CN112969466A - Method for preparing progesterone particles, progesterone particles obtained by same and injection of progesterone particles - Google Patents
Method for preparing progesterone particles, progesterone particles obtained by same and injection of progesterone particles Download PDFInfo
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Abstract
Disclosed is a method for preparing progesterone particles, in particular crystals or powders, wherein the method comprises: step 1, dissolving progesterone in a solvent to provide a progesterone solution; step 2, pumping the progesterone solution into a precipitation solvent of progesterone sheared at a high speed at a preset speed so as to precipitate the progesterone; and step 3, separating the precipitate and freeze-drying to obtain the progesterone particles; wherein the progesterone particles are progesterone crystals or progesterone powder. The method can obtain micron-sized progesterone crystals or powder and has good stability. The progesterone injection prepared by the progesterone injection not only realizes the slow release effect of at least 5 days, but also has good stability. The method has the advantages of simple operation, low cost and easy industrial amplification production.
Description
The invention relates to a method for preparing progesterone particles, in particular progesterone crystals or powder, and to the obtained progesterone crystals or powder and injections thereof.
It is well known that for drugs, the dosage form, physical form, such as crystal form, particle size, solubility, etc., of the product have a significant effect on its in vivo release, bioavailability, etc. Therefore, there is increasing interest in preparing formulations with advantageous crystal forms, advantageous particle sizes, etc.
Progesterone is widely used in clinic for treating diseases caused by luteal function deficiency, such as irregular menstruation, threatened abortion, and the like. Progesterone is known as a polymorphic substance, in which the alpha and beta crystal forms are relatively stable and have well-defined crystal structures (melting points of about 131 ℃ and 123 ℃, respectively), and both have biological activities (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-. Progesterone with different crystal structures has different melting points, apparent solubilities, optical properties, etc., and thus has an influence on in vivo metabolism, bioavailability, etc. of the obtained preparation.
The preparation method of the common polymorphic medicines in the prior art comprises the conventional methods such as solution crystallization, melting method, sublimation method, grinding method and the like, and also comprises the unconventional methods such as quick freezing, capillary generation method, high-throughput screening method, supercritical fluid method, laser induction and the like.
For example, a method for preparing a crystalline form of progesterone by concentrating an organic solution of progesterone is disclosed in CN 107417756A. However, the method disclosed in this document requires grinding or the like to obtain a sample having a satisfactory particle size distribution. Further, CN109223722A discloses a method for preparing progesterone nanocrystalline injection by freeze-drying progesterone oil-in-water emulsion. However, the method described in this document is not suitable for direct lyophilization because the amount of organic solvent used in the scale-up production of lyophilization is increased, and the size of progesterone nanocrystals is limited by the size of emulsion droplets and the adjustable range is limited.
In addition, currently the most common progesterone formulations are oral formulations and injections. Although the oral preparation is most convenient to administer and has good patient compliance, the first-pass effect is obvious, and the bioavailability is only about 10%. Therefore, the importance of developing aqueous long-acting injection of progesterone is becoming more and more significant from the clinical point of view. The aqueous long-acting progesterone injection is mainly realized by an inclusion type (such as a polymer aqueous progesterone injection and the like) and a direct type (such as a progesterone suspension type long-acting injection and a powder injection). The inclusion-type method involves the problems of drug loading, encapsulation efficiency and the like, not only is the preparation process complicated, but also the working difficulty of later quality standard formulation is increased. The direct method can conveniently control the particle size and the concentration of the progesterone according to clinical needs, so that the administration frequency is lowest, the treatment effect is optimal, and the compliance of patients is enhanced to the maximum extent.
Therefore, the development of the progesterone particles with simple process, good stability and slow release function, especially the preparation method of the crystal or the powder, has important significance.
Disclosure of Invention
In view of the problems existing in the prior art for preparing different progesterone particles, especially crystals or powder, the invention provides a preparation method of progesterone particles with good stability, and the method provided by the invention is simple to operate and is easy for industrial large-scale production.
In order to achieve the above object of the present invention, a first aspect of the present invention provides a method for preparing progesterone particles, wherein the method comprises:
step 3, separating precipitates and drying to obtain the progesterone particles; wherein the progesterone particles are progesterone crystals or progesterone powder.
