WO2020135352A1 - Procédé de préparation de particule de progestérone, particule de progestérone préparée et injection de celle-ci - Google Patents

Procédé de préparation de particule de progestérone, particule de progestérone préparée et injection de celle-ci Download PDF

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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
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progesterone
solvent
precipitation solvent
solution
rpm
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PCT/CN2019/127555
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English (en)
Chinese (zh)
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梁相永
李明
苏正兴
郭大成
易聪
魏巍
李丹
赵栋
王晶翼
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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
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Priority to CN201980071761.7A priority Critical patent/CN112969466A/zh
Publication of WO2020135352A1 publication Critical patent/WO2020135352A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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.

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Abstract

L'invention concerne un procédé de préparation d'une particule de progestérone, en particulier un cristal ou une poudre. Le procédé comprend : l'étape 1, la dissolution de la progestérone dans un solvant pour fournir une solution de progestérone ; l'étape 2, le pompage de la solution de progestérone dans un solvant de précipitation de progestérone de cisaillement à grande vitesse à une vitesse prédéterminée pour précipiter la progestérone ; et l'étape 3, la séparation du précipité et la lyophilisation de celui-ci pour obtenir la particule de progestérone, la particule de progestérone étant un cristal de progestérone ou une poudre de progestérone. En utilisant le procédé de la présente invention, un cristal ou une poudre de progestérone de taille micrométrique ayant une bonne stabilité peut être obtenu. L'injection de la progestérone préparée atteint non seulement un effet de libération prolongée d'au moins 5 jours, mais présente également une bonne stabilité. Le procédé de l'invention est simple à réaliser, est peu coûteux et peut facilement être adapté pour une production industrielle.
PCT/CN2019/127555 2018-12-28 2019-12-23 Procédé de préparation de particule de progestérone, particule de progestérone préparée et injection de celle-ci WO2020135352A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999187A (zh) * 2021-03-08 2021-06-22 河北今水生物科技有限公司 一种黄体酮胶囊及制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780670A (zh) * 2003-04-29 2006-05-31 阿克佐诺贝尔股份有限公司 反溶剂凝固方法
CN107198677A (zh) * 2017-05-25 2017-09-26 长春金赛药业股份有限公司 黄体酮混悬型长效注射剂及其制备方法和黄体酮混悬注射粉针

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780670A (zh) * 2003-04-29 2006-05-31 阿克佐诺贝尔股份有限公司 反溶剂凝固方法
CN107198677A (zh) * 2017-05-25 2017-09-26 长春金赛药业股份有限公司 黄体酮混悬型长效注射剂及其制备方法和黄体酮混悬注射粉针

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 (zh) * 2021-03-08 2021-06-22 河北今水生物科技有限公司 一种黄体酮胶囊及制备方法

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