WO2020135352A1 - Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof - Google Patents

Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof Download PDF

Info

Publication number
WO2020135352A1
WO2020135352A1 PCT/CN2019/127555 CN2019127555W WO2020135352A1 WO 2020135352 A1 WO2020135352 A1 WO 2020135352A1 CN 2019127555 W CN2019127555 W CN 2019127555W WO 2020135352 A1 WO2020135352 A1 WO 2020135352A1
Authority
WO
WIPO (PCT)
Prior art keywords
progesterone
solvent
precipitation solvent
solution
rpm
Prior art date
Application number
PCT/CN2019/127555
Other languages
French (fr)
Chinese (zh)
Inventor
梁相永
李明
苏正兴
郭大成
易聪
魏巍
李丹
赵栋
王晶翼
Original Assignee
四川科伦药物研究院有限公司
湖南科伦药物研究有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川科伦药物研究院有限公司, 湖南科伦药物研究有限公司 filed Critical 四川科伦药物研究院有限公司
Priority to CN201980071761.7A priority Critical patent/CN112969466A/en
Publication of WO2020135352A1 publication Critical patent/WO2020135352A1/en

Links

Images

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms

Definitions

  • the invention relates to a method for preparing progesterone particles, especially progesterone crystals or powders, and to the obtained progesterone crystals or powders and injections thereof.
  • Progesterone is widely used clinically to treat disorders such as irregular menstruation, threatened abortion and other corpus luteum function. It is known that progesterone is a substance with a polymorphic form, and the alpha and beta crystal forms are relatively stable and the crystal structure is clear (melting points are about 131 °C and 123 °C, respectively), and both have biological activity (R. Woolf et.al Proc. Soc. Exp. Biol. Med., 1948, 68 (1), 79-83; R. Lancaster et. al. J. Pharm. Sci., 2007, 96 (12), 3419-3431). Progesterone with different crystalline structures has different melting points, apparent solubility, optical properties, etc., so it affects the in vivo metabolism and bioavailability of the resulting preparation.
  • the common preparation methods of polymorphic drugs in the prior art include solution crystallization, melting method, sublimation method, crushing and grinding method and other conventional methods, and also include rapid freezing, capillary generation method, high-throughput screening method, supercritical fluid method , Laser induction and other unconventional methods.
  • CN107417756A discloses a method for preparing progesterone crystal form by concentrating progesterone organic solution.
  • the method disclosed in this document requires grinding and other treatments to obtain samples with particle size distributions that meet the requirements.
  • CN109223722A discloses a method for preparing progesterone nanocrystal injection by freeze-drying progesterone oil-in-water emulsion.
  • the method described in this document will increase the amount of organic solvents used in the production of lyophilization, which is not suitable for direct lyophilization.
  • the size of progesterone nanocrystals is limited by the size of the milk droplets, and the adjustable range limited.
  • progesterone preparations are oral preparations and injections.
  • oral preparation is the most convenient for administration and the patient has good compliance, its first-pass effect is remarkable, and the bioavailability is only about 10%. Therefore, from the perspective of clinical application, the development of progesterone aqueous long-acting injections is becoming more and more important.
  • the implementation methods of progesterone aqueous long-acting injections are mainly encapsulated (such as polymer-based aqueous progesterone injection, etc.) and direct (such as progesterone suspended long-acting injections and powder injections).
  • the loading type involves the problems of drug loading and encapsulation rate.
  • the direct type can conveniently control the particle size and concentration of progesterone according to clinical needs, so that the frequency of administration is the lowest and the therapeutic effect is the best, and the patient's compliance is maximized.
  • the present invention provides a method for preparing progesterone particles with good stability, and the method proposed by the present invention is simple to operate and easy to industrialize Enlarge production.
  • the first aspect of the present invention provides a method for preparing progesterone particles, wherein the method includes:
  • Step 1 dissolve progesterone in the solvent to provide a progesterone solution
  • Step 2 pumping the progesterone solution into the progesterone precipitation solvent with high-speed shearing or vigorous stirring at a predetermined speed to precipitate progesterone;
  • step 3 the precipitate is separated and dried to obtain the progesterone particles; wherein the progesterone particles are progesterone crystals or progesterone powder.
  • the present invention relates to a method of preparing progesterone crystals, wherein the method includes:
  • Progesterone is dissolved in the solvent to provide a solution of progesterone
  • the precipitation solvent is water, an organic solvent, or a mixture of water and an organic solvent
  • the precipitated progesterone is separated and freeze-dried to obtain progesterone crystals.
  • the concentration of the progesterone solution is 10 mg/mL to 500 mg/mL; further preferably 200 mg/mL to 450 mg/mL.
  • the solvent used to dissolve progesterone is an organic solvent miscible with water; preferably, the solvent used to dissolve progesterone is one selected from methanol, absolute ethanol, isopropanol, and acetone Species or a mixture thereof, or an aqueous solution of the above alcohols; preferably, the solvent used to dissolve progesterone is methanol, absolute ethanol, or 95 vol% ethanol; more preferably, the solvent used to dissolve progesterone is methanol or Absolute ethanol.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and acetone; preferably, the precipitation solvent is water, ethanol, or a mixture of water and ethanol.
  • the precipitation solvent is water; in other embodiments, the precipitation solvent is ethanol; in still other embodiments, the precipitation solvent is a mixture of ethanol and water, wherein, according to The volume ratio of water and ethanol needs to be adjusted from 20:1 to 1:20.
  • the volume ratio of water and ethanol includes but is not limited to 4:1, 1:1, and 1:4.
  • the pumping of the progesterone solution into the precipitation solvent can be controlled by a peristaltic pump, for example, the pumping speed is 50 mL/min to 500 mL/min, preferably 100 mL/min to 400 mL/min.
  • the vigorous stirring is generally 500 rpm to 2000 rpm, preferably 700 rpm to 1000 rpm.
  • the high-speed shearing can be achieved by high-speed stirring with a rotation speed of 3000 rpm to 20,000 rpm, preferably a rotation speed of 7000 rpm to 20,000 rpm.
  • the temperature of the precipitation solvent is -20°C to 25°C. More specifically, when water is used as the precipitation solvent, its temperature is 1°C to 25°C; when organic solvent is used as the precipitation solvent, the temperature of the precipitation solvent is -20°C to 0°C; when a mixture of water and organic solvent is used As the precipitation solvent, the temperature of the precipitation solvent is -10°C to 25°C, preferably, the temperature of the precipitation solvent is -10°C to 0°C.
  • the volume ratio of the pumped progesterone solution to the precipitation solvent is 1.5:1 to 1:10, preferably 1:1.5 to 1:5.
  • the pumping of the progesterone solution into the precipitation solvent can be controlled by, for example, a peristaltic pump, and the pumping speed is, for example, 50 mL/min to 500 mL/min, preferably 100 mL/min to 400 mL/min.
  • the progesterone solution may further include: 0.5 wt% to 3 wt%, preferably 1 wt% to 2 wt% surfactant based on the mass of the progesterone solution.
  • the surfactant includes, but is not limited to, polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sorbitan fatty acid ester (Span 20, 40, 60, 80), succinic acid Ester, glyceryl monostearate, etc.
  • these surfactants may be included in the progesterone precipitate. Through the separation step, for example, by washing the precipitate, a small amount of surfactant in the precipitate can be removed, so that the final powder may contain no or only a trace amount of surfactant.
  • ethanol is preferably used as the precipitation solvent; more preferably, the alpha type seed crystal may be added to the precipitation solvent in advance.
  • the type of precipitation solvent may not be affected limit.
  • the seed crystals can be added to the precipitation solvent cooled to a specific temperature, where the seed crystals can be added in the form of a powder or suspension, preferably in the form of a suspension.
  • the raw material as the seed crystal can be dispersed in water by shearing, ultrasound or the like.
  • 0.1% to 2% (w/v) surfactant for example, Tween 20, etc.
  • the amount of seed crystal added may be 0.1 wt% to 10 wt% (relative to progesterone), preferably 1 wt% to 5 wt% (relative to progesterone).
  • the separation is filtration, preferably suction filtration.
  • the freeze-drying includes: redispersing the separated precipitate in a 2 wt% to 4 wt% aqueous mannitol solution; then freeze-drying to obtain progesterone crystals with a content of ⁇ 80 wt%, for example 80wt% to 86wt%.
  • the particle size of the obtained progesterone crystal is 0.3
  • the preferred particle size range is 10 ⁇ m to 30 ⁇ m.
  • a progesterone crystal obtained by the above method having a particle size of 0.3 ⁇ m to 60 ⁇ m, preferably 10 ⁇ m to 30 ⁇ m.
  • a progesterone injection which includes a therapeutically effective amount of the progesterone crystal of the present invention.
  • the progesterone injection of the present invention may be powder injection or suspension.
  • the progesterone powder injection further includes a space stabilizer, a surfactant, an osmotic pressure regulator, and the like.
  • the progesterone suspension injection further includes water for injection, space stabilizer, surfactant, osmotic pressure adjuster, pH adjuster, and the like.
  • steric stabilizers include but are not limited to hydroxypropyl methylcellulose and its salts, polyvinylpyrrolidone, polyethylene glycols, etc.
  • surfactants include but are not limited to polysorbates, sorbitan fatty acids Ester (Span 20, 40, 60, 80), succinate, glyceryl monostearate, etc.
  • osmotic regulators include but are not limited to sugars (such as glucose, fructose, etc.), polyhydric alcohols (such as mannose) Alcohol, etc.), inorganic salts (such as sodium chloride), etc.
  • pH adjusting agents include but are not limited to hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.
  • a method for preparing progesterone powder including:
  • Progesterone is dissolved in an organic solvent to provide a solution of progesterone
  • the precipitate was separated and dried to obtain the progesterone powder.
  • the organic solution of progesterone is added to the progesterone precipitation solvent of high shear at a predetermined flow rate, so that the progesterone is quickly precipitated in the precipitation solvent.
  • the amount of progesterone added per unit time and the shear rate can be finally obtained.
  • the concentration of the progesterone solution is 10 to 300 mg/mL; further preferably 30 to 200 mg/mL.
  • the organic solvent is an organic solvent that is miscible with water, and the organic solvent may be one selected from methanol, ethanol, propanol, and ethylene glycol, or a mixed solvent of two or more of these alcohols, or It is an aqueous solution of the above alcohol.
  • the volume percentage of alcohol in the aqueous solution of alcohol is above 80 vol%, more preferably above 90 vol%, most preferably above 95 vol%.
  • the organic solvent is methanol, ethanol, or a 95 vol% ethanol aqueous solution.
  • the high-speed shearing may be achieved by high-speed stirring at a rotation speed of 700-2000 rpm.
  • the high-speed shearing can be achieved by a high-speed shearing apparatus, wherein the rotation speed of the shearing head can be 5000 to 20000 rpm.
  • the volume ratio of the progesterone solution and the precipitation solvent finally added is 1:3 to 1:30, preferably 1:10, and more preferably 1:5.
  • the progesterone precipitation solvent is water.
  • the progesterone precipitation solvent may further contain 0.1 to 2% by weight, preferably 0.3 to 0.8% by weight of surfactant.
  • surfactants may be included in the progesterone precipitate.
  • a small amount of surfactant in the precipitate can be removed, so that the final powder may contain no or only a trace amount of surfactant.
  • the surfactant is selected from polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sorbitan fatty acid ester (such as Span 20, 40, 60, 80), polyethylene dioxide Alcohol 1000 Vitamin E succinate (TPGS), polyethylene glycol 15 hydroxystearate (e.g.
  • HS15 poloxamer
  • SDS sodium lauryl sulfate
  • mono-fatty acid glycerides preferably, lecithin, cyclodextrin, and polyoxyethylene castor oil
  • the active agent is selected from one or more of Tween 20, Tween 80, sorbitan fatty acid ester (especially Span 20), and Poloxamer; further preferably, the surfactant is Tween Temperature 20.
  • the progesterone precipitation solvent may be cooled to 5-10°C in advance.
  • the cooled precipitation solvent helps progesterone precipitate out more quickly and in greater amounts.
  • progesterone powders with different particle sizes can be obtained by adjusting the flow rate in conjunction with other process conditions, such as solution concentration and shear rate of the precipitation solvent.
  • the predetermined flow rate can be adjusted in the range of 6 to 100 mL/min.
  • the separation is filtration, preferably suction filtration.
  • the drying method is freeze drying.