In particular, in some embodiments, the present invention relates to a method of preparing progesterone crystals, wherein the method comprises:
dissolving progesterone in a solvent to provide a progesterone solution;
pumping the progesterone solution into a cooled high shear or vigorously stirred eluting solvent at a predetermined rate to elute progesterone; the precipitation solvent is water, an organic solvent or a mixture of water and the organic solvent;
the precipitated progesterone was separated and freeze-dried to obtain progesterone crystals.
In some embodiments of the invention, the concentration of the progesterone solution is from 10mg/mL to 500 mg/mL; further preferably 200mg/mL to 450 mg/mL.
In some embodiments of the invention, the solvent used to dissolve the progestin is a water-miscible organic solvent; preferably, the solvent used for dissolving the progesterone is one or a mixture of methanol, absolute ethanol, isopropanol and acetone, or an aqueous solution of the above alcohols; preferably, the solvent used for dissolving the progesterone is methanol, absolute ethanol or 95 vol% ethanol; more preferably, the solvent used to dissolve progesterone is methanol or absolute ethanol.
In the present invention, appropriate heating may be performed to obtain a progesterone solution having a desired concentration.
In some embodiments of the 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 invention, the eluting solvent is water; in other embodiments, the precipitation solvent is ethanol; in still other embodiments, the eluting solvent is a mixture of ethanol and water, wherein the volume ratio of water to ethanol can be adjusted to 20:1 to 1:20 as required, for example, the volume ratio of water to ethanol includes but is not limited to 4:1, 1: 4.
In some embodiments of the invention, the pumping of the progesterone solution into the eluting solvent may be controlled by a peristaltic pump, for example at a rate of from 50mL/min to 500mL/min, preferably from 100mL/min to 400 mL/min.
In some embodiments of the invention, the vigorous stirring is typically at a speed of 500rpm to 2000rpm, preferably 700rpm to 1000 rpm. The high speed shearing may be achieved by high speed stirring at a speed of 3000rpm to 20000rpm, preferably at a speed of 7000rpm to 20000 rpm.
In some embodiments of the invention, the temperature of the eluting solvent is from-20 ℃ to 25 ℃. More specifically, when water is used as the eluting solvent, the temperature thereof is 1 ℃ to 25 ℃; when an organic solvent is used as a precipitation solvent, the temperature of the precipitation solvent is-20 ℃ to 0 ℃; when a mixture of water and an organic solvent is used as the eluting solvent, the temperature of the eluting solvent is-10 ℃ to 25 ℃, and preferably, the temperature of the eluting solvent is-10 ℃ to 0 ℃.
In some embodiments of the present invention, the volume ratio of the pumped progesterone solution to the eluting solvent is 1.5:1 to 1:10, preferably 1:1.5 to 1: 5. The pumping of the progesterone solution into the eluting solvent can be controlled, for example, by means of a peristaltic pump, at a rate of, for example, 50 to 500mL/min, preferably 100 to 400 mL/min.
For dispersion, the progesterone solution may further comprise: 0.5 to 3 wt%, preferably 1 to 2 wt% of a surfactant, based on the mass of the progesterone solution. Such surfactants include, but are not limited to, polysorbate 20 (tween 20), polysorbate 80 (tween 80), sorbitan fatty acid esters ( span 20, 40, 60, 80), succinic acid esters, glycerol monostearate, and the like. Among them, these surfactants may be contained in the progesterone precipitate. By means of a separation step, for example by washing the precipitate, small amounts of surfactant in the precipitate can be removed, so that no or only traces of surfactant can be contained in the final powder.
According to the process of the invention, in particular, to obtain the alpha crystalline form of progesterone, ethanol is preferred as the precipitation solvent; more preferably, the α -type seed crystal may be added to the precipitation solvent in advance, and in this case, the kind of the precipitation solvent may not be limited. In order to obtain the beta-crystalline form of progesterone, water is preferably used as a precipitation solvent, and methanol is preferably used as an organic solvent for dissolving the progesterone; more preferably, similarly, a β type seed crystal may be added to the eluting solvent in advance.
