WO2021179817A1 - 一种黄体酮乳剂型注射剂及其制备方法 - Google Patents

一种黄体酮乳剂型注射剂及其制备方法 Download PDF

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WO2021179817A1
WO2021179817A1 PCT/CN2021/073748 CN2021073748W WO2021179817A1 WO 2021179817 A1 WO2021179817 A1 WO 2021179817A1 CN 2021073748 W CN2021073748 W CN 2021073748W WO 2021179817 A1 WO2021179817 A1 WO 2021179817A1
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injection
progesterone
emulsion
oil
solvent
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French (fr)
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赵谦
翁伟宇
黄建明
郝越
梁婷婷
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江苏佳尔科药业集团股份有限公司
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the application relates to the field of pharmacy, in particular to a progesterone emulsion injection.
  • Progesterone (also known as progesterone, progesterone) is a natural progesterone secreted by the corpus luteum of the ovary. Its chemical name is Pregnancy-4-ene-3,20-dione, its molecular formula is C 21 H 30 O 2 , and its molecular weight is 314.47. , CAS number is 57-83-0. Progesterone is a white or almost white crystalline powder, odorless and tasteless; it is easily soluble in chloroform, soluble in ethanol, ether or vegetable oil, but insoluble in water.
  • progesterone The main pharmacological effects of progesterone are: (1) Promote the secretion of the endometrium in the later period of the menstrual cycle and thicken the endometrium to facilitate the implantation of the fertilized egg, reduce the excitability of the uterine muscles, and ensure the safe progress of pregnancy; (2) With the female Hormones work together to promote the growth of breast acini and prepare for lactation; (3) Inhibit the release of luteinizing hormone in the anterior pituitary, preventing follicles from maturing and inhibiting ovulation.
  • Progesterone can be used clinically for menstrual disorders, amenorrhea, threatened abortion and habitual abortion, dysfunctional uterine bleeding, corpus luteum insufficiency, premenstrual syndrome and perimenopausal hormone replacement therapy.
  • progesterone intramuscular injection has definite curative effect and low price. It is a traditional medicine for human assisted reproductive technology to support the corpus luteum. Oral administration of progesterone has a serious liver first pass effect, and its bioavailability is low ( ⁇ 10%), so it is not recommended for assisted reproductive technology.
  • vaginal administration is the same as that of intramuscular injection.
  • the local drug concentration in the uterus is high, and there are fewer systemic adverse reactions.
  • the incidence of vaginal bleeding during the luteal phase is high and the price is expensive. It can be seen that from the perspective of efficacy and economy, intramuscular injection is still an ideal route of administration of progesterone.
  • the existing progesterone intramuscular injection also has some shortcomings, such as: (1) pain and irritation at the injection site, easy to form local induration, occasional local aseptic abscess, the formation of local induration, aseptic abscess absorption and subsidence need Longer time; (2) The injection has a high viscosity, and it has a certain resistance when sucking and injecting with a syringe, and it is easy to re-infiltrate; (3) It needs to be injected in the hospital, and the patient's compliance is poor. The defect of progesterone intramuscular injection has a lot to do with the product formula. Progesterone is a fat-soluble substance.
  • the existing injections are oil solution type injections (commonly known as oil injections) prepared with soybean oil as a solvent. Therefore, the aforementioned problems such as injection pain, formation of induration, and inconvenience of injection often occur during use.
  • progesterone injection includes submicroemulsion injection (CN101152186B), lipomicrosphere injection (CN106074383A), cyclodextrin (or hydroxypropyl cyclodextrin) package Aqueous injections (CN109381424A, CN106727288A, CN1517091, CN104857522A), suspension injections (CN107198677A, CN107441039A), nanocrystalline injections (CN109223722A), polymer nanoparticles or microsphere injections (CN107441061A, CN107157956A).
  • the prescription and process of nanoparticle or microsphere injection are complicated, and the production is difficult; because the water solubility of progesterone in nanocrystal or suspension injection is too low, the drug may not be effectively released from the injection site, and the insoluble drug may be long-term Accumulation may cause adverse reactions; the cyclodextrin or hydroxypropyl cyclodextrin used in the cyclodextrin inclusion compound has a certain degree of nephrotoxicity and may cause cancer, so it should be used with caution. Relatively speaking, emulsion injections such as microemulsions or lipid microspheres may be an ideal alternative preparation.
  • progesterone is a fat-soluble drug, its solubility in oily solvents commonly used in emulsion injections (such as vegetable oil for injection, medium-chain fatty acid triglycerides, etc.) is not large.
  • oily solvents commonly used in emulsion injections such as vegetable oil for injection, medium-chain fatty acid triglycerides, etc.
  • the two related patents of progesterone emulsion injections CN101152186B, CN106074383A
  • the grease solvent and its amount used may not be enough to ensure that the clinical dosage of progesterone can be dissolved in these for a long time.
  • the solubility of progesterone in water is extremely low (about 20 ⁇ g/ml), so the progesterone submicroemulsion or lipomicrosphere injection prepared by the related technology may have the possibility of drug precipitation during the storage period. Since the emulsion injection is a non-clear emulsion, it is difficult to be observed once the drug precipitates. Therefore, there are great safety risks in clinical use of drug-loaded emulsion injections that have the risk of drug precipitation.
  • the purpose of this application is to provide a progesterone emulsion injection, especially an emulsion injection for intramuscular injection.
  • an injection with excellent progesterone solubility is obtained. It can greatly reduce the amount of oily solvents and greatly alleviate the adverse reactions caused by oil needle injection.
  • the progesterone injection described in the present application has a high drug encapsulation rate, and the drug does not precipitate after long-term storage.
  • a progesterone emulsion injection comprising progesterone, a grease solvent and water for injection, wherein the grease solvent is a mixture of injection oil and benzyl benzoate
  • the mass ratio of the injection oil to the benzyl benzoate is 1:5 to 5:1.
  • the mass ratio of the injection oil to the benzyl benzoate falls within the range of 1:5 to 5:1, that is, the injection oil and the benzyl benzoate
  • the ratio of the mass ratio can be any value from 0.2 to 5.
  • the mass ratio of the injection oil to the benzyl benzoate is 1:3, 1:2.5, 1:2, 2:1, 2.5:1, 3:1, etc.
  • the mass ratio of the injection oil to the benzyl benzoate is 2:3.
  • the injection oil is at least one selected from the group consisting of vegetable oil for injection and medium-chain fatty acid triglyceride for injection.
  • the injection oil can be a vegetable oil for injection, a medium-chain fatty acid triglyceride for injection, or one (or several) vegetable oils for injection (such as soybean oil for injection) and one (Or several) a mixture of medium-chain fatty acid triglycerides (for example, saturated linear fatty acid triglycerides containing 8 carbon atoms).
  • the vegetable oil for injection is selected from soybean oil for injection, castor oil for injection, corn oil for injection, rapeseed oil for injection, sesame oil for injection, olive oil for injection, peanut oil for injection, and sunflower oil for injection At least one of.
  • the medium-chain fatty acid triglyceride for injection is a saturated linear fatty acid triglyceride containing 6-12 carbon atoms.
  • the mass ratio of the progesterone to the greasy solvent is 5:100-30:100.
  • the mass ratio of the progesterone to the oily solvent falls within the range of 5:100 to 30:100, that is, the mass ratio of the progesterone to the oily solvent is The ratio can be any value from 0.05 to 0.3.
  • the mass ratio of the progesterone to the grease solvent is 10:100, 15:100, 25:100, 30:100, etc.
  • each 100 ml of the progesterone emulsion injection contains 5-40 grams of the oily solvent.
  • the progesterone emulsion injection type injection further comprises an emulsifier, glycerin, and water for injection, wherein the mass ratio of the emulsifier to the oily solvent is 5:100-50:100, and In some embodiments, each 100 ml of the progesterone emulsion injection contains 0.5 to 3 grams of the glycerin.
  • the amount of the water for injection should meet the requirements of the dosage specifications of the progesterone emulsion injection.
  • the dosage specifications of the progesterone emulsion injection may be 5mg/0.5ml, 10mg/0.5ml, 20mg/0.5ml, 5mg/1.0ml, 10mg/1.0ml, 20mg/1.0ml, 50mg /1.0ml, 50mg/2.0ml.
  • the emulsifier is selected from soybean lecithin for injection, egg yolk lecithin for injection, polysorbate 80, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer At least one of 188.
  • the emulsifier is soybean lecithin for injection, egg yolk lecithin for injection, polysorbate 80, polyoxyethylene castor oil, or polyethylene glycol 15-hydroxystearate. That is, in these examples, the emulsifier is a single-component emulsifier, which is soybean lecithin for injection, egg yolk lecithin for injection, polysorbate 80, polyoxyethylene castor oil, and polyethylene glycol 15 -One of hydroxystearate.
  • the mass ratio of the soybean lecithin for injection or egg yolk lecithin for injection to the oily solvent is 5:100-30: 100;
  • the mass ratio of the polysorbate 80 to the oily solvent is 5:100 to 30:100;
  • the mass ratio of the polyoxyethylene castor oil to the greasy solvent is 10:100-40:100;
  • the mass ratio of the polyethylene glycol 15-hydroxystearate to the grease solvent is 10:100-50: 100.