  • the operation step of freeze-drying is: redispersing the separated precipitate in a 2 wt% to 4 wt% mannitol aqueous solution and then freeze-drying to obtain the progesterone powder;
  • the step of dispersing is preferably dispersed by stirring, and the rotating speed of the stirring is preferably 500 to 1000 rpm.
  • the organic solution of progesterone is added into the progesterone precipitation solvent with high shear at a predetermined flow rate, so that the progesterone is quickly precipitated in the precipitation solvent.
  • the amount of progesterone added per unit time and the shear rate can be finally obtained.
  • micron-level progesterone particles can be obtained with good stability, and at the same time, the particle size of the finally obtained particles can be controlled and adjusted, so that the particle size can be adjusted within the range of 0.3 to 60 ⁇ m, preferably 10 to 30 ⁇ m Particulate matter.
  • the progesterone injection prepared by the present application not only achieves a sustained release effect for at least 5 days, reaches the sustained release target, can reduce the frequency of administration, improve patient compliance, and has good stability.
  • the method of the present invention is simple to operate, low in cost, and easy to scale up in industrial production.
  • FIG. 1 is an XRD pattern of a sample according to Example 1 of the present invention.
  • Example 2 is a DSC chart of the sample according to Example 1 of the present invention.
  • Example 3 is an XRD pattern of a sample according to Example 2 of the present invention.
  • Example 4 is a DSC chart of a sample according to Example 2 of the present invention.
  • Example 5 is an XRD pattern of a sample according to Example 3 of the present invention.
  • Example 6 is a DSC chart of a sample according to Example 3 of the present invention.
  • Example 7 is an XRD pattern of a sample according to Example 4 of the present invention.
  • Example 8 is a DSC chart of a sample according to Example 4 of the present invention.
  • Example 9 is an XRD pattern of a sample according to Example 5 of the present invention.
  • Example 10 is an XRD pattern of a sample according to Example 6 of the present invention.
  • Example 11 is a DSC chart of a sample according to Example 6 of the present invention.
  • Example 12 is an XRD pattern of a sample according to Example 7 of the present invention.
  • Example 13 is a graph showing the change of plasma progesterone concentration with time according to Example 17 of the present invention.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 130mL of absolute ethanol in a steel cup with jacket and cool to -20°C with a cooling circulation device.
  • Sample preparation Place the shearing head in the precipitation solvent and adjust the rotation speed to 7000 rpm.
  • the progesterone solution was pumped into the precipitation solvent at a rate of 117 mL/min (pumping time: 90 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
  • DSC detection Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 2, the sample showed an endothermic peak at 131.20°C, indicating that the obtained crystal form was ⁇ crystal form.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir and dissolve at 60°C.
  • Precipitation solvent preparation Measure 104mL of pure water and 26mL of absolute ethanol in a steel cup with jacket, and cool to -10°C with a cooling circulation device.
  • Sample preparation Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 219 mL/min (pumping time: 20 s), and filter the resulting suspension with suction The filter cake was washed with 3000mL pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min.
  • the lyophilization conditions were as shown in Example 1.
  • Dispersant preparation Weigh 0.75g Span 20, 1.9g Tween 20, 1.25g sodium dihydrogen phosphate, 2.5g disodium hydrogen phosphate, 3.05g sodium chloride in a 1000mL beaker, add 466mL water and stir until completely dissolved A dispersant is obtained.
  • Suspension preparation Weigh 2.94g of lyophilized sample (containing 2.5g of progesterone) into a 150mL beaker, add 47.06g of dispersant and shear at 4000rpm for 5min.
  • DSC detection Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 4, the sample showed endothermic peaks at 125.12°C ( ⁇ crystal form) and 131.40°C ( ⁇ crystal form), indicating that the obtained crystal form was a mixed crystal form.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 26mL of pure water and 104mL of absolute ethanol in a steel cup with jacket, and cool to -10°C with a cooling circulation device.
  • Sample preparation Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 219 mL/min (pumping time: 20 s), and filter the resulting suspension with suction
  • the filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min (the conditions for lyophilization are the same as those for example 1).
  • DSC detection Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 6, the samples showed endothermic peaks at 123.93°C ( ⁇ crystal form) and 131.60°C ( ⁇ crystal form), indicating that the obtained crystal form was a mixed crystal form.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 104mL of pure water and 26mL of absolute ethanol in a steel cup with jacket, and cool to -10°C with a cooling circulation device.
  • Sample preparation Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm.
  • the progesterone solution was pumped into the precipitation solvent at a rate of 219 mL/min (pumping time: 20 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min to obtain a lyophilized sample.
  • the lyophilized conditions were as shown in Example 1. .
  • Dispersant preparation same as in Example 2.
  • Suspension preparation Weigh 2.94g of lyophilized sample (containing 2.5g of progesterone) into a 150mL beaker, add 47.06g of dispersant and shear at 4000rpm for 5min.
  • DSC detection Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 8, the sample showed an endothermic peak at 131.17°C ( ⁇ crystal form), indicating that the obtained crystal form was ⁇ crystal form.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 130mL of pure water in a steel cup with jacket, and cool with natural water at room temperature.
  • Sample preparation Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm.
  • the progesterone solution was pumped into the precipitation solvent at a rate of 114 mL/min (pumping time: 38 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min to obtain a lyophilized sample.
  • the lyophilized conditions were as shown in Example 1. .
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 130mL of pure water in a steel cup with jacket, and cool and circulate with tap water at room temperature.
  • Sample preparation Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm.
  • the progesterone solution was pumped into the precipitation solvent at a rate of 219 mL/min (pumping time: 20 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min.
  • the lyophilization conditions were as shown in Example 1.
  • DSC detection Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 11, the sample showed an endothermic peak at 130.75°C, indicating that the obtained crystal form was ⁇ crystal form.
  • Progesterone solution preparation Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of methanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Measure 130mL of pure water in a steel cup with jacket, and cool with natural water at room temperature.
  • Sample preparation Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 114 mL/min (pumping time: 38 s), and filter the resulting suspension with suction The filter cake was washed with 3000mL pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min.
  • the lyophilization conditions were as shown in Example 1.
  • Dispersant preparation same as in Example 2.
  • Suspension preparation Weigh 2.96 g of lyophilized sample (containing 2.5 g of progesterone) into a 150 mL beaker, add 47.04 g of dispersant and shear at 4000 rpm for 5 min.
  • Progesterone solution preparation Weigh 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
  • Precipitation solvent preparation Weigh 15g of Tween 20, rinse it with a 3000mL water several times into a jacketed steel cup, and cool to 9°C with a cooling circulation device.
  • Sample preparation Place the shearing head in the precipitation solvent and adjust the rotation speed to 7000 rpm.
  • the progesterone solution was pumped into the precipitation solvent at a rate of 37 mL/min (pumping time: 117s).
  • the obtained suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
  • the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min.
  • the lyophilization conditions were the same as in Example 1.
  • Dispersant preparation same as in Example 2.
  • Suspension preparation Weigh 2.96 g of lyophilized sample (containing 2.5 g of progesterone) into a 150 mL beaker, add 47.04 g of dispersant and shear at 4000 rpm for 5 min.
  • Sample treatment The prepared suspension was divided into 10 mL vials and rolled with aluminum caps, placed at 40°C for 2 days, and taken out after 5 days for particle size test and DSC test. The test results are shown in Table 2.
  • the ⁇ -crystal progesterone will change to the ⁇ -crystal form, along with the increase in particle size.
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shear head in the precipitation solvent and adjust the rotation speed to 6000 rpm. Adjust the diameter of the liquid outlet to 0.51mm, so that the progesterone solution is pumped into the precipitation solvent at a speed of 100mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 3 g of mannitol, 100 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shearing head in the precipitation solvent, adjust the rotation speed to 8000 rpm, adjust the diameter of the liquid outlet to 0.51 mm, and pump the progesterone solution into the precipitation solvent at a speed of 50 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shearing head in the precipitation solvent, adjust the rotation speed to 8000 rpm, adjust the diameter of the liquid outlet to 0.51 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shear head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shearing head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 6 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the precipitation solvent on a magnetic stirrer, adjust the rotation speed to 2000 rpm, adjust the diameter of the outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 6 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 100mL absolute ethanol, stir to dissolve;
  • Precipitation solvent preparation Weigh 15g Tween 20, rinse it with a 3000mL water several times into a jacketed steel cup, and cool to 9°C with a cooling circulation device;
  • Sample preparation Place the shear head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 4 g of mannitol and 130 mL of water). After stirring at 500 rpm for 30 min, the solution was obtained. The suspension was lyophilized (the lyophilization conditions were the same as in Example 1).
  • Progesterone solution preparation Weigh 20g progesterone, add 65mL absolute ethanol, stir at 60°C to dissolve;
  • Precipitation solvent preparation Weigh 2.5g Tween 20, rinse it with a 1500mL water multiple times into a jacketed steel cup, and cool to 9°C with a cooling circulation device;
  • Sample preparation place the precipitation solvent on the magnetic stirrer, adjust the rotation speed to 2000 rpm to precipitate the solvent, adjust the outlet diameter to 0.90 mm, and pump the progesterone solution into the precipitation solvent at a speed of 100 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
  • Example 17 In vivo metabolism of progesterone suspension
  • mice 16 female SD rats (ovariectomized) (220g to 300g) were randomly divided into 4 groups (A, B, C, and D groups in sequence), with 4 rats in each group.
  • the reference preparation is a commercially available progesterone oily injection (50 mg/mL).
  • Mode of administration and dosage intramuscular injection of the outer thigh; Group A: commercially available progesterone oily injection, 6 mg/Kg for 5 consecutive days; Group B: the progesterone suspension of Example 4, 30 mg /Kg; Group C: the progesterone suspension of Example 2 was administered at 30 mg/Kg; Group D: the progesterone suspension of Example 7 was administered at 30 mg/Kg.
  • HPLC-MS/MS method was used to detect the content of progesterone in rat plasma to indicate the change of progesterone plasma concentration in SD rats after intramuscular injection of progesterone suspension.
  • Figure 13 shows the change curve of progesterone concentration in rat plasma with time, from the figure we can see Example 2 (mixed crystal form), Example 4 ( ⁇ crystal form), Example 7 ( ⁇ crystal form) All the prepared samples can achieve a 5-day sustained-release effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

Disclosed is a method for preparing a progesterone particulate, especially a crystal or powder. The method comprises: step 1, dissolving progesterone in a solvent to provide a progesterone solution; step 2, pumping the progesterone solution into a high-speed shearing progesterone precipitation solvent at a predetermined speed to precipitate progesterone; and step 3, separating the precipitate and freeze-drying same to obtain the progesterone particulate, wherein the progesterone particulate being a progesterone crystal or progesterone powder. By using the method of the present invention, a micron-sized progesterone crystal or powder having good stability can be obtained. The progesterone injection prepared by using same not only achieves a sustained release effect of at least 5 days, but also has good stability. The method of the present invention is simple to operate, has low cost, and is easily scaled up for industrial production.