In some embodiments of the invention, the seed crystals may be added to the precipitation solvent cooled to a specific temperature, wherein the seed crystals may be added in the form of a powder or a suspension, preferably in the form of a suspension. In the present invention, the raw material as the seed crystal may be dispersed in water by shearing, sonication, or the like. Wherein, in order to promote the dispersion of the seed crystal, 0.1-2% (w/v) of surfactant (such as Tween 20) can be added into the water. Wherein, the amount of the seed crystal added can be 0.1 wt% to 10 wt% (relative to progesterone), preferably 1 wt% to 5 wt% (relative to progesterone).
In some embodiments of the invention, the separation is filtration, preferably suction filtration.
In some embodiments of the invention, the freeze-drying comprises: re-dispersing the separated precipitate in 2-4 wt% concentration water solution of mannitol; then freeze-drying is carried out to obtain progesterone crystals with the content of more than or equal to 80 wt%, for example 80 wt% to 86 wt%.
Wherein, in the present invention, by adjusting the concentration of the progesterone solution, the pumping speed, the stirring/shearing speed, the kind of the eluting solvent and the cooling temperature, especially the stirring/shearing speed, the obtained progesterone crystals have a particle size in the range of 0.3 μm to 60 μm (D4, 3, volume weighted average particle size), preferably in the range of 10 μm to 30 μm.
According to another aspect of the present invention, there is provided progesterone crystals obtained by the above method, having a particle size of 0.3 to 60 μm, preferably 10 to 30 μm.
According to still another aspect of the present invention, there is provided a progesterone injection comprising a therapeutically effective amount of the progesterone crystal of the present invention.
The progesterone injection can be powder injection or suspension.
According to some embodiments, the progesterone powder injection further comprises a steric stabilizer, a surfactant, an osmotic pressure regulator and the like.
According to some embodiments, the progesterone suspension injection further comprises water for injection, a steric stabilizer, a surfactant, an osmotic pressure regulator, a pH regulator, and the like.
The steric stabilizer, the surfactant, the osmotic pressure regulator, the pH regulator, and the like are not particularly limited in the present invention, and pharmaceutically acceptable adjuvants in the prior art can be used. For example, steric stabilizers include, but are not limited to, hydroxypropyl methylcellulose and salts thereof, polyvinylpyrrolidone, polyethylene glycols, and the like; surfactants include, but are not limited to, polysorbates, sorbitan fatty acid esters ( span 20, 40, 60, 80), succinates, glycerol monostearate, and the like; the osmotic pressure regulator includes, but is not limited to, saccharides (e.g., glucose, fructose, etc.), polyhydric sugar alcohols (e.g., mannitol, etc.), inorganic salts (e.g., sodium chloride), etc.; pH adjusters include, but are not limited to, hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like.
In some embodiments of the present invention, there is provided a method of preparing progesterone powder comprising:
dissolving progesterone in an organic solvent to provide a progesterone solution;
adding a progesterone solution into a progesterone precipitation solvent which is sheared at a high speed at a preset flow rate; and
separating the precipitate and drying to obtain the progesterone powder.
According to the method of the present invention, an organic solution of progesterone is added to a high shear progesterone eluting solvent at a predetermined flow rate to rapidly precipitate progesterone in the eluting solvent. The progesterone powder with the required particle size can be finally obtained by controlling the amount of the progesterone added in unit time and the shearing rate. For example, generally, the smaller the flow rate of the progesterone solution, the faster the shear rate of the eluting solvent, and the smaller the particle size of the obtained progesterone powder.
In the method, the concentration of the progesterone solution is 10-300 mg/mL; more preferably 30 to 200 mg/mL.
The organic solvent is an organic solvent which is mutually soluble with water, and the organic solvent can be one of methanol, ethanol, propanol and glycol, or a mixed solvent of two or more of the alcohols, or an aqueous solution of the alcohols. Preferably, the volume percentage of alcohol in the aqueous alcohol solution is 80 vol% or more, more preferably 90 vol% or more, and most preferably 95 vol% or more. According to a preferred embodiment, the organic solvent is methanol, ethanol, or 95 vol% ethanol in water.
Appropriate heating can be performed to obtain the desired concentration of progesterone solution.