  • the mass ratio of the soybean lecithin for injection or egg yolk lecithin for injection to the oily solvent is 5:100. Any value in the range of ⁇ 30:100, such as but not limited to 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 11:100, 12:100, 13:100, 14:100, 15:100, 16:100, 17:100, 18:100, 19:100, 20:100, 21:100, 22:100, 23:100, 24:100, 25:100, 26: 100, 27:100, 28:100, 29:100, 30:100.
  • the emulsifier is one of soybean lecithin for injection and egg yolk lecithin for injection with polysorbate 80, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate and po At least one of Loxamer 188 is a mixed emulsifier. That is, in these examples, the emulsifier is a multi-component emulsifier, one of which is soybean lecithin for injection and egg yolk lecithin for injection, and the other is polysorbate. 80. One or more of polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate and poloxamer 188.
  • the emulsifier may be any one of the following mixtures: a mixture of soybean lecithin for injection and polysorbate 80, a mixture of soybean lecithin for injection and polyoxyethylene castor oil, a mixture of soybean lecithin for injection and polysorbate 80 Mixture of ethylene glycol 15-hydroxystearate, mixture of egg yolk lecithin for injection and polysorbate 80, mixture of egg yolk lecithin for injection and polyoxyethylene castor oil, egg yolk lecithin for injection and polyethylene glycol A mixture of 15-hydroxystearate, a mixture of soybean lecithin for injection, polysorbate 80 and polyoxyethylene castor oil, a mixture of soybean lecithin for injection, polysorbate 80, and polyethylene glycol 15-hydroxystearic acid Mixtures of esters, etc.
  • the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection and the mixed emulsifier is 1:2-10:11. That is to say, in the above mixed emulsifier, the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection to other types of emulsifiers is 1:1-10:1, so that the injection The mass ratio of soybean lecithin or the egg yolk lecithin for injection and the mixed emulsifier satisfies 1:2-10:11.
  • the mass ratio of the mixed emulsifier to the grease solvent is 5:100-20:100.
  • the progesterone emulsion injection further contains at least one of a stabilizer, a bacteriostatic agent, an analgesic, and a pH adjuster. Those skilled in the art can specifically choose to add one or more of these adjuvants according to actual needs.
  • the stabilizer may be at least one of oleic acid and sodium oleate;
  • the bacteriostatic agent may be benzyl alcohol, hydroxypropyl butyl ester (methyl), phenol, chlorobutanol and thimerosal
  • the analgesic may be at least one of benzyl alcohol, chlorobutanol, lidocaine or procaine hydrochloride;
  • the pH adjusting agent may be hydrochloric acid, sodium hydroxide, citric acid At least one of citric acid and sodium citrate.
  • the progesterone emulsion injection further includes an alcohol solvent
  • the mass percentage of the alcohol solvent is 0.5% to 5.0% based on the mass percentage of the progesterone emulsion injection.
  • the mass percentage of the alcohol solvent can be any value in the range of 0.5% to 5.0%, such as but not limited to 0.55%, 1.0 %, 1.5%, 2.0%, 2.55%, 2.60%, 2.65%, 2.70%, 2.75%, 2.80%, 2.85%, 2.90%, 2.95%, 3.00%, 3.05%, 3.10%, 3.15%, 3.20%, 3.25%, 3.30%, 3.35%, 3.40%, 3.45%, 3.50%, 3.55%, 3.60%, 3.65%, 3.70%, 3.75%, 3.80%, 3.85%, 3.90%, 3.95%, 4.00%, 4.05% , 4.10%, 4.15%, 4.20%, 4.25%
  • the alcohol solvent is ethanol, 1,2-propanediol, 1,3-butanediol or pivalol. Especially preferably, the alcohol solvent is 1,2-propanediol or 1,3-butanediol. Especially preferably, the alcohol solvent is 1,2-propanediol.
  • the progesterone emulsion injections described in this application can be applied to intramuscular injection, subcutaneous injection or intravenous injection.
  • the progesterone emulsion injection can be obtained by conventional preparation methods.
  • a preparation method of the progesterone emulsion injection includes: mixing the oil phase and the water phase in the formula uniformly under heating to obtain a mixed oil phase And the step of mixing the water phase; the step of mixing the mixed oil phase and the mixed water phase after high-speed shear emulsification and high-pressure homogenization to obtain an emulsion with an average particle size and particle size distribution that meets the requirements; using the emulsion 0.45 ⁇ m microporous membrane filtration steps; and, the steps of packaging, fusion sealing and sterilization.
  • an emulsifier and other water-soluble agents in the formula are added to the heated water for injection to dissolve completely to obtain the mixed water phase.
  • the mixed oil phase and the mixed water phase are first mixed under high-speed stirring, and high-speed shear emulsification under protective gas to obtain the primary emulsion; After meeting the dosage form requirements of the dosage specification, perform high-pressure homogenization under protective gas until the emulsion meets the requirements.
  • sterilization is performed by the steam sterilization method or the autoclaving method.
  • the progesterone emulsion injection meets at least one of the following indicators: (i) the average particle size is 100-250 nm, (ii) the polydispersity index is less than 0.20, and (iii) the zeta potential range is ⁇ 20mV ⁇ -40mV.
  • the verification shows that after the progesterone emulsion injection described in the present application is filtered through a 0.45 ⁇ m microporous filter membrane, the progesterone content falls within the range of 95-105% of the labeled amount, and the progesterone encapsulation rate is greater than 90%.
  • the progesterone emulsion injection of the present application has the following advantages:
  • 1A and 1C are fluorescence imaging diagrams of the progesterone emulsion-type injection of the present application containing the fluorescent dye in the verification example 2 after 30 minutes and 12 hours of intramuscular injection;
  • Figures 1B and 1D are fluorescence imaging images of the commercially available progesterone injection containing fluorescent dyes in the verification example 2 after 30 minutes and 12 hours of intramuscular injection.
  • the grease solvent in the progesterone emulsion injection of the present application is provided.
  • the grease solvent is a mixture of injection oil and benzyl benzoate, and the mass ratio of the injection oil to the benzyl benzoate is 1:5 to 5:1.
  • the mass ratio of the injection oil to the benzyl benzoate falls within the range of 1:5 to 5:1, that is, the injection oil and the benzyl benzoate
  • the ratio of the mass ratio can be any value from 0.2 to 5.
  • the mass ratio of the injection oil to the benzyl benzoate is 1:3, 1:2.5, 1:2, 2:1, 2.5:1, 3:1, etc.
  • the injection oil is selected from at least one of vegetable oil for injection and medium-chain fatty acid triglyceride for injection.
  • the injection oil can be a vegetable oil for injection, a medium-chain fatty acid triglyceride for injection, or one (or several) vegetable oils for injection (such as soybean oil for injection) and one (Or several) a mixture of medium-chain fatty acid triglycerides (for example, saturated linear fatty acid triglycerides containing 8 carbon atoms).
  • the vegetable oil for injection is selected from at least one of soybean oil for injection, castor oil for injection, corn oil for injection, rapeseed oil for injection, sesame oil for injection, olive oil for injection, peanut oil for injection, and sunflower oil for injection.
  • the medium-chain fatty acid triglyceride for injection is a saturated straight-chain fatty acid triglyceride containing 6-12 carbon atoms.
  • Grease solvent 1 Contains soybean oil for injection and benzyl benzoate, and the mass ratio of soybean oil for injection to benzyl benzoate is 2:3;
  • Grease solvent 2 contains olive oil for injection and benzyl benzoate, the mass ratio of olive oil for injection to benzyl benzoate is 2:3;
  • Grease solvent 3 Containing castor oil for injection and benzyl benzoate, the mass ratio of castor oil for injection to benzyl benzoate is 2:3;
  • Grease solvent 4 contains peanut oil for injection and benzyl benzoate, the mass ratio of peanut oil for injection to benzyl benzoate is 2:3;
  • Grease solvent 5 contains medium-chain fatty acid triglyceride for injection and benzyl benzoate, and the mass ratio of medium-chain fatty acid triglyceride for injection and benzyl benzoate is 2:3;
  • Grease solvent 6 Contains medium-chain fatty acid triglyceride for injection, soybean oil for injection and benzyl benzoate.
  • the mass ratio of medium-chain fatty acid triglyceride for injection to soybean oil for injection is 1:1, and, The mass ratio of the sum of the mass of medium-chain fatty acid triglyceride for injection and soybean oil for injection to the mass of benzyl benzoate is 2:3.
  • Grease solvent comparative example 1 Soybean oil for injection
  • Grease solvent comparative example 2 Contains olive oil for injection
  • Grease solvent comparative example 3 Castor oil for injection and benzyl benzoate
  • Grease solvent comparative example 4 Peanut oil for injection
  • Grease-based solvent comparative example 5 Medium-chain fatty acid triglycerides for injection
  • Grease-based solvent comparative example 6 Contains medium-chain fatty acid triglyceride for injection and soybean oil for injection, wherein the mass ratio of medium-chain fatty acid triglyceride for injection to soybean oil for injection is 1:1.
  • progesterone emulsion injections 1 to 3 5 mg: 1 ml, 10 mg: 1 ml, and 20 mg: 1 ml of progesterone emulsion injections 1 to 3 are provided.
  • the oily solvent contained in the progesterone emulsion injection contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of medium-chain fatty acid triglyceride to benzyl benzoate is 2:3.