Description

制备黄体酮颗粒物的方法、所得黄体酮颗粒物及其注射剂Method for preparing progesterone particles, obtained progesterone particles and injection 技术领域Technical field
本发明涉及制备黄体酮颗粒物，尤其是黄体酮晶体或粉体的方法，以及涉及所得黄体酮晶体或粉体及其注射剂。The invention relates to a method for preparing progesterone particles, especially progesterone crystals or powders, and to the obtained progesterone crystals or powders and injections thereof.
背景技术Background technique
众所周知，对于药物，产品的剂型、物理形态，诸如晶型、粒度、溶解性等对其体内释放、生物利用度等方面具有显著的影响。因此，制备具有优势晶型、优势粒度等的制剂受到越来越多的关注。As we all know, for drugs, the dosage form and physical form of products, such as crystal form, particle size, solubility, etc., have a significant impact on their in vivo release and bioavailability. Therefore, the preparation of preparations with superior crystal form, superior particle size, etc. has received more and more attention.
黄体酮在临床上广泛应用于治疗月经不调、先兆流产等黄体功能不足引起的病症。已知，黄体酮是一种具有多晶型的物质，其中的α晶型和β晶型比较稳定且晶体结构明确(熔点分别约为131℃、123℃)，均具有生物活性(R.Woolf et.al Proc.Soc.Exp.Biol.Med.,1948,68(1),79-83；R.Lancaster et.al J.Pharm.Sci.,2007,96(12),3419-3431)。不同晶型结构的黄体酮具有不同的熔点、表观溶解度、光学性质等，因此对所得制剂的体内代谢、生物利用度等造成影响。Progesterone is widely used clinically to treat disorders such as irregular menstruation, threatened abortion and other corpus luteum function. It is known that progesterone is a substance with a polymorphic form, and the alpha and beta crystal forms are relatively stable and the crystal structure is clear (melting points are about 131 ℃ and 123 ℃, respectively), and both have biological activity (R. Woolf et.al Proc. Soc. Exp. Biol. Med., 1948, 68 (1), 79-83; R. Lancaster et. al. J. Pharm. Sci., 2007, 96 (12), 3419-3431). Progesterone with different crystalline structures has different melting points, apparent solubility, optical properties, etc., so it affects the in vivo metabolism and bioavailability of the resulting preparation.
现有技术中常见的多晶型药物的制备方法包括溶液结晶、熔融法、升华法、粉碎研磨法等常规方法，并且还包括急速冷冻、毛细管生成法、高通量筛选法、超临界流体法、激光诱导等非常规方法。The common preparation methods of polymorphic drugs in the prior art include solution crystallization, melting method, sublimation method, crushing and grinding method and other conventional methods, and also include rapid freezing, capillary generation method, high-throughput screening method, supercritical fluid method , Laser induction and other unconventional methods.
例如，在CN107417756A公布了一种浓缩黄体酮有机溶液制备黄体酮晶型的方法。然而，该文献所公开的方法还需进行研磨等处理才能得到粒径分布符合要求的样品。再者，CN109223722A公开了一种通过冻干黄体酮水包油型乳液制备黄体酮纳米晶注射剂的方法。然而该文献所记载的方法一方面在放大生产冻干时使用的有机溶剂量会随之增加，不适于直接冻干， 另一方面，黄体酮纳米晶的尺寸受乳滴大小限制，可调范围有限。For example, CN107417756A discloses a method for preparing progesterone crystal form by concentrating progesterone organic solution. However, the method disclosed in this document requires grinding and other treatments to obtain samples with particle size distributions that meet the requirements. Furthermore, CN109223722A discloses a method for preparing progesterone nanocrystal injection by freeze-drying progesterone oil-in-water emulsion. However, on the one hand, the method described in this document will increase the amount of organic solvents used in the production of lyophilization, which is not suitable for direct lyophilization. On the other hand, the size of progesterone nanocrystals is limited by the size of the milk droplets, and the adjustable range limited.
此外，目前最常见的黄体酮制剂为口服制剂和注射剂。口服制剂虽然给药最为方便，患者顺应性好，但其首过效应显著，生物利用度仅为10％左右。因此，从临床应用来看，黄体酮水性长效注射剂开发的重要性越来越显著。黄体酮水性长效注射剂的实现方式主要有包载式(例如聚合物型水性黄体酮注射剂等)和直接式(例如黄体酮混悬型长效注射剂以及粉针剂)。其中包载式涉及到载药量、包封率等方面的问题，不仅制备过程较为复杂，也会增加后期质量标准制定的工作难度。而直接式可以根据临床需要方便地控制黄体酮粒径及浓度，使给药频率最低而治疗效果最佳，最大程度地增强患者的顺应性。In addition, the most common progesterone preparations are oral preparations and injections. Although the oral preparation is the most convenient for administration and the patient has good compliance, its first-pass effect is remarkable, and the bioavailability is only about 10%. Therefore, from the perspective of clinical application, the development of progesterone aqueous long-acting injections is becoming more and more important. The implementation methods of progesterone aqueous long-acting injections are mainly encapsulated (such as polymer-based aqueous progesterone injection, etc.) and direct (such as progesterone suspended long-acting injections and powder injections). Among them, the loading type involves the problems of drug loading and encapsulation rate. Not only is the preparation process more complicated, but also it will increase the difficulty of setting quality standards in the later stage. The direct type can conveniently control the particle size and concentration of progesterone according to clinical needs, so that the frequency of administration is the lowest and the therapeutic effect is the best, and the patient's compliance is maximized.
因此，开发出一种工艺简单、稳定性好、有缓释作用的黄体酮颗粒物，尤其是晶体或粉体的制备方法具有重要意义。Therefore, it is of great significance to develop a method for preparing progesterone particles with simple process, good stability and slow-release effect, especially crystals or powders.
发明内容Summary of the invention
鉴于现有技术中制备不同黄体酮颗粒物，尤其是晶体或粉体存在的问题，本发明提出了一种稳定性好的黄体酮颗粒物的制备方法，并且本发明所提出的方法操作简单，易于工业化放大生产。In view of the problems in the preparation of different progesterone particles, especially crystals or powders in the prior art, the present invention provides a method for preparing progesterone particles with good stability, and the method proposed by the present invention is simple to operate and easy to industrialize Enlarge production.
为了实现本发明的上述目的，本发明的第一方面提供了一种制备黄体酮颗粒物的方法，其中所述方法包括：In order to achieve the above object of the present invention, the first aspect of the present invention provides a method for preparing progesterone particles, wherein the method includes:
步骤1，使黄体酮溶于溶剂中以提供黄体酮溶液； Step 1, dissolve progesterone in the solvent to provide a progesterone solution;
步骤2，将所述黄体酮溶液以预定速度泵入到高速剪切或剧烈搅拌的黄体酮的析出溶剂中以使黄体酮析出；和Step 2: pumping the progesterone solution into the progesterone precipitation solvent with high-speed shearing or vigorous stirring at a predetermined speed to precipitate progesterone; and
步骤3，分离析出物并进行干燥以获得所述黄体酮颗粒物；其中，所述黄体酮颗粒物为黄体酮晶体或黄体酮粉体。In step 3, the precipitate is separated and dried to obtain the progesterone particles; wherein the progesterone particles are progesterone crystals or progesterone powder.
具体地，一些实施方案中，本发明涉及一种制备黄体酮晶体的方法，其中，所述方法包括：Specifically, in some embodiments, the present invention relates to a method of preparing progesterone crystals, wherein the method includes:
将黄体酮溶于溶剂中以提供黄体酮溶液；Progesterone is dissolved in the solvent to provide a solution of progesterone;
将所述黄体酮溶液以预定速度泵入至冷却的高速剪切或剧烈搅拌的析出溶剂中以使黄体酮析出；所述的析出溶剂为水、有机溶剂或水与有机溶剂的混合物；Pumping the progesterone solution at a predetermined speed into a cooled high-speed shearing or vigorously stirred precipitation solvent to precipitate the progesterone; the precipitation solvent is water, an organic solvent, or a mixture of water and an organic solvent;
分离所析出的黄体酮并进行冷冻干燥以获得黄体酮晶体。The precipitated progesterone is separated and freeze-dried to obtain progesterone crystals.
在本发明的一些实施方案中，所述黄体酮溶液的浓度为10mg/mL至500mg/mL；进一步优选为200mg/mL至450mg/mL。In some embodiments of the present invention, the concentration of the progesterone solution is 10 mg/mL to 500 mg/mL; further preferably 200 mg/mL to 450 mg/mL.
在本发明的一些实施方案中，溶解黄体酮所用的溶剂为与水互溶的有机溶剂；优选地，所述溶解黄体酮所用的溶剂为选自甲醇、无水乙醇、异丙醇和丙酮中的一种或它们的混合物，或者上述醇类的水溶液；优选地，所述溶解黄体酮所用的溶剂为甲醇、无水乙醇或95vol％乙醇；更优选地，所述溶解黄体酮所用的溶剂为甲醇或无水乙醇。In some embodiments of the present invention, the solvent used to dissolve progesterone is an organic solvent miscible with water; preferably, the solvent used to dissolve progesterone is one selected from methanol, absolute ethanol, isopropanol, and acetone Species or a mixture thereof, or an aqueous solution of the above alcohols; preferably, the solvent used to dissolve progesterone is methanol, absolute ethanol, or 95 vol% ethanol; more preferably, the solvent used to dissolve progesterone is methanol or Absolute ethanol.
其中，在本发明中，为获得所需浓度的黄体酮溶液，可以进行适当的加热。Among them, in the present invention, in order to obtain a desired concentration of progesterone solution, appropriate heating may be performed.
在本发明的一些实施方案中，所述有机溶剂选自甲醇、乙醇、异丙醇和丙酮中的一种或多种；优选地，所述析出溶剂为水、乙醇或水与乙醇的混合物。在本发明的一些实施方案中，所述析出溶剂为水；另一些实施方案中，所述析出溶剂为乙醇；又一些实施方案中，所述析出溶剂为乙醇和水的混合物，其中，可根据需要调节水和乙醇的体积比为20:1～1:20，例如水和乙醇的体积比包括但不限于4:1、1:1、1:4。In some embodiments of the present invention, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and acetone; preferably, the precipitation solvent is water, ethanol, or a mixture of water and ethanol. In some embodiments of the present invention, the precipitation solvent is water; in other embodiments, the precipitation solvent is ethanol; in still other embodiments, the precipitation solvent is a mixture of ethanol and water, wherein, according to The volume ratio of water and ethanol needs to be adjusted from 20:1 to 1:20. For example, the volume ratio of water and ethanol includes but is not limited to 4:1, 1:1, and 1:4.
在本发明的一些实施方案中，可通过蠕动泵控制黄体酮溶液向析出溶剂的泵入，泵入速度例如为50mL/min至500mL/min，优选100mL/min至400mL/min。In some embodiments of the present invention, the pumping of the progesterone solution into the precipitation solvent can be controlled by a peristaltic pump, for example, the pumping speed is 50 mL/min to 500 mL/min, preferably 100 mL/min to 400 mL/min.
在本发明的一些实施方案中，所述剧烈搅拌通常为500rpm至2000rpm，优选700rpm至1000rpm的转速。所述高速剪切可通过转速为3000rpm至 20000rpm的高速搅拌来实现，优选地转速为7000rpm至20000rpm。In some embodiments of the present invention, the vigorous stirring is generally 500 rpm to 2000 rpm, preferably 700 rpm to 1000 rpm. The high-speed shearing can be achieved by high-speed stirring with a rotation speed of 3000 rpm to 20,000 rpm, preferably a rotation speed of 7000 rpm to 20,000 rpm.
在本发明的一些实施方案中，所述析出溶剂的温度为-20℃至25℃。更具体地，当以水作为析出溶剂时，其温度为1℃至25℃；当以有机溶剂作为析出溶剂时，析出溶剂的温度为-20℃至0℃；当以水与有机溶剂的混合物作为析出溶剂时，析出溶剂的温度为-10℃至25℃，优选地，析出溶剂的温度为-10℃至0℃。In some embodiments of the present invention, the temperature of the precipitation solvent is -20°C to 25°C. More specifically, when water is used as the precipitation solvent, its temperature is 1°C to 25°C; when organic solvent is used as the precipitation solvent, the temperature of the precipitation solvent is -20°C to 0°C; when a mixture of water and organic solvent is used As the precipitation solvent, the temperature of the precipitation solvent is -10°C to 25°C, preferably, the temperature of the precipitation solvent is -10°C to 0°C.
在本发明一些实施方案中，泵入的黄体酮溶液与析出溶剂的体积比为1.5:1～1:10，优选为1:1.5～1:5。其中，可例如通过蠕动泵控制黄体酮溶液向析出溶剂的泵入，泵入速度例如为50mL/min至500mL/min，优选100mL/min至400mL/min。In some embodiments of the present invention, the volume ratio of the pumped progesterone solution to the precipitation solvent is 1.5:1 to 1:10, preferably 1:1.5 to 1:5. Among them, the pumping of the progesterone solution into the precipitation solvent can be controlled by, for example, a peristaltic pump, and the pumping speed is, for example, 50 mL/min to 500 mL/min, preferably 100 mL/min to 400 mL/min.
为了分散的需要，所述黄体酮溶液中可进一步包含：基于所述黄体酮溶液的质量，0.5wt％至3wt％，优选1wt％至2wt％的表面活性剂。所述表面活性剂包括但不限于聚山梨酯20(吐温20)、聚山梨酯80(吐温80)、失水山梨醇脂肪酸酯(司盘20、40、60、80)、琥珀酸酯、单硬脂酸甘油酯等。其中，这些表面活性剂可能会包含在黄体酮沉淀物中。通过分离步骤，例如通过洗涤沉淀，可除去沉淀物中的少量的表面活性剂，从而在最终的粉体中可以不含或仅含痕量的表面活性剂。For the purpose of dispersion, the progesterone solution may further include: 0.5 wt% to 3 wt%, preferably 1 wt% to 2 wt% surfactant based on the mass of the progesterone solution. The surfactant includes, but is not limited to, polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sorbitan fatty acid ester ( Span 20, 40, 60, 80), succinic acid Ester, glyceryl monostearate, etc. Among them, these surfactants may be included in the progesterone precipitate. Through the separation step, for example, by washing the precipitate, a small amount of surfactant in the precipitate can be removed, so that the final powder may contain no or only a trace amount of surfactant.
根据本发明的方法，具体地，为得到α晶型的黄体酮，优选乙醇作为析出溶剂；更优选地，可以向析出溶剂中事先加入α型晶种，此时，析出溶剂的种类可以不受限制。为得到β晶型的黄体酮，优选以水作为析出溶剂，甲醇作为溶解黄体酮的有机溶剂；更优选地，类似地，可以事先向析出溶剂中加入β型晶种。According to the method of the present invention, specifically, in order to obtain the alpha crystal form of progesterone, ethanol is preferably used as the precipitation solvent; more preferably, the alpha type seed crystal may be added to the precipitation solvent in advance. At this time, the type of precipitation solvent may not be affected limit. In order to obtain the β-crystal form of progesterone, it is preferable to use water as the precipitation solvent and methanol as the organic solvent to dissolve the progesterone; more preferably, similarly, the β-type seed crystal may be added to the precipitation solvent in advance.
