至65℃溶解得到水相备用；
(2)将橄榄油加热至65℃，分别加入蛋黄磷脂酰胆碱(PC-98T，上海艾韦特医药科技有限公司)和蛋黄磷脂酰甘油(EPG，上海艾韦特医药科技有限公司)溶解后，加入前列地尔，搅拌使其溶解，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，在65℃下以10000rpm的剪切速度进行剪切分散15分钟，形成初乳；
(4)将步骤(3)所得的初乳用氢氧化钠调pH至7.1，经微射流仪(美国MFIC公司M-110P型号的微射流仪)高压匀化3次，压力1000～1200bar，流出液的温度为30℃，得到精乳；将所得的精乳经0.45μm滤膜初滤，再经0.22μm微孔滤膜过滤除菌；
将步骤(4)所得滤液进行冷冻干燥，先快速冷冻至-45℃，再升温至-35℃，维持3小时；再进行一次干燥：温度-30℃，时间24小时；而后进行二次干燥：温度30℃，时间6小时，即得注射用前列地尔脂肪乳A2。
实施例3
本实施例用于说明本发明的注射用前列地尔脂肪乳及其制备方法。
配方：
Figure PCTCN2015077642-appb-000003
制备过程：
(1)将蔗糖加入到1000mL水中加热至65℃溶解得到水相备用；
(2)将精制大豆油加热至65℃，分别加入蛋黄磷脂酰胆碱(PC-98T， 上海艾韦特医药科技有限公司)和蛋黄磷脂酰甘油(EPG，上海艾韦特医药科技有限公司)溶解后，加入前列地尔，搅拌使其溶解，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，在65℃下以10000rpm的剪切速度进行剪切分散15分钟，形成初乳；
(4)将步骤(3)所得的初乳用氢氧化钠调pH至7.2，经微射流仪(美国MFIC公司M-110P型号的微射流仪)高压匀化3次，压力1000～1200bar，流出液的温度为25℃，得到精乳；将所得的精乳经0.45μm滤膜初滤，再经0.22μm微孔滤膜过滤除菌；
将步骤(4)所得滤液进行冷冻干燥，先快速冷冻至-45℃，再升温至-35℃，维持3小时；再进行一次干燥：温度-30℃，时间24小时；而后进行二次干燥：温度30℃，时间6小时，即得注射用前列地尔脂肪乳A3。
实施例4
本实施例用于说明本发明的注射用前列地尔脂肪乳及其制备方法。
配方：
Figure PCTCN2015077642-appb-000004
制备过程：
(1)将蔗糖加入到1000mL水中加热至55℃溶解得到水相备用；
(2)将橄榄油和中链甘油三酯加热至55℃，分别加入蛋黄磷脂酰胆碱(PC-98T，上海艾韦特医药科技有限公司)和二硬脂酰基磷脂酰甘油钠 (DSPG，上海东尚生物科技有限公司)溶解后，加入前列地尔，搅拌使其溶解，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，在55℃，下以8000rpm的剪切速度进行剪切分散30分钟，形成初乳；
(4))将步骤(3)所得的初乳经微射流仪(美国MFIC公司M-110P型号的微射流仪)高压匀化3次，压力800～1000bar，流出液的温度为25℃，得到精乳；将所得的精乳经0.45μm滤膜初滤，再经0.22μm微孔滤膜过滤除菌；
将步骤(4)所得滤液进行冷冻干燥，先快速冷冻至-45℃，再升温至-35℃，维持3小时；再进行一次干燥：温度-30℃，时间24小时；而后进行二次干燥：温度30℃，时间6小时，即得注射用前列地尔脂肪乳A4。
实施例5
本实施例用于说明本发明的注射用前列地尔脂肪乳及其制备方法。
配方：
Figure PCTCN2015077642-appb-000005
制备过程：
(1)将蔗糖加入到1000mL水中加热至70℃溶解得到水相备用；
(2)将橄榄油加热至70℃，分别加入DMPC和DMPG溶解后，加入前列地尔，搅拌使其溶解，得到油相；
(3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，在70℃ 下以10000rpm的剪切速度进行剪切分散15分钟，形成初乳；
(4)将步骤(3)所得的初乳经微射流仪(美国MFIC公司M-110P型号的微射流仪)高压匀化3次，压力1000-1200bar，流出液的温度为15℃，得到精乳；将所得的精乳经0.45μm滤膜初滤，再经0.22μm微孔滤膜过滤除菌；
将步骤(4)所得滤液进行冷冻干燥，先快速冷冻至-45℃，再升温至-35℃，维持3小时；再进行一次干燥：温度-30℃，时间24小时；而后进行二次干燥：温度30℃，时间6小时，即得注射用前列地尔脂肪乳A5。
对比例1