  • the progesterone emulsion injection also contains egg yolk lecithin for injection and glycerin as emulsifiers; wherein the mass ratio of the egg yolk lecithin for injection to the oily solvent is 12:100, per 100 ml of the corpus luteum
  • the ketone injection contains 2.5 grams of the glycerin.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 1 Specification 5mg:1ml, the formula includes: 5g progesterone, 60g benzyl benzoate, 40g medium-chain fatty acid triglyceride, 12g egg yolk lecithin, 25g glycerol, water for injection to 1000ml.
  • Progesterone Emulsion Injection 2 Specification 10mg:1ml, the formula includes: 10g progesterone, 60g benzyl benzoate, 40g medium-chain fatty acid triglyceride, 12g egg yolk lecithin, 25g glycerol, water for injection to 1000ml.
  • Progesterone Emulsion Injection 3 Specification 20mg: 1ml, the formula includes: 20g progesterone, 60g benzyl benzoate, 40g medium-chain fatty acid triglyceride, 12g egg yolk lecithin, 25g glycerol, water for injection to 1000ml.
  • the preparation method of the above-mentioned progesterone emulsion injection is as follows, the specific formula of each injection is different, but the preparation method steps are the same.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injections 1 to 3 of this example is milky white, the pH is 6.5, the average particle size of the emulsion is 182nm, the PDI is 0.15, and the zeta potential is -22.6mV , The drug content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation rate is greater than 90%.
  • a progesterone emulsion injection 4 of 50 mg: 1 ml is provided.
  • the oily solvent contained in the progesterone emulsion injection 4 contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of medium-chain fatty acid triglyceride to benzyl benzoate is 2:3.
  • the progesterone emulsion injection also contains egg yolk lecithin for injection as an emulsifier, sodium oleate as a stabilizer, and glycerin; wherein the mass ratio of the egg yolk lecithin for injection to the oily solvent is 12.5 : 100, each 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerin.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 4 Specification 50mg:1ml, the formula includes: 50g progesterone, 120g benzyl benzoate, 80g medium chain fatty acid triglyceride, 25g egg yolk lecithin, 0.3g sodium oleate, 25g glycerin, water for injection plus To 1000ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 4 of this embodiment is milky white, the pH value is 6.6, the average particle size of the milk droplets (Zeta average) is 195 nm, the PDI is 0.16, and the Zeta potential is -32.2 mV.
  • the content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • the oily solvent contained in the progesterone emulsion injection 5 contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of medium-chain fatty acid triglyceride to benzyl benzoate is 5:4.
  • the progesterone emulsion injection also contains polysorbate 80 (also known as Tween 80) as an emulsifier, and glycerin; wherein the mass ratio of the polysorbate 80 to the oily solvent is 23.1:100
  • Each 100 ml of the progesterone emulsion injection contains 2.0 g of the glycerin.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 5 Specification 10mg: 1ml, the formula includes: 10g of progesterone, 48g of benzyl benzoate, 60g of medium-chain fatty acid triglyceride, 25g of polysorbate 80, 20g of glycerol, and water for injection to 1000ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 5 of this embodiment is milky white, the pH value is 6.5, the average particle size of the milk droplets (Zeta average) is 163 nm, the PDI is 0.08, and the Zeta potential is -24.4 mV.
  • the content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • a progesterone emulsion injection 6 of 50 mg: 1 ml is provided.
  • the oily solvent contained in the progesterone emulsion injection 6 includes castor oil for injection and benzyl benzoate, wherein the mass ratio of castor oil for injection to benzyl benzoate is 1:3.
  • the progesterone emulsion injection also contains a mixture of soy lecithin for injection and poloxamer 188 as an emulsifier, oleic acid as a stabilizer, and glycerin; wherein the emulsifier and the oily solvent are The mass ratio is 12:100, and every 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerin. And, in the emulsifier, the mass ratio of soy lecithin for injection to poloxamer 188 is 5:1.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 6 Specification 50mg: 1ml, the formula includes: 50g of progesterone, 150g of benzyl benzoate, 50g of castor oil for injection, 20g of soy lecithin for injection, 4g of poloxamer 188, 0.5g of oleic acid , Glycerin 25g, water for injection is added to 1000ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 6 of this example is milky white, the pH value is 6.5, the average particle size of the milk droplets (Zeta average) is 171nm, the PDI is 0.08, the Zeta potential is -28.7mV, and the drug The content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • the oily solvent contained in the progesterone emulsion injection 7 includes soybean oil for injection and benzyl benzoate, wherein the mass ratio of soybean oil for injection to benzyl benzoate is 2:3.
  • the progesterone emulsion injection also contains a mixture of soybean lecithin for injection and polyoxyethylene 35 castor oil as an emulsifier, and glycerin; wherein the mass ratio of the emulsifier to the oily solvent is 12:100
  • Each 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerin.
  • the mass ratio of soybean lecithin for injection to polyoxyethylene 35 castor oil is 5:1.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 7 Specification 10mg: 0.5ml, the formula includes: 20g progesterone, 60g benzyl benzoate, 40g soybean oil for injection, 10g soybean lecithin for injection, 2g polyoxyethylene 35 castor oil, 25g glycerol, Add water for injection to 1000ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 7 of this example is milky white, the pH value is 6.6, the Zeta average particle size is 160 nm, the PDI is 0.10, the Zeta potential is -23.2 mV, and the drug The content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • a progesterone emulsion injection 8 of 50 mg: 2 ml is provided.
  • the oily solvent contained in the progesterone emulsion injection 8 includes medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of medium-chain fatty acid triglyceride to benzyl benzoate is 3:7.
  • the progesterone emulsion injection also contains a mixture of egg yolk lecithin for injection and poloxamer 188 as an emulsifier, benzyl alcohol as a bacteriostatic agent, and glycerin; wherein, the emulsifier and the oily solvent
  • the mass ratio is 12:100, and every 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerin.
  • the mass ratio of egg yolk lecithin for injection to poloxamer 188 is 5:1.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 8 Specifications 20mg: 2ml, the formula includes: progesterone 25g, benzyl benzoate 70g, medium chain fatty acid triglyceride 30g, egg yolk lecithin for injection 10g, poloxamer 188 2g, benzyl alcohol 10g , Glycerin 25g, water for injection is added to 1000ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 8 of this example is milky white, the pH value is 6.8, the average particle size of the milk droplets (Zeta average) is 168nm, the PDI is 0.09, the Zeta potential is -24.4mV, and the drug The content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • the oily solvent contained in the progesterone emulsion injection 9 includes castor oil for injection and benzyl benzoate, wherein the mass ratio of castor oil for injection to benzyl benzoate is 1:1.5.
  • the progesterone emulsion injection also contains egg yolk lecithin for injection (for example, egg yolk lecithin PL-100M), glycerin, and 1,2-propylene glycol as an emulsifier.
  • the mass ratio of the emulsifier to the oily solvent is 12:100, each 100 ml of the progesterone emulsion injection contains 2.5 grams of the glycerin, and every 100 ml of the progesterone emulsion injection contains 1,2- Propylene glycol 1.28g.
  • the specific formulation of the progesterone emulsion injection in this embodiment is as follows.
  • Progesterone Emulsion Injection 9 Specification 20mg:1ml, formula includes: 10g progesterone, 45g benzyl benzoate, 30g castor oil for injection, 9g egg yolk lecithin for injection, 6.40g 1,2 propylene glycol, 12.5g glycerin, injection Add water to 500ml.
  • the preparation method includes the following steps:
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection 9 of this example is milky white, the pH value is 6.0, the average particle size of the milk droplets (Zeta average) is 181nm, the PDI is 0.12, and the Zeta potential is -28.7mV.
  • the content falls within the range of 95%-105% of the labeled amount, and the drug encapsulation efficiency is greater than 90%.
  • progesterone emulsion injection without benzyl benzoate the specification is 20mg:1ml.
  • the specific formula is: 20 g of progesterone, 50 g of soybean oil for injection, 50 g of medium-chain fatty acid triglycerides, 12 g of egg yolk lecithin for injection, 25 g of glycerin, and water for injection to 1000 ml.
  • the preparation method of the progesterone is the same as in Example 2, and will not be repeated here.
  • the prepared progesterone emulsion injection was used to measure the average particle size of the emulsion droplets (Zeta average), polydispersity index PDI and Zeta potential with a laser particle size analyzer. Take another injection and filter it with a 0.45 ⁇ m microporous membrane. Take the additional filtrate and dilute it with absolute ethanol so that the labeled concentration of progesterone in the diluent is about 100 ⁇ g/ml, according to the HPLC under the 2015 Chinese Pharmacopoeia Progesterone Method to analyze and calculate the content of the drug in the injection. Separately, the injection was centrifuged in a 100nm sieve filter, and the additional filtrate was taken and diluted with ethanol for one time. The concentration was determined by HPLC to calculate the encapsulation efficiency of progesterone in the emulsion.
  • the verification shows that the appearance of the progesterone emulsion injection of this comparative example 1 is milky white, the pH value is 6.5, the average particle size of the milk droplets (Zeta average) is 178nm, the PDI is 0.14, and the Zeta potential is -25.0mV. The content falls within 88.7% of the labeled amount, and the drug encapsulation rate is greater than 90%.