本发明的一些实施方案中，可将晶种加入到冷却至特定温度的析出溶剂中，其中晶种可以以粉末或混悬液形式，优选以混悬液形式来加入。在本发明中，作为晶种的原料可通过剪切、超声等途径分散于水中。其中， 为了促进晶种的分散，水中可加入0.1％～2％(w/v)的表面活性剂(例如吐温20等)。其中，加入的晶种的量可为0.1wt％～10wt％(相对于黄体酮)，优选为1wt％～5wt％(相对于黄体酮)。In some embodiments of the invention, the seed crystals can be added to the precipitation solvent cooled to a specific temperature, where the seed crystals can be added in the form of a powder or suspension, preferably in the form of a suspension. In the present invention, the raw material as the seed crystal can be dispersed in water by shearing, ultrasound or the like. Among them, in order to promote the dispersion of seed crystals, 0.1% to 2% (w/v) surfactant (for example, Tween 20, etc.) may be added to the water. Wherein, the amount of seed crystal added may be 0.1 wt% to 10 wt% (relative to progesterone), preferably 1 wt% to 5 wt% (relative to progesterone).
在本发明的一些实施方案中，所述分离为过滤，优选抽滤。In some embodiments of the invention, the separation is filtration, preferably suction filtration.
在本发明的一些实施方案中，所述冷冻干燥包括：将分离得到的沉淀物重新分散于2wt％至4wt％甘露醇水溶液中；然后进行冻干以得到含量≥80wt％的黄体酮晶体，例如80wt％至86wt％。In some embodiments of the present invention, the freeze-drying includes: redispersing the separated precipitate in a 2 wt% to 4 wt% aqueous mannitol solution; then freeze-drying to obtain progesterone crystals with a content of ≥80 wt%, for example 80wt% to 86wt%.
其中，在本发明中，通过调节黄体酮溶液浓度、泵入速度、搅拌/剪切速度、析出溶剂的种类和冷却温度，尤其是调节搅拌/剪切速度，所得黄体酮晶体的粒径在0.3μm至60μm(D[4,3]，体积加权平均粒径)范围内，优选粒径范围为10μm至30μm。Among them, in the present invention, by adjusting the concentration of progesterone solution, pumping speed, stirring/shearing speed, type of precipitation solvent and cooling temperature, especially adjusting the stirring/shearing speed, the particle size of the obtained progesterone crystal is 0.3 Within the range of μm to 60 μm (D[4,3], volume-weighted average particle size), the preferred particle size range is 10 μm to 30 μm.
根据本发明的另一方面，提供了由上述方法得到的黄体酮晶体，所述黄体酮晶体具有0.3μm至60μm，优选10μm至30μm的粒径。According to another aspect of the present invention, there is provided a progesterone crystal obtained by the above method, the progesterone crystal having a particle size of 0.3 μm to 60 μm, preferably 10 μm to 30 μm.
根据本发明的又一方面，提供了一种黄体酮注射剂，包括治疗有效量的本发明的黄体酮晶体。According to yet another aspect of the present invention, there is provided a progesterone injection, which includes a therapeutically effective amount of the progesterone crystal of the present invention.
本发明的黄体酮注射剂可为粉针剂或混悬剂。The progesterone injection of the present invention may be powder injection or suspension.
根据部分实施方式，所述黄体酮粉针剂进一步包括空间稳定剂、表面活性剂和渗透压调节剂等。According to some embodiments, the progesterone powder injection further includes a space stabilizer, a surfactant, an osmotic pressure regulator, and the like.
根据部分实施方式，所述黄体酮混悬液注射剂还包括注射用水、空间稳定剂、表面活性剂、渗透压调节剂和pH调节剂等。According to some embodiments, the progesterone suspension injection further includes water for injection, space stabilizer, surfactant, osmotic pressure adjuster, pH adjuster, and the like.
本发明对上述空间稳定剂、表面活性剂、渗透压调节剂和pH调节剂等没有特别限制，可使用现有技术中可药用的适宜的佐剂。例如，空间稳定剂包括但不限于羟丙基甲基纤维素及其盐类、聚乙烯吡咯烷酮、聚乙二醇类等；表面活性剂包括但不限于聚山梨酯类、失水山梨醇脂肪酸酯(司盘20、40、60、80)、琥珀酸酯、单硬脂酸甘油酯等；渗透压调节剂包括但不 限于糖类(如葡萄糖，果糖等)、多羟糖醇(如甘露醇等)、无机盐类(如氯化钠)等；pH调节剂包括但不限于盐酸、氢氧化钠、磷酸二氢钠、磷酸氢二钠等。In the present invention, the above-mentioned steric stabilizer, surfactant, osmotic pressure adjuster, pH adjuster, etc. are not particularly limited, and a suitable pharmaceutically acceptable adjuvant in the prior art can be used. For example, steric stabilizers include but are not limited to hydroxypropyl methylcellulose and its salts, polyvinylpyrrolidone, polyethylene glycols, etc.; surfactants include but are not limited to polysorbates, sorbitan fatty acids Ester ( Span 20, 40, 60, 80), succinate, glyceryl monostearate, etc.; osmotic regulators include but are not limited to sugars (such as glucose, fructose, etc.), polyhydric alcohols (such as mannose) Alcohol, etc.), inorganic salts (such as sodium chloride), etc.; pH adjusting agents include but are not limited to hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.
在本发明的部分实施方案中，提供了制备黄体酮粉体的方法，包括：In some embodiments of the present invention, a method for preparing progesterone powder is provided, including:
使黄体酮溶于有机溶剂中以提供黄体酮溶液；Progesterone is dissolved in an organic solvent to provide a solution of progesterone;
将黄体酮溶液以预定流量加入高速剪切的黄体酮析出溶剂中；和Add the progesterone solution to the progesterone precipitation solvent with high shear at a predetermined flow rate; and
分离沉淀物并干燥以获得所述黄体酮粉体。The precipitate was separated and dried to obtain the progesterone powder.
根据本发明的方法，黄体酮的有机溶液以预定流量加入高速剪切的黄体酮析出溶剂中，使黄体酮迅速在析出溶剂中析出沉淀。通过控制单位时间内加入的黄体酮量以及剪切速率最终可以获得所需粒径的黄体酮粉体。例如，通常来说黄体酮溶液的流量越小，析出溶剂的剪切速率越快，则获得的黄体酮粉体的粒径越小。According to the method of the present invention, the organic solution of progesterone is added to the progesterone precipitation solvent of high shear at a predetermined flow rate, so that the progesterone is quickly precipitated in the precipitation solvent. By controlling the amount of progesterone added per unit time and the shear rate, progesterone powder with the desired particle size can be finally obtained. For example, generally speaking, the smaller the flow rate of the progesterone solution and the faster the shear rate of the precipitation solvent, the smaller the particle size of the progesterone powder obtained.
本发明的方法中所述黄体酮溶液的浓度为10～300mg/mL；进一步优选为30～200mg/mL。In the method of the present invention, the concentration of the progesterone solution is 10 to 300 mg/mL; further preferably 30 to 200 mg/mL.
所述有机溶剂为与水互溶的有机溶剂，所述有机溶剂可选自甲醇、乙醇、丙醇和乙二醇中的一种，或者是这些醇中的两种或更多种的混合溶剂，或者是上述醇的水溶液。优选地，所述醇的水溶液中醇的体积百分比在80vol％以上，更优选在90vol％以上，最优选为95vol％以上。根据较佳的实施方式，所述有机溶剂为甲醇、乙醇、或95vol％乙醇水溶液。The organic solvent is an organic solvent that is miscible with water, and the organic solvent may be one selected from methanol, ethanol, propanol, and ethylene glycol, or a mixed solvent of two or more of these alcohols, or It is an aqueous solution of the above alcohol. Preferably, the volume percentage of alcohol in the aqueous solution of alcohol is above 80 vol%, more preferably above 90 vol%, most preferably above 95 vol%. According to a preferred embodiment, the organic solvent is methanol, ethanol, or a 95 vol% ethanol aqueous solution.
为获得所需的黄体酮溶液的浓度，可以进行适当的加热。In order to obtain the desired concentration of the progesterone solution, appropriate heating may be performed.
根据部分实施方式，本发明的方法中，所述高速剪切可通过转速为700～2000rpm的高速搅拌实现。根据部分实施方式，所述高速剪切可通过高速剪切仪来实现，其中剪切头转速可为5000～20000rpm。According to some embodiments, in the method of the present invention, the high-speed shearing may be achieved by high-speed stirring at a rotation speed of 700-2000 rpm. According to some embodiments, the high-speed shearing can be achieved by a high-speed shearing apparatus, wherein the rotation speed of the shearing head can be 5000 to 20000 rpm.
最终加入的所述黄体酮溶液和析出溶剂的体积比为1:3～1:30，优选为1:10，进一步优选为1:5。The volume ratio of the progesterone solution and the precipitation solvent finally added is 1:3 to 1:30, preferably 1:10, and more preferably 1:5.
根据部分实施方式，所述黄体酮析出溶剂为水。According to some embodiments, the progesterone precipitation solvent is water.
为了分散的需要，所述黄体酮析出溶剂中可进一步包含0.1～2wt％，优选0.3～0.8wt％的表面活性剂。For the purpose of dispersion, the progesterone precipitation solvent may further contain 0.1 to 2% by weight, preferably 0.3 to 0.8% by weight of surfactant.
这些表面活性剂可能会包含在黄体酮沉淀物中。通过分离步骤，例如通过洗涤沉淀，可除去沉淀物中的少量的表面活性剂，从而在最终的粉体中可以不含或仅含痕量的表面活性剂。These surfactants may be included in the progesterone precipitate. Through the separation step, for example, by washing the precipitate, a small amount of surfactant in the precipitate can be removed, so that the final powder may contain no or only a trace amount of surfactant.
所述表面活性剂选自聚山梨酯20(吐温20)、聚山梨酯80(吐温80)、失水山梨醇脂肪酸酯(如司盘20、40、60、80)、聚乙二醇1000维生素E琥珀酸酯(TPGS)、聚乙二醇15羟硬脂酸酯(如
Figure PCTCN2019127555-appb-000001
HS15)、泊洛沙姆、十二烷基硫酸钠(SDS)、单脂肪酸甘油酯、卵磷脂、环糊精、和聚氧乙烯蓖麻油中的一种或多种；优选地，所述表面活性剂选自吐温20、吐温80、失水山梨醇脂肪酸酯(特别是司盘20)、泊洛沙姆中的一种或多种；进一步优选地，所述表面活性剂为吐温20。 The surfactant is selected from polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), sorbitan fatty acid ester (such as Span 20, 40, 60, 80), polyethylene dioxide Alcohol 1000 Vitamin E succinate (TPGS), polyethylene glycol 15 hydroxystearate (e.g.
Figure PCTCN2019127555-appb-000001
HS15), poloxamer, sodium lauryl sulfate (SDS), one or more of mono-fatty acid glycerides, lecithin, cyclodextrin, and polyoxyethylene castor oil; preferably, the surface The active agent is selected from one or more of Tween 20, Tween 80, sorbitan fatty acid ester (especially Span 20), and Poloxamer; further preferably, the surfactant is Tween Temperature 20.
根据一种实施方式，所述黄体酮析出溶剂可预先冷却至5～10℃。冷却的析出溶剂有助于黄体酮更快速和更大量地析出。According to one embodiment, the progesterone precipitation solvent may be cooled to 5-10°C in advance. The cooled precipitation solvent helps progesterone precipitate out more quickly and in greater amounts.
本发明的方法中，通过流量的调节，配合其他工艺条件，如溶液浓度、析出溶剂的剪切速率等可以获得不同粒径的黄体酮粉体。通常来说，预定流量可在6～100mL/min范围内调节。In the method of the present invention, progesterone powders with different particle sizes can be obtained by adjusting the flow rate in conjunction with other process conditions, such as solution concentration and shear rate of the precipitation solvent. Generally speaking, the predetermined flow rate can be adjusted in the range of 6 to 100 mL/min.
当所有黄体酮溶液均加入到析出溶剂后，将沉淀的黄体酮分离，并干燥。After all progesterone solutions are added to the precipitation solvent, the precipitated progesterone is separated and dried.
在部分实施方式中，所述分离为过滤，优选抽滤。In some embodiments, the separation is filtration, preferably suction filtration.
在部分实施方式中，所述干燥的方式为冷冻干燥。In some embodiments, the drying method is freeze drying.
在部分实施方式中，所述冷冻干燥的操作步骤为：将分离得到的沉淀物重新分散于2wt％～4wt％甘露醇水溶液中之后通过冻干得到所述黄体酮粉体；In some embodiments, the operation step of freeze-drying is: redispersing the separated precipitate in a 2 wt% to 4 wt% mannitol aqueous solution and then freeze-drying to obtain the progesterone powder;
其中，所述分散的步骤优选通过搅拌方式分散，所述搅拌的转速优选500～1000rpm。Wherein, the step of dispersing is preferably dispersed by stirring, and the rotating speed of the stirring is preferably 500 to 1000 rpm.
其中，黄体酮的有机溶液以预定流量加入高速剪切的黄体酮析出溶剂中，使黄体酮迅速在析出溶剂中析出沉淀。通过控制单位时间内加入的黄体酮量以及剪切速率最终可以获得所需粒径的黄体酮粉体。例如，通常来说黄体酮溶液的流量越小，析出溶剂的剪切速率越快，则获得的黄体酮粉体的粒径越小。Among them, the organic solution of progesterone is added into the progesterone precipitation solvent with high shear at a predetermined flow rate, so that the progesterone is quickly precipitated in the precipitation solvent. By controlling the amount of progesterone added per unit time and the shear rate, progesterone powder with the desired particle size can be finally obtained. For example, generally speaking, the smaller the flow rate of the progesterone solution and the faster the shear rate of the precipitation solvent, the smaller the particle size of the progesterone powder obtained.
通过本发明的方法可获得微米级的黄体酮颗粒物且稳定性好，同时可以对最终获得的颗粒物的粒径进行可控调节，从而获得粒径在0.3～60μm，优选10～30μm范围内可调的颗粒物。通过进一步的药代动力学实验证实，采用本申请制备的黄体酮注射剂不仅实现至少5天的缓释效果，达到了缓释目标，能够减少给药频率，提高患者顺应性，而且稳定性好。此外，本发明的方法操作简单，成本低，易于工业化放大生产。By the method of the present invention, micron-level progesterone particles can be obtained with good stability, and at the same time, the particle size of the finally obtained particles can be controlled and adjusted, so that the particle size can be adjusted within the range of 0.3 to 60 μm, preferably 10 to 30 μm Particulate matter. Through further pharmacokinetic experiments, it is confirmed that the progesterone injection prepared by the present application not only achieves a sustained release effect for at least 5 days, reaches the sustained release target, can reduce the frequency of administration, improve patient compliance, and has good stability. In addition, the method of the present invention is simple to operate, low in cost, and easy to scale up in industrial production.
附图说明BRIEF DESCRIPTION
图1为根据本发明的实施例1的样品的XRD图谱；FIG. 1 is an XRD pattern of a sample according to Example 1 of the present invention;
图2为根据本发明的实施例1的样品的DSC图谱；2 is a DSC chart of the sample according to Example 1 of the present invention;
图3为根据本发明的实施例2的样品的XRD图谱；3 is an XRD pattern of a sample according to Example 2 of the present invention;
图4为根据本发明的实施例2的样品的DSC图谱；4 is a DSC chart of a sample according to Example 2 of the present invention;
图5为根据本发明的实施例3的样品的XRD图谱；5 is an XRD pattern of a sample according to Example 3 of the present invention;
图6为根据本发明的实施例3的样品的DSC图谱；6 is a DSC chart of a sample according to Example 3 of the present invention;
图7为根据本发明的实施例4的样品的XRD图谱；7 is an XRD pattern of a sample according to Example 4 of the present invention;
图8为根据本发明的实施例4的样品的DSC图谱；8 is a DSC chart of a sample according to Example 4 of the present invention;
图9为根据本发明的实施例5的样品的XRD图谱；9 is an XRD pattern of a sample according to Example 5 of the present invention;