根据实施例1所述的方法，所不同的是，采用0.6g的油酸代替蛋黄磷脂酰甘油，以及用氢氧化钠调节pH至7，得到前列地尔脂肪乳B1。
对比例2
根据实施例1所述的方法，所不同的是，采用0.6g的维生素E代替蛋黄磷脂酰甘油，以及用氢氧化钠调节pH至7，得到前列地尔脂肪乳B2。
对比例3
根据实施例3所述的方法，所不同的是，采用的磷脂酰胆碱为5g，得到前列地尔脂肪乳B3。
对比例4
根据实施例3所述的方法，所不同的是，采用的磷脂酰胆碱为22g，得到前列地尔脂肪乳B4。
对比例5
根据实施例3所述的方法，所不同的是，采用的蛋黄磷脂酰甘油为50mg，得到前列地尔脂肪乳B5。
对比例6
根据实施例3所述的方法，所不同的是，采用的蛋黄磷脂酰甘油为800mg，得到前列地尔脂肪乳B6。
测试例1
将上述制备的样品在40℃下放置，在第10天、30天取样测定前列地尔含量，与0天的前列地尔含量进行对比，计算得到前列地尔含量下降百分率(％)，即前列地尔含量下降百分率＝(第0天测得的前列地尔含量-第n天取样测定的前列地尔含量)/第0天测得的前列地尔含量×100％。
含量测定方法：柱后衍生+HPLC法
色谱柱：C18柱(型号：YMC；250×4.6mm，5μm)
流动相：0.0067mol/L磷酸盐缓冲液(pH为6.3)-乙腈(体积比为3:1)(其中，该磷酸盐缓冲液的制备为：取磷酸二氢钾9.07g，加水使溶解，制成1000ml，另取无水磷酸氢二钠9.46g，加水使溶解，制成1000ml，将后者加到前者中，直至pH为6.3，取此液100ml加水至1000ml，摇匀，即得)。
进样量：20μl；流速：1.0ml/min；检测波长：278nm；柱温：60℃；
柱后反应管：聚四氟乙烯管(
Figure PCTCN2015077642-appb-000006
)；
柱后反应液：1mol/L氢氧化钾溶液；
反应液流速：0.5ml/min；
各个脂肪乳的前列地尔含量下降百分率见下表1所示：
表1
脂肪乳 10天 30天
A1 2.3％ 6.4％
A2 1.6％ 5.2％
A3 2.2％ 6.2％
A4 1.8％ 5.5％
A5 1.9％ 5.3％
B1 4.2％ 12.3％
B2 2.7％ 8.1％
B3 2.5％ 7.9％
B4 2.3％ 7.4％
B5 2.6 7.7％
B6 2.2％ 7.3％
通过表1的结果可以看出，本发明的特定含量配比的前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂的注射用前列地尔脂肪乳能够获得更高的稳定性。根据A1和A2的结果对比可见，采用橄榄油的脂肪乳的稳定性略优于采用大豆油的。
测试例2：冻干前后的乳粒粒径的测试
检查方法：动态激光散射粒径测定法(美国PSS公司，型号NICOMP380ZLS)
具体试验操作：分别取0.1ml实施例和对比例在冷冻干燥前所得的乳剂，加纯化水(已预先用孔径0.22μm的膜过滤)稀释至500mL，混匀，作为测试液样品，采用动态激光散射粒径测定法分别对这些样品进行测定，平均粒径和粒径分布的测试结果如表2中所示。
另外，分别取冻干后所得的脂肪乳A1-A5和B1-B6先用注射用水复溶后照上述操作测定，平均粒径和粒径分布的测定结果如表2中所示。
其中，平均粒径是指美国药典USP729方法I规定的平均粒径，其是通过动态光散射样的方法计算的；
粒径分布是采用动态光散射测定平均粒径时同时计算得出的粒径分布值(P.I.)，该值越大，粒径分布越差，粒子大小的均匀性越差。
表2
Figure PCTCN2015077642-appb-000007
通过表2的数据可以看出，相对于对比例，本申请的特定含量配比的前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂的注射用前列地尔脂肪乳能够获得乳粒平均粒径为150-230nm，粒径分布小于0.2的注射用前列地尔脂肪乳；其中，采用其他成分代替磷脂酰甘油时，所得的脂肪乳的粒径冻干前后差异较大，且粒径分布超出了0.2(例如将实施例1与对比例1和2进行比较)；另外，当磷脂酰胆碱或磷脂酰甘油的用量大于或者小于本发明的量时，所得脂肪乳的粒径分布都相应地变差(实施例3和对比例3-6的结果比较看出)。特别地，通过实施例1和实施例2对比可以看出，在甘油存在下，优选采用较高量的磷脂酰甘油。另外，本发明意外的发现，甘油对冻干前后粒径分布有很大的影响，即在不加甘油的情况下，即使降低磷脂酰甘油的用量，冻干后粒径分布也没有显著变化。