  • Verification Example 1 The dissolved progesterone content in progesterone injection after placement
  • Example 2 Example 3
  • Example 4 Amount of progesterone in dissolved state (indicated %) 75.2% 98.8% 98.0% 98.6%
  • Verification example 2 Progesterone emulsion injection spread at the injection site after intramuscular injection
  • the diffusion of the progesterone emulsion injection in this application at the injection site after intramuscular injection is verified. Specifically, in this verification example, the progesterone emulsion injection described in Example 5 was taken, and the oil-soluble fluorescent dye IR780 was added, and the IR780 was fully sonicated to dissolve the IR780.
  • Figure 1A is a fluorescence imaging image 30 minutes after the injection of the progesterone emulsion injection described in this application
  • Figure 1B is a fluorescence imaging image 30 minutes after the injection of a commercially available progesterone injection
  • Figure 1C is the progesterone injection described in this application The fluorescence imaging image after 12 hours of emulsion injection
  • Figure 1D is the fluorescence imaging image after 12 hours of injection of commercially available progesterone injection.
  • Verification Example 3 Test of local induration and fat deposition caused by the progesterone emulsion injection of the present application after intramuscular injection
  • the progesterone emulsion injection described in this application causes local induration and fat accumulation after intramuscular injection.
  • the progesterone emulsion injection described in Example 5 was taken as the experimental group, and the commercially available progesterone injection was taken as the control group.
  • Experimental animal female New Zealand rabbit, weighing 2.5 ⁇ 3.0kg.
  • mice New Zealand rabbits were randomly divided into 2 groups, 3 rabbits in each group.
  • the progesterone emulsion injection in Example 5 was used as the test group, and the commercially available progesterone injection was used as the control group.
  • the rabbits were injected with 1 ml intramuscularly on the hind leg for 10 consecutive days to check the induration of the injection site.
  • the animals were sacrificed 24 hours after the last injection, and the skin at the injection site was cut to observe the deposition of fat.
  • the injection site of the control group could feel obvious induration when touched by hand, while the test group could not feel the induration at the injection site.
  • the skin at the injection site was cut and observed.
  • the control group had visible fat deposits around the injection site, while the test group had no fat deposits.

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Abstract

一种黄体酮乳剂型注射剂，包含黄体酮、油脂性溶剂与注射用水，其中，所述油脂性溶剂为注射用油和苯甲酸苄酯的混合物，并且，所述注射用油与所述苯甲酸苄酯的质量比为1:5～5:1。本申请所述的黄体酮乳剂型注射剂中，黄体酮溶解性极好，可大大减少油脂性溶剂的用量，极大缓解油针注射引发的不良反应。同时，本申请所述的黄体酮乳剂型注射剂的药物包封率高，长期放置后药物不析出。

Description

一种黄体酮乳剂型注射剂及其制备方法
交叉引用
本申请要求于2020年03月10日提交中国专利局、申请号为202010163625.5、发明名称为“一种黄体酮乳剂型注射剂及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及制药领域，特别涉及一种黄体酮乳剂型注射剂。
背景技术
黄体酮(Progesterone，又称孕酮、黄体素)是卵巢黄体分泌的天然孕激素，化学名为孕留-4-烯-3，20-二酮，分子式为C 21H 30O 2，分子量314.47，CAS号为57-83-0。黄体酮为白色或类白色的结晶性粉末，无臭，无味；在三氯甲烷中极易溶解，在乙醇、乙醚或植物油中溶解，在水中不溶。
黄体酮的药理作用主要为：(1)月经周期后期促使子宫内膜分泌，内膜增厚，以利受精卵着床，并降低子宫肌肉兴奋度，保证妊娠的安全进行；(2)与雌激素共同作用，促进乳腺腺泡的生长，为产乳作准备；(3)抑制垂体前叶促黄体生成激素的释放，使卵泡不能发育成熟，抑制排卵。黄体酮在临床上可用于月经失调、闭经、先兆流产和习惯性流产、功能失调性子宫出血、黄体功能不足、经前期综合征及围绝经期的激素替代治疗等。
目前市售黄体酮单方制剂及规格有：注射剂(5、10、20mg/1mL，50mg/2mL)、胶囊(100mg)、软胶囊(50、100、200mg)、阴道栓剂(25mg)和阴道缓释凝胶(8％/90mg)。这些上市制剂涉及的给药途径有：肌肉注射、口服和阴道粘膜给药。黄体酮肌肉注射液的疗效确切，价格低廉，是人类辅助生殖技术黄体支持的传统用药。黄体酮口服给药存在严重的肝首过效应，生物利用度低(<10％)，不推荐用于辅助生殖技术中。阴道给药与肌肉注射的药效相同，子宫局部药物浓度高，全身的不良反应较少，但黄体期阴道出血的发生率高，且价格昂贵。由此可见，从药效和经济性的角度来看，肌肉注射仍是黄体酮较理想的给药途径。
然而，现有的黄体酮肌肉注射液也存在着一些缺陷，如：(1)注射部位疼痛和刺激，易形成局部硬结，偶发局部无菌脓肿，形成的局部硬结、无菌脓肿的吸收消退需较长时间；(2)注射液粘度较大，在使用注射器吸取及注射时有一定的阻力，易回渗；(3)需在医院注射，患者顺应性较差。黄体酮肌肉注射液的缺陷与产品配方有很大关系。黄体酮为脂溶性物质，现有注射剂是以大豆油为溶剂配成的油溶液型注射液(俗称油针)，故使用时常出现 前面提及的诸如注射疼痛、形成硬结、注射不便等问题。