图10为根据本发明的实施例6的样品的XRD图谱；10 is an XRD pattern of a sample according to Example 6 of the present invention;
图11为根据本发明的实施例6的样品的DSC图谱；11 is a DSC chart of a sample according to Example 6 of the present invention;
图12为根据本发明的实施例7的样品的XRD图谱；12 is an XRD pattern of a sample according to Example 7 of the present invention;
图13为根据本发明的实施例17所得到的血浆中黄体酮浓度随时间的变化曲线。13 is a graph showing the change of plasma progesterone concentration with time according to Example 17 of the present invention.
具体实施方式detailed description
下面将结合本发明具体实施方式及附图，对本发明实施方式中的技术方案进行清楚、完整地描述，显然，所描述的实施方式仅仅是本发明的一部分实施方式，而不是全部的实施方式。基于本发明中的实施方式，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施方式，都属于本发明保护的范围。The technical solutions in the embodiments of the present invention will be described clearly and completely in combination with the specific embodiments of the present invention and the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by a person of ordinary skill in the art without making creative work fall within the protection scope of the present invention.
以下通过具体实施例来进一步说明本发明的各方面，本发明的各个优点将通过以下实施例显示出来。The following further describes the aspects of the present invention through specific embodiments, and the advantages of the present invention will be shown through the following embodiments.
其中，在以下实施例中，除非另有说明，否则所有的试剂、仪器等都商购所得。In the following examples, all reagents and instruments are commercially available unless otherwise stated.
实施例1.黄体酮样品的制备Example 1. Preparation of progesterone sample
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：量取130mL无水乙醇于带夹套钢杯中，用冷却循环装置冷却至-20℃。 Precipitation solvent preparation : Measure 130mL of absolute ethanol in a steel cup with jacket and cool to -20℃ with a cooling circulation device.
样品制备：将剪切头置入析出溶剂中，转速调至7000rpm。将黄体酮溶液以117mL/min的速度泵入析出溶剂中(泵入时间：90s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Place the shearing head in the precipitation solvent and adjust the rotation speed to 7000 rpm. The progesterone solution was pumped into the precipitation solvent at a rate of 117 mL/min (pumping time: 90 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇14g，水400mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(东富龙，LYO-2)，冻干条件如下表1。Transfer the solid precipitate to a mannitol solution (containing 14g of mannitol and 400mL of water), and after stirring at 500rpm for 30min, freeze the resulting suspension (Tongfulong, LYO-2). 1.
表1.冻干条件Table 1. Freeze-drying conditions
Figure PCTCN2019127555-appb-000002
Figure PCTCN2019127555-appb-000002
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝23.339μm。 Particle size test : The particle size is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=23.339 μm.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图1所示，在2θ＝12.7101°处出现明显衍射峰，为α晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Figure 1, a significant diffraction peak appeared at 2θ=12.7101° , Is α crystal form.
DSC检测：用梅特勒DSC(DSC 500，METTLER TOLEDO)对所得样品进行测试(35℃至160℃，10K/min)。如图2所示，样品在131.20℃出现吸热峰，表明所得晶型为α晶型。 DSC detection : Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 2, the sample showed an endothermic peak at 131.20°C, indicating that the obtained crystal form was α crystal form.
实施例2.黄体酮混悬液的制备Example 2. Preparation of progesterone suspension
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃条件搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir and dissolve at 60℃.
析出溶剂配制：量取104mL纯水、26mL无水乙醇于带夹套钢杯中，用冷却循环装置冷却至-10℃。 Precipitation solvent preparation : Measure 104mL of pure water and 26mL of absolute ethanol in a steel cup with jacket, and cool to -10℃ with a cooling circulation device.
样品制备：将剪切头置入析出溶剂中，转速调至7000rpm，将黄体酮溶液以219mL/min的速度泵入析出溶剂中(泵入时间：20s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 219 mL/min (pumping time: 20 s), and filter the resulting suspension with suction The filter cake was washed with 3000mL pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干，冻干条件如实施例1中所示。The solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min. The lyophilization conditions were as shown in Example 1.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图3所示，在2θ＝12.7213°(α晶型)和2θ＝13.6486°(β晶型)出现衍射峰，为混合晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Fig. 3, at 2θ=12.7213° (α crystal form) And 2θ = 13.6486° (β crystal form) diffraction peak, which is a mixed crystal form.
分散剂配制：称量0.75g司盘20、1.9g吐温20、1.25g磷酸二氢钠、2.5g磷酸氢二钠、3.05g氯化钠置于1000mL烧杯中，加入466mL水搅拌至完全溶解得到分散剂。 Dispersant preparation : Weigh 0.75g Span 20, 1.9g Tween 20, 1.25g sodium dihydrogen phosphate, 2.5g disodium hydrogen phosphate, 3.05g sodium chloride in a 1000mL beaker, add 466mL water and stir until completely dissolved A dispersant is obtained.
混悬液制备：称量2.94g冻干样品(含黄体酮2.5g)置于150mL烧杯中，加入分散剂47.06g后于4000rpm条件下剪切5min。 Suspension preparation : Weigh 2.94g of lyophilized sample (containing 2.5g of progesterone) into a 150mL beaker, add 47.06g of dispersant and shear at 4000rpm for 5min.
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝15.846μm。 Particle size test : The particle size is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=15.846 μm.
DSC检测：用梅特勒DSC(DSC 500，METTLER TOLEDO)对所得样品进行测试(35℃至160℃，10K/min)。如图4所示，样品在125.12℃(β晶型)、131.40℃(α晶型)出现吸热峰，表明所得晶型为混合晶型。 DSC detection : Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 4, the sample showed endothermic peaks at 125.12°C (β crystal form) and 131.40°C (α crystal form), indicating that the obtained crystal form was a mixed crystal form.
实施例3.黄体酮样品的制备Example 3. Preparation of progesterone sample
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：量取26mL纯水、104mL无水乙醇于带夹套钢杯中，用冷却循环装置冷却至-10℃。 Precipitation solvent preparation : Measure 26mL of pure water and 104mL of absolute ethanol in a steel cup with jacket, and cool to -10℃ with a cooling circulation device.
样品制备：将剪切头置入析出溶剂中，转速调至7000rpm，将黄体酮溶液以219mL/min的速度泵入析出溶剂中(泵入时间：20s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 219 mL/min (pumping time: 20 s), and filter the resulting suspension with suction The filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min (the conditions for lyophilization are the same as those for example 1).
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝29.164μm。 Particle size test : The particle size is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=29.164 μm.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图5所示，在2θ＝12.7192°(α晶型)和2θ＝13.6487°(β晶型)出现衍射峰，为混合晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Figure 5, at 2θ=12.7192° (α crystal form) And 2θ = 13.6487° (β crystal form) diffraction peak, which is a mixed crystal form.
DSC检测：用梅特勒DSC(DSC 500，METTLER TOLEDO)对所得样品进行测试(35℃至160℃，10K/min)。如图6所示，样品在123.93℃(β晶型)及131.60℃(α晶型)表现出吸热峰，表明所得晶型为混合晶型。 DSC detection : Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 6, the samples showed endothermic peaks at 123.93°C (β crystal form) and 131.60°C (α crystal form), indicating that the obtained crystal form was a mixed crystal form.
实施例4.黄体酮混悬液的制备Example 4. Preparation of progesterone suspension
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：量取104mL纯水、26mL无水乙醇于带夹套钢杯中，用冷却循环装置冷却至-10℃。 Precipitation solvent preparation : Measure 104mL of pure water and 26mL of absolute ethanol in a steel cup with jacket, and cool to -10℃ with a cooling circulation device.
晶种混悬液配制：称量α晶型黄体酮10g于0.2％(w/v)吐温20溶液(90g)中，7000rpm条件下剪切20min后即得(D[4,3]＝5.207μm)。 Preparation of seed crystal suspension : Weigh 10g of alpha crystalline progesterone in 0.2% (w/v) Tween 20 solution (90g), which is obtained after shearing at 7000rpm for 20min (D[4,3]=5.207 μm).
样品制备：向析出溶剂中加入晶种混悬液10g，将剪切头置入析出溶剂中，转速调至7000rpm。将黄体酮溶液以219mL/min的速度泵入析出溶剂中(泵入时间：20s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm. The progesterone solution was pumped into the precipitation solvent at a rate of 219 mL/min (pumping time: 20 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干得到冻干样品，冻干条件如实施例1中所示。The solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min to obtain a lyophilized sample. The lyophilized conditions were as shown in Example 1. .
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图7所示，在2θ＝12.7214°处出现明显衍射峰，为α晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Figure 7, a significant diffraction peak appeared at 2θ=12.7214° , Is α crystal form.
分散剂配制：同实施例2。 Dispersant preparation : same as in Example 2.
混悬液制备：称量2.94g冻干样品(含黄体酮2.5g)置于150mL烧杯中，加入分散剂47.06g后于4000rpm条件下剪切5min。 Suspension preparation : Weigh 2.94g of lyophilized sample (containing 2.5g of progesterone) into a 150mL beaker, add 47.06g of dispersant and shear at 4000rpm for 5min.
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝10.509μm。 Particle size test : The particle size is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=10.509 μm.
DSC检测：用梅特勒DSC(DSC 500，METTLER TOLEDO)对所得 样品进行测试(35℃至160℃，10K/min)。如图8所示，样品在131.17℃(α晶型)出现吸热峰，表明所得晶型为α晶型。 DSC detection : Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 8, the sample showed an endothermic peak at 131.17°C (α crystal form), indicating that the obtained crystal form was α crystal form.
实施例5.黄体酮样品的制备Example 5. Preparation of progesterone samples
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：量取130mL纯水于带夹套钢杯中，室温自然水冷却循环。 Precipitation solvent preparation : Measure 130mL of pure water in a steel cup with jacket, and cool with natural water at room temperature.
晶种混悬液配制：称量另一批β晶型黄体酮10g于0.2％(w/v)吐温20溶液(90g)中，7000rpm条件下剪切20min后即得(D[4,3]＝5.682μm)。 Preparation of seed suspension : Weigh another batch of β crystal progesterone 10g in 0.2% (w/v) Tween 20 solution (90g), then shear at 7000rpm for 20min to get (D[4,3 ] = 5.682 μm).
样品制备：向析出溶剂中加入晶种混悬液10g，将剪切头置入析出溶剂中，转速调至7000rpm。将黄体酮溶液以114mL/min的速度泵入析出溶剂中(泵入时间：38s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm. The progesterone solution was pumped into the precipitation solvent at a rate of 114 mL/min (pumping time: 38 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干得到冻干样品，冻干条件如实施例1中所示。The solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min to obtain a lyophilized sample. The lyophilized conditions were as shown in Example 1. .
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝11.792μm。 Particle size test : Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=11.792 μm.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图9所示，在2θ＝13.6175°处出现明显衍射峰，为β晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Fig. 9, a significant diffraction peak appeared at 2θ=13.6175° , Is β crystal.
实施例6.黄体酮样品的制备Example 6. Preparation of progesterone sample
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：量取130mL纯水于带夹套钢杯中，室温自来水冷却循环。 Precipitation solvent preparation : Measure 130mL of pure water in a steel cup with jacket, and cool and circulate with tap water at room temperature.
晶种混悬液配制：同实施例4。 Preparation of seed crystal suspension : same as Example 4.
样品制备：向析出溶剂中加入晶种混悬液10g，将剪切头置入析出溶剂中，转速调至7000rpm。将黄体酮溶液以219mL/min的速度泵入析出溶剂中(泵入时间：20s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Add 10 g of seed suspension to the precipitation solvent, place the shear head in the precipitation solvent, and adjust the rotation speed to 7000 rpm. The progesterone solution was pumped into the precipitation solvent at a rate of 219 mL/min (pumping time: 20 s), the resulting suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干，冻干条件如实施例1中所示。The solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min. The lyophilization conditions were as shown in Example 1.
粒径测试：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝12.632μm。 Particle size test : The particle size is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=12.632 μm.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图10所示，在2θ＝12.7181°出现衍射峰，为α晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical). As shown in Fig. 10, the diffraction peak appeared at 2θ=12.7181°, as α crystal form.
DSC检测：用梅特勒DSC(DSC 500，METTLER TOLEDO)对所得样品进行测试(35℃至160℃，10K/min)。如图11所示，样品在130.75℃出现吸热峰，表明所得晶型为α晶型。 DSC detection : Mettler DSC (DSC 500, METTLER TOLEDO) was used to test the obtained samples (35°C to 160°C, 10K/min). As shown in Fig. 11, the sample showed an endothermic peak at 130.75°C, indicating that the obtained crystal form was α crystal form.
实施例7.黄体酮混悬液的制备Example 7. Preparation of progesterone suspension
黄体酮溶液配制：称取5g吐温20和90g黄体酮，加入200mL甲醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 5g of Tween 20 and 90g of progesterone, add 200mL of methanol, and stir at 60°C to dissolve.
析出溶剂配制：量取130mL纯水于带夹套钢杯中，室温自然水冷却循环。 Precipitation solvent preparation : Measure 130mL of pure water in a steel cup with jacket, and cool with natural water at room temperature.