因此，在本发明的一种优选的实施方式中，能够获得乳粒平均粒径为150-190nm，特别是冻干前后的粒径差值在10-30nm，粒径分布在0.1以下的 注射用前列地尔脂肪乳。该优选的实施方式可以为不采用甘油的实施方式，或者可以为在采用甘油时，所述磷脂酰甘油的含量为大于60重量份的实施方式。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (10)

  1. 一种注射用前列地尔脂肪乳，其特征在于，该脂肪乳含有前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂，其中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份，所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份。
  2. 根据权利要求1所述的注射用前列地尔脂肪乳，其中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为2400-3000重量份，所述磷脂酰甘油的含量为24-48重量份，所述注射用油的含量为4000-12000重量份，所述冻干保护剂的含量为20000-30000重量份。
  3. 根据权利要求1或2所述的注射用前列地尔脂肪乳，其中，该脂肪乳由前列地尔、磷脂酰胆碱、磷脂酰甘油、注射用油和冻干保护剂组成。
  4. 根据权利要求1-3中任意一项所述的注射用前列地尔脂肪乳，其中，所述磷脂酰胆碱为蛋黄中提取的磷脂酰胆碱、合成的磷脂酰胆碱或它们的任意组合；优选地，所述合成的磷脂酰胆碱为二硬脂酰基磷脂酰胆碱、二油酰基磷脂酰胆碱、二棕榈酰基磷脂酰胆碱、二肉豆蔻酰基磷脂酰胆碱、二癸酰基磷脂酰胆碱、二月桂酰基磷脂酰胆碱、二芥酰基磷脂酰胆碱、1-硬脂酰基-2-油酰基磷脂酰胆碱、1-棕榈酰基-2-油酰基磷脂酰胆碱、1-肉豆蔻酰基-2-油酰基磷脂酰胆碱、1-硬脂酰基-2-棕榈酰基磷脂酰胆碱、1-硬脂酰基-2-肉豆蔻酰基磷脂酰胆碱、1-棕榈酰基-2-硬脂酰基磷脂酰胆碱、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱、1-肉豆蔻酰基-2-硬脂酰基磷脂酰胆碱、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱或它们的任意组合。
  5. 根据权利要求1-3中任意一项所述的注射用前列地尔脂肪乳，其中，所述磷脂酰甘油为蛋黄中提取的蛋黄磷脂酰甘油及其盐、合成的磷脂酰甘油及其盐或它们的任意组合；优选地，所述合成的磷脂酰甘油为二硬脂酰基磷脂酰甘油及其盐、二油酰基磷脂酰甘油及其盐、二棕榈酰基磷脂酰甘油及其盐、二肉豆蔻酰基磷脂酰甘油及其盐、1-棕榈酰基-2-油酰基磷脂酰甘油及其盐、二芥酰磷脂酰甘油及其盐、二月桂酰磷脂酰甘油及其盐或它们的任意组合。
  6. 根据权利要求1-3中任意一项所述的注射用前列地尔脂肪乳，其中，所述注射用油为大豆油、花生油、红花油、棉籽油、橄榄油、椰子油、麻油、鱼油、中链甘油单酯、中链甘油双酯、中链甘油三酯、油酸乙酯、乙酰化单甘油酯、丙二醇双酯、亚油酸甘油酯、聚乙二醇月桂酸甘油酯或它们的任意组合。
  7. 根据权利要求1-3中任意一项所述的注射用前列地尔脂肪乳，其中，所述冻干保护剂为乳糖、蔗糖、海藻糖、右旋糖苷或它们的任意组合。
  8. 一种权利要求1-7中任意一项所述的注射用前列地尔脂肪乳的制备方法，其特征在于，该方法包括：
    (1)将冻干保护剂溶解于水中得到水相；
    (2)将注射用油、磷脂酰胆碱、磷脂酰甘油和前列地尔混合，得到油相；
    (3)将步骤(2)所得的油相加入到步骤(1)所得的水相中，剪切分散以形成初乳，其中，在该初乳中，相对于1重量份的前列地尔，所述磷脂酰胆碱的含量为1200-4000重量份，所述磷脂酰甘油的含量为12-120重量份， 所述注射用油的含量为2000-20000重量份，所述冻干保护剂的含量为16000-60000重量份；
    (4)将所述初乳高压匀化形成精乳，并除菌、冷冻干燥。
  9. 根据权利要求8所述的方法，其中，步骤(3)中，所述剪切分散的条件包括：分散时间为10-60分钟，剪切速度为3000-10000rpm，温度为50-70℃。
  10. 根据权利要求9所述的方法，其中，步骤(4)中，所述高压匀化的条件包括：压力为600-2000bar，匀化次数为3-6次，温度为15-30℃。
PCT/CN2015/077642 2014-04-29 2015-04-28 一种注射用前列地尔脂肪乳及其制备方法 WO2015165373A1 (zh)

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