为克服黄体酮现有肌肉注射液的不足，研究者进行了多种尝试。已公开的期刊论文和专利中涉及黄体酮注射剂的新品种或新技术包括：亚微乳注射剂(CN101152186B)、脂微球注射液(CN106074383A)、环糊精(或羟丙基环糊精)包合物的水溶液型注射液(CN109381424A、CN106727288A、CN1517091、CN104857522A)、混悬型注射液(CN107198677A、CN107441039A)、纳米晶注射剂(CN109223722A)、聚合物纳米粒或微球注射剂(CN107441061A、CN107157956A)。其中，纳米粒或微球注射剂的处方和工艺复杂，生产难度大；纳米晶或混悬型注射液中由于黄体酮的水溶性过低，可能导致药物无法从注射部位有效释放，且不溶性药物长期堆积可能引发不良反应；环糊精包合物中用到的环糊精或羟丙基环糊精有一定的肾毒性，并可能致癌，使用宜慎重。相对而言，微乳或脂微球这类的乳剂型注射液可能是一种比较理想的替代制剂。
技术问题
黄体酮虽为脂溶性药物，但其在乳剂型注射液常用的油脂性溶剂(如注射用植物油、中链脂肪酸甘油三酯等)中的溶解度并不大。目前已经公开的两个黄体酮乳剂型注射液的相关专利(CN101152186B、CN106074383A)均未考虑到这个问题，采用的油脂性溶剂及其用量可能均不足以保证临床用量的黄体酮能够长期溶解在这些油脂性溶剂中，而黄体酮在水中的溶解度又极低(约20μg/ml)，故采用相关技术制备的黄体酮亚微乳或脂微球注射液在贮存期存在药物析出的可能性。由于乳剂型注射液是非澄明的乳浊液，药物一旦析出难以被观察到，故在临床使用有药物析出风险的载药乳剂型注射剂存在很大的安全隐患。
因此，有必要提出一种新的黄体酮乳剂型注射剂，以解决上述技术问题。
技术解决方案
本申请的目的在于提供一种黄体酮乳剂型注射剂，尤其是一种供肌肉注射用的乳剂型注射剂，通过所述油脂性溶剂的具体选择，获得了一种黄体酮溶解性极好的注射剂，可大大减少油脂性溶剂的用量，极大缓解油针注射引发的不良反应。同时，本申请所述的黄体酮注射剂的药物包封率高，长期放置后药物不析出。
为了达到上述目的，根据本申请的一方面，提供一种黄体酮乳剂型注射剂，包含黄体酮、油脂性溶剂与注射用水，其中，所述油脂性溶剂为注射用油和苯甲酸苄酯的混合物，并且，所述注射用油与所述苯甲酸苄酯的质量比为1:5～5:1。本领域技术人员可以理解的是，所述注射用油与所述苯甲酸苄酯的质量比落入1:5～5:1的范围，即，所述注射用油与所述苯甲酸苄酯的质量比的比值可以是0.2至5中的任意一个数值。例如，所述注射用油与所述苯甲酸苄酯的质量比为1:3，1:2.5，1:2，2:1，2.5:1，3:1等。
在一较优实施例中，所述注射用油与所述苯甲酸苄酯的质量比为2:3。
在一些实施例中，所述注射用油选自注射用植物油和注射用中链脂肪酸甘油三酯中的至少一种。也就是说，所述注射用油可以是注射用植物油，也可以是注射用中链脂肪酸甘油三酯，也可以是一种(或几种)注射用植物油(例如注射用大豆油)与一种(或几种)中链脂肪酸甘油三酯(例如含有8个碳原子的饱和直链脂肪酸甘油三脂)的混合。
在一些实施例中，所述注射用植物油选自注射用大豆油、注射用蓖麻油、注射用玉米油、注射用菜油、注射用芝麻油、注射用橄榄油、注射用花生油和注射用葵花子油中的至少一种。
在一些实施例中，所述注射用中链脂肪酸甘油三酯为含6～12个碳原子的饱和直链脂肪酸甘油三酯。
在一些实施例中，所述黄体酮与所述油脂性溶剂的质量比为5:100～30:100。本领域技术人员可以理解的是，所述黄体酮与所述油脂性溶剂的质量比落入5:100～30:100的范围，即，所述黄体酮与所述油脂性溶剂的质量比的比值可以是0.05至0.3中的任意一个数值。例如，所述黄体酮与所述油脂性溶剂的质量比为10:100，15:100，25:100，30:100等。
在一些实施例中，每100毫升所述黄体酮乳剂型注射剂含有5～40克所述油脂性溶剂。
在一些实施例中，所述黄体酮注乳剂型射液还包含乳化剂、甘油及注射用水，其中，所述乳化剂与所述油脂性溶剂的质量比为5:100～50:100，并且，在一些实施例中，每100毫升所述黄体酮乳剂型注射剂含有0.5～3克所述甘油。
本领域技术人员可以理解的是，除了上述油脂性溶剂、所述乳化剂及所述甘油的特定比例要求外，所述注射用水的用量应当满足所述黄体酮乳剂型注射剂的剂量规格的要求。例如，在本申请中，所述黄体酮乳剂型注射剂的剂量规格可以是5mg/0.5ml，10mg/0.5ml，20mg/0.5ml，5mg/1.0ml，10mg/1.0ml，20mg/1.0ml，50mg/1.0ml，50mg/2.0ml。所述黄体酮乳剂型注射剂中各组分的用量满足上述记载的各要求后，所述注射用水的用量满足剂量规格的要求。
在一些实施例中，所述乳化剂选自注射用大豆卵磷脂、注射用蛋黄卵磷脂、聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇15-羟基硬脂酸酯和泊洛沙姆188中的至少一种。
在一些实施例中，所述乳化剂为注射用大豆卵磷脂、注射用蛋黄卵磷脂、聚山梨酯80、聚氧乙烯蓖麻油或聚乙二醇15-羟基硬脂酸酯。也就是说，在这些实施例中，所述乳化剂为单一组份乳化剂，为注射用大豆卵磷脂、注射用蛋黄卵磷脂、聚山梨酯80、聚氧乙烯蓖麻油和聚乙二醇15-羟基硬脂酸酯中的一种。
当所述乳化剂为所述注射用大豆卵磷脂或注射用蛋黄卵磷脂时，所述注射用大豆卵磷脂或注射用蛋黄卵磷脂与所述油脂性溶剂的质量比为5:100～30:100；
当所述乳化剂为所述聚山梨酯80时，所述聚山梨酯80与所述油脂性溶剂的质量比为5:100～30:100；
当所述乳化剂为所述聚氧乙烯蓖麻油时，所述聚氧乙烯蓖麻油与所述油脂性溶剂的质量比为10:100～40:100；
当所述乳化剂为所述聚乙二醇15-羟基硬脂酸酯时，所述聚乙二醇15-羟基硬脂酸酯与所述油脂性溶剂的质量比为10:100～50:100。
优选地，当所述乳化剂为所述注射用大豆卵磷脂或注射用蛋黄卵磷脂时，所述注射用大豆卵磷脂或注射用蛋黄卵磷脂与所述油脂性溶剂的质量比为5:100～30:100范围内的任意数值，例如但不限于5:100、6:100、7:100、8:100、9:100、10:100、11:100、12:100、13:100、14:100、15:100、16:100、17:100、18:100、19:100、20:100、21:100、22:100、23:100、24:100、25:100、26:100、27:100、28:100、29:100、30:100。
在一些实施例中，所述乳化剂为注射用大豆卵磷脂和注射用蛋黄卵磷脂中的一者与聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇15-羟基硬脂酸酯和泊洛沙姆188中的至少一种而形成的混合乳化剂。也就是说，在这些实施例中，所述乳化剂为多组份乳化剂，其中一个组份为注射用大豆卵磷脂和注射用蛋黄卵磷脂中的一种，另一组份为聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇15-羟基硬脂酸酯和泊洛沙姆188中的一种或几种。例如，所述乳化剂可以是以下混合物中的任意一种：注射用大豆卵磷脂与聚山梨酯80的混合物，注射用大豆卵磷脂与聚氧乙烯蓖麻油的混合物，注射用大豆卵磷脂与聚乙二醇15-羟基硬脂酸酯的混合物，注射用蛋黄卵磷脂与聚山梨酯80的混合物，注射用蛋黄卵磷脂与聚氧乙烯蓖麻油的混合物，注射用蛋黄卵磷脂与聚乙二醇15-羟基硬脂酸酯的混合物，注射用大豆卵磷脂与聚山梨酯80及聚氧乙烯蓖麻油的混合物，注射用大豆卵磷脂与聚山梨酯80及聚乙二醇15-羟基硬脂酸酯的混合物等。
在上述实施例中，所述注射用大豆卵磷脂或所述注射用蛋黄卵磷脂与所述混合乳化剂的质量比为1:2～10:11。也就是说，在上述混合乳化剂中，所述注射用大豆卵磷脂或所述注射用蛋黄卵磷脂与其他种类的乳化剂的质量比为1:1～10:1，以使得所述注射用大豆卵磷脂或所述注射用蛋黄卵磷脂与所述混合乳化剂的质量比满足1:2～10:11。
在上述实施例中，所述混合乳化剂与所述油脂性溶剂的质量比为5:100～20:100。
在一些实施例中，所述黄体酮乳剂型注射剂还包含稳定剂、抑菌剂、止痛剂和pH调节剂中的至少一种。本领域技术人员可以根据实际需要而具体选择添加该些辅剂中的一种或 几种。
在上述实施例中，所述稳定剂可以是油酸和油酸钠中的至少一种；所述抑菌剂可以是苯甲醇、羟丙丁酯(甲酯)、苯酚、三氯叔丁醇和硫柳汞中的至少一种；所述止痛剂可以是苯甲醇、三氯叔丁醇、利多卡因或盐酸普鲁卡因中的至少一种；所述pH调节剂可以是盐酸、氢氧化钠，枸橼酸和枸橼酸钠中的至少一种。
在一些实施例中，所述黄体酮乳剂型注射剂还包括醇溶剂，以所述黄体酮乳剂型注射剂的质量百分比计，所述醇溶剂的质量百分比为0.5％～5.0％。本领域技术人员可以理解的是，以所述黄体酮乳剂型注射剂的质量百分比计，所述醇溶剂的质量百分比可以是0.5％～5.0％范围内的任意数值，例如但不限于0.55％、1.0％、1.5％、2.0％、2.55％、2.60％、2.65％、2.70％、2.75％、2.80％、2.85％、2.90％、2.95％、3.00％、3.05％、3.10％、3.15％、3.20％、3.25％、3.30％、3.35％、3.40％、3.45％、3.50％、3.55％、3.60％、3.65％、3.70％、3.75％、3.80％、3.85％、3.90％、3.95％、4.00％、4.05％、4.10％、4.15％、4.20％、4.25％、4.30％、4.35％、4.40％、4.45％、4.50％、4.55％、4.60％、4.65％、4.70％、4.75％、4.80％、4.85％、4.90％、4.95％、5.00％。
优选地，所述醇溶剂为乙醇、1,2-丙二醇、1,3-丁二醇或特戊醇。尤其优选地，所述醇溶剂为1,2-丙二醇或1,3-丁二醇。尤其优选地，所述醇溶剂为1,2-丙二醇。