样品制备：将剪切头置入析出溶剂中，转速调至7000rpm，将黄体酮溶液以114mL/min的速度泵入析出溶剂中(泵入时间：38s)，将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。 Sample preparation : Place the shear head in the precipitation solvent, adjust the rotation speed to 7000 rpm, pump the progesterone solution into the precipitation solvent at a speed of 114 mL/min (pumping time: 38 s), and filter the resulting suspension with suction The filter cake was washed with 3000mL pure water.
将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干，冻干条件如实施例1中所 示。The solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min. The lyophilization conditions were as shown in Example 1.
XRD检测：用粉末衍射仪(X'Pert 3 Powder，Malvern Panalytical)对样品进行XRD测试(Cu，40mA，3.5°～40°)，如图12所示，在2θ＝13.6175°处出现明显衍射峰，为β晶型。 XRD detection : XRD test (Cu, 40mA, 3.5°～40°) was performed on the sample with a powder diffractometer (X'Pert 3 Powder, Malvern Panalytical), as shown in Figure 12, a significant diffraction peak appeared at 2θ=13.6175° , Is β crystal.
分散剂配制：同实施例2。 Dispersant preparation : same as in Example 2.
混悬液制备：称量2.96g冻干样品(含黄体酮2.5g)置于150mL烧杯中，加入分散剂47.04g后于4000rpm条件下剪切5min。 Suspension preparation : Weigh 2.96 g of lyophilized sample (containing 2.5 g of progesterone) into a 150 mL beaker, add 47.04 g of dispersant and shear at 4000 rpm for 5 min.
粒径测试：用马尔文MasterSizer 3000测量所得混悬液粒径(水为测定载体)，平均粒径D[4,3]＝12.989μm。 Particle size test : The particle size of the obtained suspension is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=12.989 μm.
实施例8.黄体酮晶体转化Example 8. Progesterone crystal transformation
黄体酮溶液配制：称取90g黄体酮，加入200mL无水乙醇，于60℃下搅拌溶解。 Progesterone solution preparation : Weigh 90g of progesterone, add 200mL of absolute ethanol, and stir at 60°C to dissolve.
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃。 Precipitation solvent preparation : Weigh 15g of Tween 20, rinse it with a 3000mL water several times into a jacketed steel cup, and cool to 9°C with a cooling circulation device.
样品制备：将剪切头置入析出溶剂中，转速调至7000rpm。将黄体酮溶液以37mL/min的速度泵入析出溶剂中(泵入时间：117s)。将得到的混悬液进行抽滤，滤饼用3000mL纯水洗涤。将固体沉淀物转移至甘露醇溶液中(含甘露醇6g，水160mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干，冻干条件同实施例1。 Sample preparation : Place the shearing head in the precipitation solvent and adjust the rotation speed to 7000 rpm. The progesterone solution was pumped into the precipitation solvent at a rate of 37 mL/min (pumping time: 117s). The obtained suspension was subjected to suction filtration, and the filter cake was washed with 3000 mL of pure water. The solid precipitate was transferred to a mannitol solution (containing 6 g of mannitol and 160 mL of water), and the resulting suspension was lyophilized after stirring at 500 rpm for 30 min. The lyophilization conditions were the same as in Example 1.
分散剂配制：同实施例2。 Dispersant preparation : same as in Example 2.
混悬液制备：称量2.96g冻干样品(含黄体酮2.5g)置于150mL烧杯中，加入分散剂47.04g后于4000rpm条件下剪切5min。 Suspension preparation : Weigh 2.96 g of lyophilized sample (containing 2.5 g of progesterone) into a 150 mL beaker, add 47.04 g of dispersant and shear at 4000 rpm for 5 min.
粒径测试：用马尔文MasterSizer 3000测量所得混悬液粒径(水为测定载体)，平均粒径D[4,3]＝16.553μm。 Particle size test : The particle size of the obtained suspension is measured with Malvern MasterSizer 3000 (water is the measurement carrier), and the average particle size D[4,3]=16.553 μm.
样品处理：将制备的混悬液分装于10mL西林瓶中并轧铝盖，置于40℃ 条件下放置2天、5天后取出进行粒径测试及DSC检测，检测结果如表2所示。Sample treatment: The prepared suspension was divided into 10 mL vials and rolled with aluminum caps, placed at 40°C for 2 days, and taken out after 5 days for particle size test and DSC test. The test results are shown in Table 2.
从检测结果来看，在混悬液状态下，β晶型黄体酮会向α晶型转变，同时伴随粒径增长。From the test results, in the suspension state, the β-crystal progesterone will change to the α-crystal form, along with the increase in particle size.
表2.粒径检测及DSC检测结果Table 2. Particle size detection and DSC detection results
Figure PCTCN2019127555-appb-000003
Figure PCTCN2019127555-appb-000003
实施例9.制备黄体酮粉体Example 9. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解； Progesterone solution preparation : Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃； Precipitation solvent preparation : Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至6000rpm。调节出液口直径为0.51mm，使黄体酮溶液以100mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇3g，水100mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。 Sample preparation : Place the shear head in the precipitation solvent and adjust the rotation speed to 6000 rpm. Adjust the diameter of the liquid outlet to 0.51mm, so that the progesterone solution is pumped into the precipitation solvent at a speed of 100mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 3 g of mannitol, 100 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝8.450μm。 Particle size test result : The particle size is measured with Malvern MasterSizer 3000 (water is the carrier for the measurement), and the average particle size D[4,3]=8.450 μm.
实施例10.制备黄体酮粉体Example 10. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢 杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至8000rpm，调节出液口直径为0.51mm，使黄体酮溶液以50mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shearing head in the precipitation solvent, adjust the rotation speed to 8000 rpm, adjust the diameter of the liquid outlet to 0.51 mm, and pump the progesterone solution into the precipitation solvent at a speed of 50 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝6.653μm。Particle size test results: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=6.653μm.
实施例11.制备黄体酮粉体Example 11. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至8000rpm，调节出液口直径为0.51mm，使黄体酮溶液以20mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shearing head in the precipitation solvent, adjust the rotation speed to 8000 rpm, adjust the diameter of the liquid outlet to 0.51 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝3.386μm。Particle size test results: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=3.386μm.
实施例12.制备黄体酮粉体Example 12. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至15000rpm，调节出液口直径为0.16mm，使黄体酮溶液以20mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shear head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝0.538μm。Particle size test result: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=0.538μm.
实施例13.制备黄体酮粉体Example 13. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至15000rpm，调节出液口直径为0.16mm，使黄体酮溶液以6mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shearing head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 6 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝0.356μm。Particle size test result: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=0.356μm.
实施例14.制备黄体酮粉体Example 14. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入600mL 95％乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 600mL 95% ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water to the jacketed steel cup multiple times, and cool to 9°C with a cooling circulation device;
样品制备：将析出溶剂置于磁力搅拌器上，转速调至2000rpm，调节 出液口直径为0.16mm，使黄体酮溶液以6mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the precipitation solvent on a magnetic stirrer, adjust the rotation speed to 2000 rpm, adjust the diameter of the outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 6 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝15.425μm。Particle size test results: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=15.425μm.
实施例15.制备黄体酮粉体Example 15. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入100mL无水乙醇，搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 100mL absolute ethanol, stir to dissolve;
析出溶剂配制：称取15g吐温20，用3000mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 15g Tween 20, rinse it with a 3000mL water several times into a jacketed steel cup, and cool to 9°C with a cooling circulation device;
样品制备：将剪切头置入析出溶剂中，转速调至15000rpm，调节出液口直径为0.16mm，使黄体酮溶液以20mL/min的速度泵入析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: Place the shear head in the precipitation solvent, adjust the rotation speed to 15000 rpm, adjust the diameter of the liquid outlet to 0.16 mm, and pump the progesterone solution into the precipitation solvent at a speed of 20 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to a mannitol solution (containing 4 g of mannitol and 130 mL of water). After stirring at 500 rpm for 30 min, the solution was obtained. The suspension was lyophilized (the lyophilization conditions were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝1.447μm。Particle size test result: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=1.447μm.
实施例16.制备黄体酮粉体Example 16. Preparation of progesterone powder
黄体酮溶液配制：称取20g黄体酮，加入65mL无水乙醇，于60℃下搅拌使之溶解；Progesterone solution preparation: Weigh 20g progesterone, add 65mL absolute ethanol, stir at 60℃ to dissolve;
析出溶剂配制：称取2.5g吐温20，用1500mL水多次冲洗至带夹套钢杯中，用冷却循环装置冷却至9℃；Precipitation solvent preparation: Weigh 2.5g Tween 20, rinse it with a 1500mL water multiple times into a jacketed steel cup, and cool to 9°C with a cooling circulation device;
样品制备：将析出溶剂置于磁力搅拌器上，转速调至2000rpm析出溶剂，调节出液口直径为0.90mm，使黄体酮溶液以100mL/min的速度泵入 析出溶剂中。当黄体酮溶液全部加入后，抽滤，将得到的滤饼用3000mL的纯水洗涤，将固体沉淀物转移至甘露醇溶液中(含甘露醇4g，水130mL)，500rpm条件下搅拌30min后将得到的混悬液进行冻干(冻干条件同实施例1)。Sample preparation: place the precipitation solvent on the magnetic stirrer, adjust the rotation speed to 2000 rpm to precipitate the solvent, adjust the outlet diameter to 0.90 mm, and pump the progesterone solution into the precipitation solvent at a speed of 100 mL/min. After all the progesterone solution was added, suction filtration was performed, the obtained filter cake was washed with 3000 mL of pure water, and the solid precipitate was transferred to the mannitol solution (containing 4 g of mannitol, 130 mL of water), and stirred at 500 rpm for 30 min. The resulting suspension was lyophilized (the conditions for lyophilization were the same as in Example 1).
粒径测试结果：用马尔文MasterSizer 3000测量粒径(水为测定载体)，平均粒径D[4,3]＝58.162μm。Particle size test results: Malvern MasterSizer 3000 is used to measure the particle size (water is the measurement carrier), and the average particle size D[4,3]=58.162μm.
实施例17.黄体酮混悬液的体内代谢Example 17. In vivo metabolism of progesterone suspension
实验动物：SD雌性大鼠(切除卵巢)16只(220g～300g)，随机分为4组(依次为A、B、C、D组)，每组4只。Experimental animals: 16 female SD rats (ovariectomized) (220g to 300g) were randomly divided into 4 groups (A, B, C, and D groups in sequence), with 4 rats in each group.
参比制剂为市售黄体酮油性注射液(50mg/mL)。The reference preparation is a commercially available progesterone oily injection (50 mg/mL).
给药方式及剂量：大腿外侧肌肉注射给药；A组：市售黄体酮油性注射液，给药6mg/Kg，连续5天；B组：实施例4的黄体酮混悬液，给药30mg/Kg；C组：实施例2的黄体酮混悬液，给药30mg/Kg；D组：实施例7的黄体酮混悬液，给药30mg/Kg。Mode of administration and dosage: intramuscular injection of the outer thigh; Group A: commercially available progesterone oily injection, 6 mg/Kg for 5 consecutive days; Group B: the progesterone suspension of Example 4, 30 mg /Kg; Group C: the progesterone suspension of Example 2 was administered at 30 mg/Kg; Group D: the progesterone suspension of Example 7 was administered at 30 mg/Kg.
采样及检测：给药后，B、C、D组分别于给药前(0h)、给药后0.5h、1h、2h、3h、4h、6h、8h和1d(24h)、2d(48h)、3d(72h)、4d(96h)、5d(120h)6天(144h)静脉取血0.3ml于肝素化EP管中；A组于第1天给药前(0h)、给药后(0d)0.5h、1h、2h、3h、4h、6h、8h，第2、3、4天给药前(当天的0h)和给药后3h，第5天给药前(当天0h)和给药当天的0.5h、1h、2h、3h、4h、6h、8h、24h和48h，静脉取血0.3ml于肝素化EP管中。采集的全血4000rpm离心10min以分离血浆，所收集的血浆在冰箱中于-80℃保存待测。Sampling and testing: after administration, groups B, C, and D were administered before (0h), 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 1d (24h), and 2d (48h) , 3d (72h), 4d (96h), 5d (120h) 6 days (144h) venous blood 0.3ml in heparinized EP tube; group A before administration (0h) on day 1 and after administration (0d ) 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, before dosing on days 2, 3, 4 (0h on the day) and 3h after dosing, before dosing on day 5 (0h on the day) and dosing On the day of 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 24h and 48h, 0.3ml of blood was taken intravenously in a heparinized EP tube. The collected whole blood was centrifuged at 4000 rpm for 10 min to separate the plasma, and the collected plasma was stored in the refrigerator at -80°C for testing.
检测方法：HPLC-MS/MS法检测大鼠血浆中黄体酮含量以表明SD大鼠肌肉注射黄体酮混悬液后黄体酮血浆浓度变化。Detection method: HPLC-MS/MS method was used to detect the content of progesterone in rat plasma to indicate the change of progesterone plasma concentration in SD rats after intramuscular injection of progesterone suspension.
图13示出了大鼠血浆中黄体酮浓度随时间的变化曲线，从图中可以看 出实施例2(混合晶型)、实施例4(α晶型)、实施例7(β晶型)制备的样品均可以达到5天缓释效果。Figure 13 shows the change curve of progesterone concentration in rat plasma with time, from the figure we can see Example 2 (mixed crystal form), Example 4 (α crystal form), Example 7 (β crystal form) All the prepared samples can achieve a 5-day sustained-release effect.