According to some embodiments, the high speed shearing may be achieved by high speed stirring at a speed of 700 to 2000 rpm. According to some embodiments, the high speed shearing may be achieved by a high speed shear apparatus, wherein the shear head rotation speed may be 5000-20000 rpm.
The volume ratio of the finally added progesterone solution to the precipitation solvent is 1: 3-1: 30, preferably 1:10, and more preferably 1: 5.
According to some embodiments, the progesterone eluting solvent is water.
The progesterone precipitation solvent may further contain 0.1 to 2 wt%, preferably 0.3 to 0.8 wt% of a surfactant for dispersion.
These surfactants may be included in the progesterone precipitate. By means of a separation step, for example by washing the precipitate, small amounts of surfactant in the precipitate can be removed, so that no or only traces of surfactant can be contained in the final powder.
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 glycol 1000 vitamin E succinate (TPGS), and polyethylene glycol 15 hydroxystearate (such as polyethylene glycol 15 hydroxystearate)
HS15), poloxamer, Sodium Dodecyl Sulfate (SDS), fatty acid monoglyceride, lecithin, cyclodextrin, and polyoxyethylene castor oil; preferably, the surfactant is selected from one or more of tween 20, tween 80, sorbitan fatty acid esters (in particular span 20), poloxamers; further preferably, the surfactant is tween 20.
According to one embodiment, the progesterone eluting solvent may be pre-cooled to 5-10 ℃. The cooled eluting solvent helps the progesterone to elute more rapidly and in greater quantities.
In the method, the progesterone powder with different particle sizes can be obtained by adjusting the flow and matching with other process conditions, such as solution concentration, shearing rate of a precipitated solvent and the like. Generally, the predetermined flow rate can be adjusted within a range of 6-100 mL/min.
When all the progesterone solution was added to the eluting solvent, the precipitated progesterone was separated and dried.
In some embodiments, the separation is filtration, preferably suction filtration.
In some embodiments, the drying is by freeze drying.
In some embodiments, the freeze-drying step comprises: re-dispersing the separated precipitate in 2-4 wt% concentration water solution of mannitol, and freeze drying to obtain progesterone powder;
the step of dispersing is preferably dispersing by a stirring mode, and the rotating speed of stirring is preferably 500-1000 rpm.
Wherein, the organic solution of the progesterone is added into the progesterone precipitation solvent which is sheared at a high speed with a preset flow rate, so that the progesterone is rapidly precipitated in the precipitation solvent. The progesterone powder with the required particle size can be finally obtained by controlling the amount of the progesterone added in unit time and the shearing rate. For example, generally, the smaller the flow rate of the progesterone solution, the faster the shear rate of the eluting solvent, and the smaller the particle size of the obtained progesterone powder.
The method can obtain micron-sized progesterone particles with good stability, and can controllably adjust the particle size of the finally obtained particles, so that the particles with adjustable particle size within the range of 0.3-60 mu m, preferably 10-30 mu m are obtained. Further pharmacokinetic experiments prove that the progesterone injection prepared by the application realizes a sustained release effect for at least 5 days, achieves a sustained release target, can reduce the administration frequency, improves the compliance of patients, and has good stability. In addition, the method of the invention has simple operation and low cost, and is easy for industrial amplification production.
Figure 1 is an XRD pattern of a sample according to example 1 of the present invention;
FIG. 2 is a DSC profile of a sample according to example 1 of the present invention;
figure 3 is an XRD pattern of a sample according to example 2 of the present invention;
FIG. 4 is a DSC profile of a sample according to example 2 of the present invention;
figure 5 is an XRD pattern of a sample according to example 3 of the present invention;
FIG. 6 is a DSC profile of a sample according to example 3 of the present invention;
figure 7 is an XRD pattern of a sample according to example 4 of the present invention;
FIG. 8 is a DSC profile of a sample according to example 4 of the present invention;
figure 9 is an XRD spectrum of a sample according to example 5 of the present invention;
figure 10 is an XRD pattern of a sample according to example 6 of the present invention;
FIG. 11 is a DSC profile of a sample of example 6 according to the present invention;
figure 12 is an XRD spectrum of a sample according to example 7 of the present invention;
fig. 13 is a time-dependent profile of the concentration of progesterone in plasma obtained in example 17 according to the present invention.