在一些实施例中，本申请所述黄体酮乳剂型注射剂可以应用于肌肉注射、皮下注射或静脉注射。
在本申请中，所述黄体酮乳剂型注射剂可以以常规制备方法获得。
当然，根据本申请的另一方面，还提供所述黄体酮乳剂型注射剂的制备方法，所述制备方法包括：将配方中的油相和水相分别在加热状态下混合均匀以获得混合油相和混合水相的步骤；将所述混合油相与混合水相混合后经高速剪切乳化及高压均质，以获得平均粒径及粒径分布符合要求的乳剂的步骤；将所述乳剂用0.45μm微孔滤膜滤过滤的步骤；以及，分装、熔封并灭菌的步骤。
在上述制备方法中，在获得所述混合油相的步骤中，将苯甲酸苄酯与注射用油按比例混合后，加热状态下加入黄体酮及配方中的其他油相，溶解完全以获得混合油相。
在上述制备方法中，在获得所述混合水相的步骤中，向加热的注射用水加入乳化剂及配方中的其他水溶性试剂，溶解完全以获得混合水相。
在上述制备方法中，在获得乳剂的步骤中，首先在高速搅拌下将所述混合油相与混合水相混合，在保护气体下高速剪切乳化以获得初级乳剂；然后，在加注射用水至符合剂量规格的剂型要求后，在保护气体下进行高压均质，直至乳剂符合要求。
在上述制备方法中，以流通蒸汽灭菌法或热压灭菌法进行灭菌。
在上述制备方法中，所述黄体酮乳剂型注射剂满足以下指标中的至少一项：(i)平均粒径为100～250nm，(ii)多分散指数小于0.20，(iii)Zeta电位范围为-20mV～-40mV。
经验证表明，本申请所述黄体酮乳剂型注射剂经过0.45μm微孔滤膜滤过后，黄体酮含量落在标示量的95～105％范围内，黄体酮包封率大于90％。
有益效果
与现有的黄体酮注射剂相比，本申请的所述黄体酮乳剂型注射剂具有以下优点：
(1)本申请所述黄体酮乳剂型注射剂中，通过苯甲酸苄酯的引入，使得油脂性溶剂对黄体酮有很好的溶解性，可大大减少油脂性溶剂的用量，极大缓解油针注射引发的不良反应；
(2)经验证表明，本申请所述黄体酮乳剂型注射剂的药物包封率高，长期放置后药物不析出；
(3)本申请所述黄体酮乳剂型注射剂同时还符合中国药典制剂通则注射剂项下的各项规定。
附图说明
图1A和图1C为验证例2中含荧光染料的本申请所述黄体酮乳剂型注射剂肌肉注射30分钟和12小时后的荧光成像图；
图1B和图1D为验证例2中含荧光染料的市售黄体酮注射剂肌肉注射30分钟和12小时后的荧光成像图。
本发明的实施方式
以下，结合具体实施方式，对本申请的技术进行详细描述。应当知道的是，以下具体实施方式仅用于帮助本领域技术人员理解本申请，而非对本申请的限制。
实施例1.油脂性溶剂
在本实施例中，提供本申请所述黄体酮乳剂型注射剂中的所述油脂性溶剂。
所述油脂性溶剂为注射用油和苯甲酸苄酯的混合物，并且，所述注射用油与所述苯甲酸苄酯的质量比为1:5～5:1。本领域技术人员可以理解的是，所述注射用油与所述苯甲酸苄酯的质量比落入1:5～5:1的范围，即，所述注射用油与所述苯甲酸苄酯的质量比的比值可以是0.2至5中的任意一个数值。例如，所述注射用油与所述苯甲酸苄酯的质量比为1:3，1:2.5，1:2，2:1，2.5:1，3:1等。
所述注射用油选自注射用植物油和注射用中链脂肪酸甘油三酯中的至少一种。也就是说，所述注射用油可以是注射用植物油，也可以是注射用中链脂肪酸甘油三酯，也可以是 一种(或几种)注射用植物油(例如注射用大豆油)与一种(或几种)中链脂肪酸甘油三酯(例如含有8个碳原子的饱和直链脂肪酸甘油三脂)的混合。
所述注射用植物油选自注射用大豆油、注射用蓖麻油、注射用玉米油、注射用菜油、注射用芝麻油、注射用橄榄油、注射用花生油和注射用葵花子油中的至少一种。所述注射用中链脂肪酸甘油三酯为含6～12个碳原子的饱和直链脂肪酸甘油三酯。
在本实施例中，提供以下几种油脂性溶剂作为示范例。
油脂性溶剂1：包含注射用大豆油与苯甲酸苄酯，注射用大豆油与苯甲酸苄酯的质量比为2:3；
油脂性溶剂2：包含注射用橄榄油与苯甲酸苄酯，注射用橄榄油与苯甲酸苄酯的质量比为2:3；
油脂性溶剂3：包含注射用蓖麻油与苯甲酸苄酯，注射用蓖麻油与苯甲酸苄酯的质量比为2:3；
油脂性溶剂4：包含注射用花生油与苯甲酸苄酯，注射用花生油与苯甲酸苄酯的质量比为2:3；
油脂性溶剂5：包含注射用中链脂肪酸甘油三酯与苯甲酸苄酯，注射用中链脂肪酸甘油三酯与苯甲酸苄酯的质量比为2:3；
油脂性溶剂6：包含注射用中链脂肪酸甘油三酯、注射用大豆油与苯甲酸苄酯，其中，注射用中链脂肪酸甘油三酯与注射用大豆油的质量比为1:1，并且，注射用中链脂肪酸甘油三酯与注射用大豆油的质量之和与苯甲酸苄酯的质量比为2:3。
为了验证本申请所述油脂性溶剂对于黄体酮的溶解性，申请人还将上述油脂性溶剂1～6中的苯甲酸苄酯去除，以形成油脂性溶剂比较例1～6。即：
油脂性溶剂比较例1：注射用大豆油；
油脂性溶剂比较例2：含注射用橄榄油；
油脂性溶剂比较例3：注射用蓖麻油与苯甲酸苄酯；
油脂性溶剂比较例4：注射用花生油；
油脂性溶剂比较例5：注射用中链脂肪酸甘油三酯；
油脂性溶剂比较例6：包含注射用中链脂肪酸甘油三酯与注射用大豆油，其中，注射用中链脂肪酸甘油三酯与注射用大豆油的质量比为1:1。
分别取5ml上述油脂性溶剂1～6及油脂性溶剂比较例1～6，加入过量的黄体酮，于25℃振摇24小时，离心取上清液，滤过，取续滤液用无水乙醇适当稀释后，用HPLC法(2015年版中国药典二部黄体酮项下的HPLC法)测定黄体酮的浓度，计算各溶剂中的溶解度， 见表1。
表1.黄体酮在油脂性溶剂1～6及油脂性溶剂比较例1～6中的溶解度
溶剂 组份 黄体酮溶解度(mg/ml)
油脂性溶剂1 注射用大豆油-苯甲酸苄酯 300.3
油脂性溶剂2 注射用橄榄油-苯甲酸苄酯 298.8
油脂性溶剂3 注射用蓖麻油-苯甲酸苄酯 303.2
油脂性溶剂4 注射用花生油-苯甲酸苄酯 259.7
油脂性溶剂5 注射用中链脂肪酸甘油三酯-苯甲酸苄酯 320.6
油脂性溶剂6 中链脂肪酸甘油三酯-大豆油-苯甲酸苄酯 310.0
油脂性溶剂比较例1 注射用大豆油 18.0
油脂性溶剂比较例2 注射用橄榄油 17.7
油脂性溶剂比较例3 注射用蓖麻油 19.0
油脂性溶剂比较例4 注射用花生油 15.5
油脂性溶剂比较例5 注射用中链脂肪酸甘油三酯 32.8
油脂性溶剂比较例6 中链脂肪酸甘油三酯-大豆油 25.1
由表1数据清晰可见地，注射用中链脂肪酸甘油三酯对于黄体酮的溶解度大于注射用植物油对于黄体酮的溶解度；注射用中链脂肪酸甘油三酯与注射用油的混合物对于黄体酮的溶解度则明显优于单一使用注射用植物油。而利用本申请所述的含有苯甲酸苄酯的油脂性溶剂，则极显著地增加了黄体酮的溶解度。
实施例2.黄体酮乳剂型注射剂1～3
在本实施例中，提供5mg:1ml、10mg:1ml及20mg:1ml的黄体酮乳剂型注射剂1～3。所述黄体酮乳剂型注射剂中包含的油脂性溶剂包含中链脂肪酸甘油三酯与苯甲酸苄酯，其中，中链脂肪酸甘油三酯与苯甲酸苄酯的质量比为2:3。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用蛋黄卵磷脂和甘油；其中，所述注射用蛋黄卵磷脂与所述油脂性溶剂的质量比为12:100，每100毫升所述黄体酮注射剂含有2.5克所述甘油。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂1：规格5mg:1ml，配方包括：黄体酮5g，苯甲酸苄酯60g，中链脂肪酸甘油三酯40g，蛋黄卵磷脂12g，甘油25g，注射用水加至1000ml。
黄体酮乳剂型注射剂2：规格10mg:1ml，配方包括：黄体酮10g，苯甲酸苄酯60g，中链脂肪酸甘油三酯40g，蛋黄卵磷脂12g，甘油25g，注射用水加至1000ml。
黄体酮乳剂型注射剂3：规格20mg:1ml，配方包括：黄体酮20g，苯甲酸苄酯60g，中链脂肪酸甘油三酯40g，蛋黄卵磷脂12g，甘油25g，注射用水加至1000ml。
上述黄体酮乳剂型注射剂的制备方法如下，各注射剂的具体配方不同，但制备方法步骤相同。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与中链脂肪酸甘油三酯混合，加热至65℃，加入黄体酮和蛋黄卵磷脂，搅拌至溶解，作为混合油相；
(2)将甘油溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂1～3的外观为乳白色，pH值为6.5，乳滴平均粒径(Zeta average)为182nm，PDI为0.15，Zeta电位为-22.6mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例3.黄体酮乳剂型注射剂4
在本实施例中，提供50mg:1ml的黄体酮乳剂型注射剂4。
所述黄体酮乳剂型注射剂4中包含的油脂性溶剂包含中链脂肪酸甘油三酯与苯甲酸苄酯，其中，中链脂肪酸甘油三酯与苯甲酸苄酯的质量比为2:3。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用蛋黄卵磷脂，作为稳定剂的油酸钠，以及甘油；其中，所述注射用蛋黄卵磷脂与所述油脂性溶剂的质量比为12.5:100，每100毫升所述黄体酮乳剂型注射剂含有2.5克所述甘油。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂4：规格50mg:1ml，配方包括：黄体酮50g，苯甲酸苄酯120g， 中链脂肪酸甘油三酯80g，蛋黄卵磷脂25g，油酸钠0.3g，甘油25g，注射用水加至1000ml。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与中链脂肪酸甘油三酯混合，加热至65℃，加入黄体酮和蛋黄卵磷脂，搅拌至溶解，作为混合油相；