Claims (15)

  1. 一种制备黄体酮颗粒物的方法，所述方法包括：A method for preparing progesterone particles, the method comprising:
    步骤1，使黄体酮溶于溶剂中以提供黄体酮溶液；Step 1, dissolve progesterone in the solvent to provide a progesterone solution;
    步骤2，将所述黄体酮溶液以预定速度泵入到高速剪切或剧烈搅拌的黄体酮的析出溶剂中以使黄体酮析出；和Step 2: pumping the progesterone solution into the progesterone precipitation solvent with high-speed shearing or vigorous stirring at a predetermined speed to precipitate progesterone; and
    步骤3，分离析出物并进行干燥以获得所述黄体酮颗粒物；Step 3: Separate the precipitate and dry it to obtain the progesterone particles;
    其中，所述黄体酮颗粒物为黄体酮晶体或黄体酮粉体。Wherein, the progesterone particles are progesterone crystals or progesterone powder.
  2. 根据权利要求1所述的方法，其中，步骤2进一步为：将所述黄体酮溶液以预定速度泵入至冷却的高速剪切或剧烈搅拌的析出溶剂中以使黄体酮析出；所述析出溶剂为水、有机溶剂或水与有机溶剂的混合物；The method according to claim 1, wherein step 2 is further: pumping the progesterone solution at a predetermined speed into a cooled high-speed shearing or vigorously stirred precipitation solvent to precipitate the progesterone; the precipitation solvent It is water, organic solvent or a mixture of water and organic solvent;
    所述步骤3中的干燥优选为冷冻干燥。The drying in step 3 is preferably freeze drying.
  3. 根据权利要求2所述的方法，其中所述有机溶剂选自甲醇、乙醇、异丙醇和丙酮中的一种或多种；优选地，所述析出溶剂为水、乙醇或水与乙醇的混合物。The method according to claim 2, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and acetone; preferably, the precipitation solvent is water, ethanol, or a mixture of water and ethanol.
  4. 根据权利要求1至3中任一项所述的方法，其中所述析出溶剂的温度为-20℃至25℃；优选地，当以水作为析出溶剂时，温度为1℃至25℃；当以有机溶剂作为析出溶剂时，析出溶剂的温度为-20℃至0℃；当以水与有机溶剂的混合物作为析出溶剂时，析出溶剂的温度为-10℃至25℃。The method according to any one of claims 1 to 3, wherein the temperature of the precipitation solvent is -20°C to 25°C; preferably, when water is used as the precipitation solvent, the temperature is 1°C to 25°C; when When an organic solvent is used as the precipitation solvent, the temperature of the precipitation solvent is -20°C to 0°C; when a mixture of water and an organic solvent is used as the precipitation solvent, the temperature of the precipitation solvent is -10°C to 25°C.
  5. 根据权利要求1至4中任一项所述的方法，其中所述剧烈搅拌的转速为500rpm至2000rpm，优选700rpm至2000rpm，或者优选700rpm至1000rpm；所述高速剪切通过转速为3000rpm至20000rpm，优选5000rpm至20000rmp或者优选7000rpm至20000rpm的剪切仪来实现。The method according to any one of claims 1 to 4, wherein the rotation speed of the vigorous stirring is 500 rpm to 2000 rpm, preferably 700 rpm to 2000 rpm, or preferably 700 rpm to 1000 rpm; the high-speed shear passing speed is 3000 rpm to 20,000 rpm, It is preferably achieved by a shear meter of 5000 rpm to 20,000 rpm or preferably 7000 rpm to 20,000 rpm.
  6. 根据权利要求1至5中任一项所述的方法，其中溶解黄体酮所用的溶剂为与水互溶的有机溶剂；优选地，所述步骤1中溶解黄体酮所用的溶 剂为选自甲醇、无水乙醇、乙二醇、异丙醇和丙酮中的一种或它们的混合物，或者上述醇类的水溶液；进一步优选地，所述步骤1中溶解黄体酮所用的溶剂为选自甲醇、无水乙醇、异丙醇和丙酮中的一种或它们的混合物，或者上述醇类的水溶液。The method according to any one of claims 1 to 5, wherein the solvent used to dissolve progesterone is an organic solvent miscible with water; preferably, the solvent used to dissolve progesterone in step 1 is selected from methanol, no One or a mixture of water ethanol, ethylene glycol, isopropanol, and acetone, or an aqueous solution of the above alcohols; further preferably, the solvent used for dissolving progesterone in step 1 is selected from methanol and absolute ethanol , One of isopropyl alcohol and acetone or a mixture thereof, or an aqueous solution of the above alcohols.
  7. 根据权利要求1至6中任一项所述的方法，所述黄体酮溶液的泵入速度为6mL/min至500mL/min。The method according to any one of claims 1 to 6, wherein the pumping speed of the progesterone solution is 6 mL/min to 500 mL/min.
  8. 根据权利要求1至7中任一项所述的方法，其中，所述黄体酮溶液的浓度为10mg/mL至500mg/mL。The method according to any one of claims 1 to 7, wherein the concentration of the progesterone solution is 10 mg/mL to 500 mg/mL.
  9. 根据权利要求2至8中任一项所述的方法，其中所述冷冻干燥包括：将分离析出的黄体酮重新分散于2wt％至4wt％甘露醇水溶液中；然后进行冻干。The method according to any one of claims 2 to 8, wherein the freeze-drying comprises: redispersing the separated progesterone in a 2 wt% to 4 wt% aqueous solution of mannitol; and then freeze-drying.
  10. 根据权利要求1至9中任一项所述的方法，其中向所述黄体酮溶液中加入表面活性剂以使所述黄体酮溶液进一步包含，基于所述黄体酮溶液的质量，0.5wt％至3wt％，优选1wt％至2wt％的表面活性剂；或者向所述黄体酮的析出溶剂中加入表面活性剂使析出溶剂中进一步包含，基于析出溶剂的质量，0.1～2wt％，优选0.3～0.8wt％的表面活性剂。The method according to any one of claims 1 to 9, wherein a surfactant is added to the progesterone solution so that the progesterone solution further comprises, based on the mass of the progesterone solution, 0.5 wt% to 3wt%, preferably 1wt% to 2wt% surfactant; or adding the surfactant to the progesterone precipitation solvent to further include the precipitation solvent, based on the mass of the precipitation solvent, 0.1 to 2wt%, preferably 0.3 to 0.8 wt% surfactant.
  11. 根据权利要求1至10中任一项所述的方法，优选乙醇作为析出溶剂，得到α晶型的黄体酮；The method according to any one of claims 1 to 10, preferably ethanol is used as a precipitation solvent to obtain alpha crystalline progesterone;
    或者，优选水作为析出溶剂，甲醇作为溶解黄体酮的有机溶剂，得到β晶型的黄体酮。Alternatively, it is preferable to use water as a precipitation solvent and methanol as an organic solvent for dissolving progesterone to obtain progesterone of β crystal form.
  12. 根据权利要求1至11中任一项所述的方法，其中所述方法进一步包括：在将所述黄体酮溶液加入至所述析出溶剂之前，将预定晶型的晶种加入至析出溶剂中以更稳定地得到对应晶型的黄体酮。The method according to any one of claims 1 to 11, wherein the method further comprises: before adding the progesterone solution to the precipitation solvent, adding a seed crystal of a predetermined crystal form to the precipitation solvent to Progesterone corresponding to the crystalline form is obtained more stably.
  13. 根据权利要求1至12中任一项所述的方法，其中，泵入的黄体酮溶液与析出溶剂的体积比为1.5:1～1:30。The method according to any one of claims 1 to 12, wherein the volume ratio of the pumped progesterone solution to the precipitation solvent is 1.5:1 to 1:30.
  14. 一种黄体酮晶体或粉体，所述黄体酮晶体根据权利要求1至13中任一项所述的方法制备得到，所述黄体酮晶体或粉体具有D[4,3]为0.3μm至60μm的粒径。A progesterone crystal or powder prepared according to the method of any one of claims 1 to 13, wherein the progesterone crystal or powder has a D[4,3] of 0.3 μm to 60μm particle size.
  15. 一种黄体酮注射剂，其中所述注射剂包括有效量的权利要求14所述的黄体酮晶体或粉体。A progesterone injection, wherein the injection comprises an effective amount of the progesterone crystal or powder of claim 14.
PCT/CN2019/127555 2018-12-28 2019-12-23 Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof WO2020135352A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980071761.7A CN112969466A (en) 2018-12-28 2019-12-23 Method for preparing progesterone particles, progesterone particles obtained by same and injection of progesterone particles