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the specific embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Various aspects of the invention are further illustrated by the following specific examples, and various advantages of the invention are shown by the following examples.
In the following examples, all reagents, instruments and the like were commercially available unless otherwise specified.
Example 1 preparation of progesterone samples
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of absolute ethanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 130mL of absolute ethyl alcohol is measured in a steel cup with a jacket and cooled to-20 ℃ by a cooling circulation device.
Sample preparation: the shearing head was placed in the eluting solvent and the rotation speed was adjusted to 7000 rpm. The progesterone solution was pumped into the eluting solvent at a rate of 117mL/min (pump time: 90s), the resulting suspension was suction filtered, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to mannitol solution (containing 14g mannitol in 400mL water), and the resulting suspension was lyophilized (Toffulon, LYO-2) after stirring at 500rpm, the lyophilization conditions being as described in Table 1 below.
TABLE 1 Freeze drying conditions
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝23.339μm。
XRD detection: using powder diffractometer (X' Pert)3XRD testing (Cu, 40mA, 3.5 ° to 40 °) was performed on the sample by Powder, Malvern Panalytical), and as shown in fig. 1, a distinct diffraction peak appeared at 12.7101 ° at 2 θ, which is in the α form.
DSC detection: the resulting samples were tested with a Mettler DSC (DSC 500, Mettler TOLEDO) (35 ℃ to 160 ℃, 10K/min). As shown in fig. 2, the sample showed an endothermic peak at 131.20 ℃, indicating that the resulting crystal form was the α crystal form.
Example 2 preparation of progesterone suspension
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone are weighed, 200mL of absolute ethanol is added, and the mixture is stirred and dissolved at the temperature of 60 ℃.
Preparation of precipitated solvent: 104mL of pure water and 26mL of absolute ethyl alcohol are measured in a steel cup with a jacket and cooled to-10 ℃ by a cooling circulation device.
Sample preparation: the shearing head was placed in the eluting solvent, the rotational speed was adjusted to 7000rpm, the progesterone solution was pumped into the eluting solvent at a rate of 219mL/min (pump time: 20s), the resulting suspension was suction filtered, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to mannitol solution (containing 6g of mannitol, 160mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized, the lyophilization conditions being as indicated in example 1.
XRD detection: using powder diffractometer (X' Pert)3Powder, Malvern Panalytical) XRD measurements (Cu, 40mA, 3.5 ° -40 °) were performed on the samples, as shown in fig. 3, with diffraction peaks appearing at 12.7213 ° (α crystal form) and 2 θ 13.6486 ° (β crystal form), as mixed crystal form.
Preparation of dispersing agent: weighing 0.75g of span 20, 1.9g of Tween 20, 1.25g of sodium dihydrogen phosphate, 2.5g of disodium hydrogen phosphate and 3.05g of sodium chloride, placing in a 1000mL beaker, adding 466mL of water, and stirring until the mixture is completely dissolved to obtain the productTo a dispersant.
Suspension preparation: 2.94g of the lyophilized sample (containing 2.5g of progesterone) was weighed into a 150mL beaker, 47.06g of dispersant was added and sheared at 4000rpm for 5 min.
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝15.846μm。
DSC detection: the resulting samples were tested with a Mettler DSC (DSC 500, Mettler TOLEDO) (35 ℃ to 160 ℃, 10K/min). As shown in fig. 4, endothermic peaks appeared at 125.12 ℃ (β crystal form), 131.40 ℃ (α crystal form) of the sample, indicating that the obtained crystal form is a mixed crystal form.
Example 3 preparation of progesterone samples
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of absolute ethanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 26mL of pure water and 104mL of absolute ethyl alcohol are measured in a steel cup with a jacket and cooled to-10 ℃ by a cooling circulation device.
Sample preparation: the shearing head was placed in the eluting solvent, the rotation speed was adjusted to 7000rpm, the progesterone solution was pumped into the eluting solvent at a rate of 219mL/min (pump time: 20s), the resulting suspension was filtered under suction, the filter cake was washed with 3000mL of pure water, the solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160mL of water), and the resulting suspension was lyophilized after stirring at 500rpm for 30min (lyophilization conditions as in example 1).