(2)将甘油和油酸钠溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂4的外观为乳白色，pH值为6.6，乳滴平均粒径(Zeta average)为195nm，PDI为0.16，Zeta电位为-32.2mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例4.黄体酮乳剂型注射剂5
在本实施例中，提供10mg:1ml的黄体酮注乳剂型射液5。
所述黄体酮乳剂型注射剂5中包含的油脂性溶剂包含中链脂肪酸甘油三酯与苯甲酸苄酯，其中，中链脂肪酸甘油三酯与苯甲酸苄酯的质量比为5:4。所述黄体酮乳剂型注射剂还包含作为乳化剂的聚山梨酯80(又称为吐温80)，以及甘油；其中，所述聚山梨酯80与所述油脂性溶剂的质量比为23.1:100，每100毫升所述黄体酮乳剂型注射剂含有2.0克所述甘油。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂5：规格10mg:1ml，配方包括：黄体酮10g，苯甲酸苄酯48g，中链脂肪酸甘油三酯60g，聚山梨酯80为25g，甘油20g，注射用水加至1000ml。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与中链脂肪酸甘油三酯混合，加热至65℃，加入黄体酮搅拌至溶解，作为混合油相；
(2)将甘油和聚山梨酯80溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂5的外观为乳白色，pH值为6.5，乳滴平均粒径(Zeta average)为163nm，PDI为0.08，Zeta电位为-24.4mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例5.黄体酮乳剂型注射剂6
在本实施例中，提供50mg:1ml的黄体酮乳剂型注射剂6。
所述黄体酮乳剂型注射剂6中包含的油脂性溶剂包含注射用蓖麻油与苯甲酸苄酯，其中，注射用蓖麻油与苯甲酸苄酯的质量比为1:3。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用大豆卵磷脂与泊洛沙姆188的混合物，作为稳定剂的油酸，以及甘油；其中，所述乳化剂与所述油脂性溶剂的质量比为12:100，每100毫升所述黄体酮乳剂型注射剂含有2.5克所述甘油。并且，在所述乳化剂中，注射用大豆卵磷脂与泊洛沙姆188的质量比为5:1。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂6：规格50mg:1ml，配方包括：黄体酮50g，苯甲酸苄酯150g，注射用蓖麻油50g，注射用大豆卵磷脂20g，泊洛沙姆188为4g，油酸0.5g，甘油25g，注射用水加至1000ml。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与注射用蓖麻油混合，加热至65℃，加入黄体酮、油酸和注射用大 豆卵磷脂搅拌至溶解，作为混合油相；
(2)将甘油和泊洛沙姆188溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂6的外观为乳白色，pH值为6.5，乳滴平均粒径(Zeta average)为171nm，PDI为0.08，Zeta电位为-28.7mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例6.黄体酮乳剂型注射剂7
在本实施例中，提供10mg:0.5ml的黄体酮乳剂型注射剂7。
所述黄体酮乳剂型注射剂7中包含的油脂性溶剂包含注射用大豆油与苯甲酸苄酯，其中，注射用大豆油与苯甲酸苄酯的质量比为2:3。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用大豆卵磷脂与聚氧乙烯35蓖麻油的混合物，以及甘油；其中，所述乳化剂与所述油脂性溶剂的质量比为12:100，每100毫升所述黄体酮乳剂型注射剂含有2.5克所述甘油。并且，在所述乳化剂中，注射用大豆卵磷脂与聚氧乙烯35蓖麻油的质量比为5:1。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂7：规格10mg:0.5ml，配方包括：黄体酮20g，苯甲酸苄酯60g，注射用大豆油40g，注射用大豆卵磷脂10g，聚氧乙烯35蓖麻油2g，甘油25g，注射用水加至1000ml。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与注射用大豆油混合，加热至65℃，加入黄体酮和注射用大豆卵磷脂搅拌至溶解，作为混合油相；
(2)将甘油和聚氧乙烯35蓖麻油溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂7的外观为乳白色，pH值为6.6，乳滴平均粒径(Zeta average)为160nm，PDI为0.10，Zeta电位为-23.2mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例7.黄体酮乳剂型注射剂8
在本实施例中，提供50mg:2ml的黄体酮乳剂型注射剂8。
所述黄体酮乳剂型注射剂8中包含的油脂性溶剂包含中链脂肪酸甘油三酯与苯甲酸苄酯，其中，中链脂肪酸甘油三酯与苯甲酸苄酯的质量比为3:7。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用蛋黄卵磷脂与泊洛沙姆188的混合物，作为抑菌剂的苯甲醇，以及甘油；其中，所述乳化剂与所述油脂性溶剂的质量比为12:100，每100毫升所述黄体酮乳剂型注射剂含有2.5克所述甘油。并且，在所述乳化剂中，注射用蛋黄卵磷脂与泊洛沙姆188的质量比为5:1。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂8：规格20mg:2ml，配方包括：黄体酮25g，苯甲酸苄酯70g，中链脂肪酸甘油三酯30g，注射用蛋黄卵磷脂10g，泊洛沙姆188 2g，苯甲醇10g，甘油25g，注射用水加至1000ml。
所述制备方法包括以下步骤：
(1)将苯甲酸苄酯与中链脂肪酸甘油三酯混合，加热至65℃，加入黄体酮、注射用蛋黄卵磷脂和苯甲醇搅拌至溶解，作为混合油相；
(2)将甘油和泊洛沙姆188溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保 护下继续高速搅拌10分钟制得初乳，用注射用水稀释至1000ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂8的外观为乳白色，pH值为6.8，乳滴平均粒径(Zeta average)为168nm，PDI为0.09，Zeta电位为-24.4mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
实施例9.黄体酮乳剂型注射剂9
在本实施例中，提供20mg:1ml的黄体酮乳剂型注射剂9。
所述黄体酮乳剂型注射剂9中包含的油脂性溶剂包含注射用蓖麻油与苯甲酸苄酯，其中，注射用蓖麻油与苯甲酸苄酯的质量比为1:1.5。所述黄体酮乳剂型注射剂还包含作为乳化剂的注射用蛋黄卵磷脂(例如蛋黄卵磷脂PL-100M)，甘油，以及1,2-丙二醇。所述乳化剂与所述油脂性溶剂的质量比为12:100，每100毫升所述黄体酮乳剂型注射剂含有2.5克所述甘油，每100毫升所述黄体酮乳剂型注射剂含有1,2-丙二醇1.28g。
作为一个示范例，本实施例所述黄体酮乳剂型注射剂的具体配方如下。
黄体酮乳剂型注射剂9：规格20mg:1ml，配方包括：黄体酮10g，苯甲酸苄酯45g，注射用蓖麻油30g，注射用蛋黄卵磷脂9g，1,2丙二醇6.40g，甘油12.5g，注射用水加至500ml。
所述制备方法包括以下步骤：
(1)将1,2-丙二醇、苯甲酸苄酯与注射用蓖麻油混合，加热至65℃，加入黄体酮和注射用蛋黄卵磷脂搅拌至溶解，作为混合油相；
(2)将甘油溶解在注射用水中，加热至65℃，作为混合水相；
(3)在高速搅拌下(15000rpm)，将混合油相缓慢加入到混合水相中，并在氮气流保护下继续高速搅拌10分钟制得初乳，用注射用水稀释至500ml；
(4)氮气流保护下，将初乳用高压均质机反复均化至平均粒径(Zeta average)小于 250nm，且PDI<0.2；
(5)用0.45μm微孔滤膜滤过，分装(每支1ml)，充氮、熔封；以及，
(6)121℃热压灭菌15min。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本实施例的所述黄体酮乳剂型注射剂9的外观为乳白色，pH值为6.0，乳滴平均粒径(Zeta average)为181nm，PDI为0.12，Zeta电位为-28.7mV，药物含量落在标示量95％～105％的范围内，药物包封率均大于90％。
对比例1.不含苯甲酸苄酯的黄体酮乳剂型注射剂(每支含注射剂1ml，内含黄体酮20mg)
在本对比例1中，提供一种不含苯甲酸苄酯的黄体酮乳剂型注射剂，规格为20mg:1ml。具体配方为：黄体酮20g，注射用大豆油50g，中链脂肪酸甘油三酯50g，注射用蛋黄卵磷脂12g，甘油25g，注射用水加至1000ml。所述黄体酮的制备方法与实施例2相同，在此不再赘述。