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201811618644 2018-12-28
CN201811618644.1 2018-12-28
CN201910734810 2019-08-09
CN201910734810.2 2019-08-09

Publications (1)

Publication Number Publication Date
WO2020135352A1 true WO2020135352A1 (en) 2020-07-02

Family

ID=71126815

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/127555 WO2020135352A1 (en) 2018-12-28 2019-12-23 Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof

Country Status (2)

Country Link
CN (1) CN112969466A (en)
WO (1) WO2020135352A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999187A (en) * 2021-03-08 2021-06-22 河北今水生物科技有限公司 Progesterone capsule and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780670A (en) * 2003-04-29 2006-05-31 阿克佐诺贝尔股份有限公司 Antisolvent solidification process
CN107198677A (en) * 2017-05-25 2017-09-26 长春金赛药业股份有限公司 Progesterone suspension type long-acting injection and preparation method thereof and progesterone, which are suspended, injects powder pin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780670A (en) * 2003-04-29 2006-05-31 阿克佐诺贝尔股份有限公司 Antisolvent solidification process
CN107198677A (en) * 2017-05-25 2017-09-26 长春金赛药业股份有限公司 Progesterone suspension type long-acting injection and preparation method thereof and progesterone, which are suspended, injects powder pin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DOAA RAGAB ET AL: "Crystallization of Progesterone for Pulmonary Drug Delivery", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 99, no. 3, 18 August 2009 (2009-08-18), pages 1123 - 1137, XP055714431, ISSN: 0022-3549, DOI: 10.1002/jps.21896 *
EUNBI CHO ET AL: "Enhanced Dissolution of Megestrol Acetate Microcrystals Prepared by Antisolvent Precipitation Process Using Hydrophilic Additives", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 396, no. 1-2, 30 August 2010 (2010-08-30), pages 91 - 98, XP027169576, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2010.06.016 *
JAVIER A. FALCON ET AL: "In Situ Monitoring of Antisolvent Addition Crystallization with Principal Components Analysis of Raman Spectra", CRYSTAL GROWTH & DESIGN, vol. 4, no. 3, 10 April 2004 (2004-04-10), pages 457 - 463, XP055714436, ISSN: 1528-7483, DOI: 10.1021/cg034206y *
ROBERT W LANCASTER ET AL: "The Polymorphism of Progesterone: Stabilization of a ‘Disappearing’ Polymorph by Co-Crystallization", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 96, no. 12, 1 December 2007 (2007-12-01), pages 3419 - 3431, XP055714443, ISSN: 0022-3549, DOI: 10.1002/jps.20983 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999187A (en) * 2021-03-08 2021-06-22 河北今水生物科技有限公司 Progesterone capsule and preparation method thereof

Also Published As

Publication number Publication date
CN112969466A (en) 2021-06-15

Similar Documents

Publication Publication Date Title
US8663703B2 (en) Drug microparticles, processes of preparing them and a drug delivery vehicle comprising them
JP5372032B2 (en) Controlled release sterile injection aripiprazole formulations and methods
WO2017166451A1 (en) Pharmaceutical preparation of palbociclib and preparation method thereof
CN101309669A (en) Compositions of lipoxygenase inhibitors
WO2016029828A1 (en) Crystalline free acid, hemicalcium salt and α-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof
US20100151037A1 (en) Method for the preparation of nanoparticles containing a poorly water-soluble pharmaceutically active compound
Yu et al. Stabilized amorphous glibenclamide nanoparticles by high-gravity technique
WO2015156572A1 (en) Method for preparing polymeric microspheres containing drug
WO2018108163A1 (en) Talazoparib pharmaceutical composition and applications thereof
WO2006026935A2 (en) Pharmaceutical composition for rectal or vaginal application comprising a platinum complex
WO2020135352A1 (en) Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof
JP2016513706A (en) Ophthalmic preparations
WO2012026896A1 (en) Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof
Han et al. In vitro and in vivo evaluation of core–shell mesoporous silica as a promising water-insoluble drug delivery system: Improving the dissolution rate and bioavailability of celecoxib with needle-like crystallinity
CN112451483B (en) Preparation method of paliperidone palmitate suspension
CN102579373B (en) Amoitone B nano crystallization preparation and preparation method thereof
WO2021115389A1 (en) Fulvestrant pharmaceutical composition, preparation method therefor, and application thereof
WO2016119114A1 (en) Puerarin nanocrystalline capsule and preparation method therefor
CN109419771B (en) Testosterone undecanoate sustained-release pharmaceutical composition, and preparation method and application thereof
WO2023036003A1 (en) Long-acting brexpiprazole preparation for injection and preparation method therefor
CN107157956B (en) Skeleton type progesterone sustained release microspheres, preparation method thereof and progesterone sustained release injection
CN105982877B (en) Puerarin nano crystal capsule and preparation method thereof
CN110478316A (en) A kind of aprepitant nanocrystal suspension and its preparation method and application
WO2021073548A1 (en) Pharmaceutical composition
KR20230148584A (en) Method of preparing nanoparticles comprising poorly water soluble drugs for treating heaptitis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19906294

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19906294

Country of ref document: EP

Kind code of ref document: A1