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝29.164μm。
XRD detection: using powder diffractometer (X' Pert)3Powder, Malvern Panalytical) XRD measurements (Cu, 40mA, 3.5 ° to 40 °) were performed on the samples, as shown in fig. 5, with diffraction peaks at 12.7192 ° (α crystal form) and 13.6487 ° (β crystal form) appearing at 2 θ,is a mixed crystal form.
DSC detection: the resulting samples were tested with a Mettler DSC (DSC 500, Mettler TOLEDO) (35 ℃ to 160 ℃, 10K/min). As shown in fig. 6, the sample showed endothermic peaks at 123.93 ℃ (β crystal form) and 131.60 ℃ (α crystal form), indicating that the obtained crystal form is a mixed crystal form.
Example 4 preparation of progesterone suspension
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of absolute ethanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 104mL of pure water and 26mL of absolute ethyl alcohol are measured in a steel cup with a jacket and cooled to-10 ℃ by a cooling circulation device.
Preparation of seed suspension: weighing 10g of alpha crystal form progesterone in 0.2% (w/v) Tween 20 solution (90g), and shearing at 7000rpm for 20min to obtain (D4, 3)]＝5.207μm)。
Sample preparation:10 g of seed crystal suspension was added to the eluting solvent, and the shearing head was placed in the eluting solvent, and the rotation speed was adjusted to 7000 rpm. The progesterone solution was pumped into the eluting solvent at a rate of 219mL/min (pump time: 20s), the resulting suspension was suction filtered, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to a mannitol solution (containing 6g of mannitol, 160mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized to obtain a lyophilized sample, the lyophilization conditions being as described in example 1.
XRD detection: using powder diffractometer (X' Pert)3XRD testing (Cu, 40mA, 3.5 ° to 40 °) was performed on the sample by Powder, Malvern Panalytical), and as shown in fig. 7, a distinct diffraction peak appeared at 12.7214 ° at 2 θ, which is in the α form.
Preparation of dispersing agent: the same as in example 2.
Suspension preparation: weighing 2.94g of the lyophilized sample (Containing 2.5g of progesterone) was placed in a 150mL beaker and sheared at 4000rpm for 5min after 47.06g of dispersant was added.
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝10.509μm。
DSC detection: the resulting samples were tested with a Mettler DSC (DSC 500, Mettler TOLEDO) (35 ℃ to 160 ℃, 10K/min). As shown in fig. 8, the sample showed an endothermic peak at 131.17 ℃ (form α), indicating that the resulting form was form α.
Example 5 preparation of progesterone samples
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of absolute ethanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 130mL of pure water is measured in a steel cup with a jacket, and the water is cooled and circulated at room temperature by natural water.
Preparation of seed suspension: weighing another batch of beta-crystal form progesterone 10g in 0.2% (w/v) Tween 20 solution (90g), shearing at 7000rpm for 20min to obtain (D4, 3)]＝5.682μm)。
Sample preparation:10 g of seed crystal suspension was added to the eluting solvent, and the shearing head was placed in the eluting solvent, and the rotation speed was adjusted to 7000 rpm. The progesterone solution was pumped into the eluting solvent at a rate of 114mL/min (pump time: 38s), the resulting suspension was filtered with suction, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to a mannitol solution (containing 6g of mannitol, 160mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized to obtain a lyophilized sample, the lyophilization conditions being as described in example 1.
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝11.792μm。
XRD detection: using powder diffractometer (X' Pert) 3XRD testing (Cu, 40mA, 3.5 ° -40 °) was performed on the sample by Powder, Malvern Panalytical), and as shown in fig. 9, a distinct diffraction peak appeared at 13.6175 ° at 2 θ, which is in the β crystal form.
Example 6 preparation of progesterone samples
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of absolute ethanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 130mL of pure water is measured in a steel cup with a jacket, and the water is cooled and circulated by room temperature tap water.
Preparation of seed suspension: the same as in example 4.
Sample preparation:10 g of seed crystal suspension was added to the eluting solvent, and the shearing head was placed in the eluting solvent, and the rotation speed was adjusted to 7000 rpm. The progesterone solution was pumped into the eluting solvent at a rate of 219mL/min (pump time: 20s), the resulting suspension was suction filtered, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to mannitol solution (containing 6g of mannitol, 160mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized, the lyophilization conditions being as indicated in example 1.