取制得的黄体酮乳剂型注射剂，用激光粒度仪测定乳滴平均粒径(Zeta average)、多分散指数PDI和Zeta电位。另取注射剂，用0.45μm微孔滤膜滤过，取续滤液用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方法进行分析，计算注射剂中药物的含量。另取注射剂置100nm筛板滤器中离心，取续滤液，用乙醇稀释一倍后，用HPLC法测定浓度，计算乳剂中黄体酮的包封率。
经验证表明，本对比例1的所述黄体酮乳剂型注射剂的外观为乳白色，pH值为6.5，乳滴平均粒径(Zeta average)为178nm，PDI为0.14，Zeta电位为-25.0mV，药物含量落在标示量的88.7％，药物包封率均大于90％。
由此可见，在本对比例1的不含苯甲酸苄酯的黄体酮乳剂型注射剂中，药物的含量偏低，这是由于黄体酮在油相(注射用大豆油与中链脂肪酸甘油三酯的混合物)中的溶解度不足，析出的药物在滤过时被截留所致。
验证例1.放置后黄体酮注射剂中溶解状态的黄体酮含量
取对比例1和实施例2、3和4中的黄体酮乳剂型注射剂，在25℃、相对湿度60％的条件下放置3个月。取乳剂，用0.45μm微孔滤膜滤过，取续滤液，用无水乙醇适当稀释，使稀释液中黄体酮的标示浓度约为100μg/ml，按2015年版中国药典黄体酮项下的HPLC方 法进行分析，计算注射剂中溶解状态的黄体酮含量，结果见表2。
表2.室温放置3个月后溶解状态的黄体酮含量
  对比例1 实施例2 实施例3 实施例4
溶解状态的黄体酮量(标示％) 75.2％ 98.8％ 98.0％ 98.6％
由表2结果显示，不含苯甲酸苄酯的对比例1中，溶解状态的黄体酮量仅占总量的75.2％，提示有黄体酮析出。在浑浊的乳剂体系中，用肉眼无法看到析出的固体，注射给药存在很大风险。而加入苯甲酸苄酯的黄体酮乳剂型注射剂中(实施例2、3和4)，黄体酮仍均以溶解状态存在，体现出了明显的优越性。
验证例2.黄体酮乳剂型注射剂肌肉注射后在注射部位的扩散情况
在本验证例中验证本申请所述黄体酮乳剂型注射剂肌肉注射后在注射部位的扩散情况。具体地，在本验证例中，取实施例5所述的黄体酮乳剂型注射剂，加入油溶性荧光染料IR780，充分超声，使IR780溶解。
另外，作为对照，另取市售普通黄体酮油溶液型注射剂，同样加入油溶性荧光染料IR780超声溶解。
取市售SD大鼠，用戊巴比妥麻醉，将右侧大腿注射部位剃毛，用75％乙醇消毒后肌肉注射。将含IR780的市售黄体酮油溶液注射0.2ml，及含IR780的本申请所述黄体酮乳剂型注射剂分别主色0.5ml，注入的两个供试品中油溶性溶剂的体积相同，均为0.2ml。
于给药后30分钟和12小时在小动物整体荧光成像仪上观测注射部位的荧光，观测条件：IR780激发波长为770nm，发射波长为830nm，曝光时间为10s。荧光成像图见图1A至图1D。
其中，图1A为注射本申请所述黄体酮乳剂型注射剂30分钟后的荧光成像图，图1B为注射市售黄体酮注射剂30分钟后的荧光成像图；图1C为注射本申请所述黄体酮乳剂型注射剂12小时后的荧光成像图，图1D为注射市售黄体酮注射剂12小时后的荧光成像图。
由图1A与图1B所示，本申请所述黄体酮乳剂型注射剂与市售黄体酮注射剂在肌注30分钟后的荧光区域相差不大，说明此时本申请所述黄体酮乳剂型注射剂中的油脂性溶剂都集中在注射区域附近。随时间推移，如图1A和图1C所示，本申请所述黄体酮乳剂型注射剂的荧光区域扩大很多，而如图1B和图1D所示，市售黄体酮注射剂的荧光区域未见明显变化，这说明本申请所述黄体酮乳剂型注射剂在肌肉注射后油脂性溶剂在肌肉组织中的扩散明显，从而可以减少注射部位发生硬结等不良反应。
验证例3.本申请所述黄体酮乳剂型注射剂肌肉注射后引发局部硬结及脂肪沉积的试验
在本验证例中验证本申请所述黄体酮乳剂型注射剂肌肉注射后引发局部硬结及脂肪沉 积的试验。具体地，在本验证例中，取实施例5所述的黄体酮乳剂型注射剂为实验组，以市售黄体酮注射剂为对照组。
实验动物：雌性新西兰兔，体重2.5～3.0kg。
实验方法：取新西兰兔随机分成2组，每组3只。以实施例5中的黄体酮乳剂型注射剂为试验组，市售黄体酮注射剂为对照组，分别于兔后腿处肌肉注射1ml，连续注射10天，检查注射部位的硬结情况。于末次注射24小时后将动物处死，剪开注射部位的皮肤，观察脂肪的沉积情况。
结果：对照组注射部位用手触摸均能感觉到明显的硬结，而试验组注射部位感觉不到硬结。将注射部位的皮肤剪开观察，对照组在注射部位周围有肉眼可见的脂肪沉积，试验组则未见脂肪沉积。结果证实，本申请所述的黄体酮乳剂型注射剂，可显著减轻注射部位的不良反应。
本申请已由上述相关实施例加以描述，然而上述实施例仅为实施本申请的范例。必需指出的是，已公开的实施例并未限制本申请的范围。相反地，包含于权利要求书的精神及范围的修改及均等设置均包括于本申请的范围内。

Claims (16)

  1. 一种黄体酮乳剂型注射剂，包含黄体酮、油脂性溶剂与注射用水，其特征在于，所述油脂性溶剂为注射用油和苯甲酸苄酯的混合物，并且，所述注射用油与所述苯甲酸苄酯的质量比为1:5～5:1。
  2. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述注射用油选自注射用植物油和注射用中链脂肪酸甘油三酯中的至少一种。
  3. 如权利要求2所述的黄体酮乳剂型注射剂，其特征在于，所述注射用植物油选自注射用大豆油、注射用蓖麻油、注射用玉米油、注射用菜油、注射用芝麻油、注射用橄榄油、注射用花生油和注射用葵花子油中的至少一种。
  4. 如权利要求2所述的黄体酮乳剂型注射剂，其特征在于，所述注射用中链脂肪酸甘油三酯为含6～12个碳原子的饱和直链脂肪酸甘油三酯。
  5. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述黄体酮与所述油脂性溶剂的质量比为5:100～30:100。
  6. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，每100毫升所述黄体酮乳剂型注射剂含有5～40克所述油脂性溶剂。
  7. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述黄体酮乳剂型注射剂还包含乳化剂及甘油；其中，所述乳化剂与所述油脂性溶剂的质量比为5:100～50:100，并且，每100毫升所述黄体酮乳剂型注射剂含有0.5～3克所述甘油。
  8. 如权利要求7所述的黄体酮乳剂型注射剂，其特征在于，所述乳化剂选自注射用大豆卵磷脂、注射用蛋黄卵磷脂、聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇15-羟基硬脂酸酯和泊洛沙姆188中的至少一种。
  9. 如权利要求8所述的黄体酮乳剂型注射剂，其特征在于，所述乳化剂为注射用大豆卵磷脂、注射用蛋黄卵磷脂、聚山梨酯80、聚氧乙烯蓖麻油或聚乙二醇15-羟基硬脂酸酯；其中，所述注射用大豆卵磷脂或注射用蛋黄卵磷脂与所述油脂性溶剂的质量比为5:100～30:100；所述聚山梨酯80与所述油脂性溶剂的质量比为5:100～30:100；
    所述聚氧乙烯蓖麻油与所述油脂性溶剂的质量比为10:100～40:100；
    所述聚乙二醇15-羟基硬脂酸酯与所述油脂性溶剂的质量比为10:100～50:100。
  10. 如权利要求8所述的黄体酮乳剂型注射剂，其特征在于，所述乳化剂为注射用大豆卵磷脂和注射用蛋黄卵磷脂中的一者与聚山梨酯80、聚氧乙烯蓖麻油、聚乙二醇15-羟基硬脂酸酯和泊洛沙姆188中的至少一种而形成的混合乳化剂；其中，所述注射用大豆卵磷脂或所述 注射用蛋黄卵磷脂与所述混合乳化剂的质量比为1:2～10:11。
  11. 如权利要求10所述的黄体酮乳剂型注射剂，其特征在于，所述混合乳化剂与所述油脂性溶剂的质量比为5:100～20:100。
  12. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述黄体酮乳剂型注射剂还包含稳定剂、抑菌剂、止痛剂和pH调节剂中的至少一种。
  13. 如权利要求12所述的黄体酮乳剂型注射剂，其特征在于，所述稳定剂选自油酸和油酸钠中的至少一种；所述抑菌剂选自苯甲醇、羟丙丁酯(甲酯)、苯酚、三氯叔丁醇和硫柳汞中的至少一种；所述止痛剂选自苯甲醇、三氯叔丁醇、利多卡因或盐酸普鲁卡因中的至少一种；所述pH调节剂选自盐酸、氢氧化钠，枸橼酸和枸橼酸钠中的至少一种。
  14. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述黄体酮乳剂型注射剂满足以下指标中的至少一项：(i)平均粒径为100～250nm，(ii)多分散指数小于0.20，(iii)Zeta电位范围为-20mV～-40mV。
  15. 如权利要求1所述的黄体酮乳剂型注射剂，其特征在于，所述黄体酮乳剂型注射剂还包括醇溶剂，以所述黄体酮乳剂型注射剂的质量百分比计，所述醇溶剂的质量百分比为0.5％～5.0％。
  16. 一种如权利要求1所述的黄体酮乳剂型注射剂的制备方法，其特征在于，所述制备方法包括：将配方中的油相和水相分别在加热状态下混合均匀以获得混合油相和混合水相的步骤；将所述混合油相与混合水相混合后经高速剪切乳化及高压均质，以获得平均粒径及粒径分布符合要求的乳剂的步骤；
    将所述乳剂用0.45μm微孔滤膜过滤的步骤；以及，
    分装、熔封并灭菌的步骤。
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