Particle size measurement: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝12.632μm。
XRD detection: using powder diffractometer (X' Pert)3Powder, Malvern Panalytical) XRD measurements (Cu, 40mA, 3.5 ° to 40 °) were performed on the samples, as shown in fig. 10, with a diffraction peak at 12.7181 ° at 2 θ, in the α form.
DSC detection: the resulting samples were tested with a Mettler DSC (DSC 500, Mettler TOLEDO) (35 ℃ to 160 ℃, 10K/min). As shown in fig. 11, the sample showed an endothermic peak at 130.75 ℃, indicating that the resulting crystal form was the α crystal form.
Example 7 preparation of progesterone suspension
Progesterone solution preparation: 5g of Tween 20 and 90g of progesterone were weighed, 200mL of methanol was added, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: 130mL of pure water is measured in a steel cup with a jacket, and the water is cooled and circulated at room temperature by natural water.
Sample preparation: the shearing head was placed in the eluting solvent, the rotational speed was adjusted to 7000rpm, the progesterone solution was pumped into the eluting solvent at a rate of 114mL/min (pump time: 38s), the resulting suspension was suction filtered, and the filter cake was washed with 3000mL of pure water.
The solid precipitate was transferred to mannitol solution (containing mannitol 6g, water 160mL) and after stirring at 500rpm for 30min, the resulting suspension was lyophilized, the lyophilization conditions being as described in example 1.
XRD detection: using powder diffractometer (X' Pert)3XRD testing (Cu, 40mA, 3.5 ° -40 °) was performed on the sample by Powder, Malvern Panalytical), and as shown in fig. 12, a distinct diffraction peak appeared at 13.6175 ° at 2 θ, which is in the β crystal form.
Preparation of dispersing agent: the same as in example 2.
Suspension preparation: 2.96g of the lyophilized sample (containing 2.5g of progesterone) was weighed into a 150mL beaker, 47.04g of dispersant was added and sheared at 4000rpm for 5 min.
Particle size measurement: the resulting suspension was measured for particle size using a Malvern MasterSizer 3000 (water was the assay vehicle), and the average particle size D [4,3]]＝12.989μm。
Example 8 Crystal transformation of Progesterone
Progesterone solution preparation: 90g of progesterone was weighed, added to 200mL of absolute ethanol, and dissolved at 60 ℃ with stirring.
Preparation of precipitated solvent: weighing 15g of Tween 20, washing with 3000mL of water for multiple times into a steel cup with a jacket, and cooling with a cooling circulation deviceTo 9 ℃.
Sample preparation: the shearing head was placed in the eluting solvent and the rotation speed was adjusted to 7000 rpm. The progesterone solution was pumped into the eluting solvent at a rate of 37mL/min (pump time: 117 s). The resulting suspension was filtered with suction and the filter cake was washed with 3000mL of purified water. The solid precipitate was transferred to a mannitol solution (containing 6g of mannitol and 160mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized under the same conditions as in example 1.
Preparation of dispersing agent: the same as in example 2.
Suspension preparation: 2.96g of the lyophilized sample (containing 2.5g of progesterone) was weighed into a 150mL beaker, 47.04g of dispersant was added and sheared at 4000rpm for 5 min.
Particle size measurement: the resulting suspension was measured for particle size using a Malvern MasterSizer 3000 (water was the assay vehicle), and the average particle size D [4,3]]＝16.553μm。
Sample treatment: and (3) the prepared suspension is divided into 10mL penicillin bottles, aluminum covers are rolled, the bottles are placed at 40 ℃ for 2 days and 5 days, then the bottles are taken out for particle size test and DSC detection, and the detection results are shown in Table 2.
From the detection results, in the suspension state, the beta-form progesterone is converted into the alpha-form, and the particle size is increased.
TABLE 2 particle size measurement and DSC measurement results
Example 9 preparation of progesterone powder
Progesterone solution preparation: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of precipitated solvent: weighing 15g of Tween 20, washing with 3000mL of water for multiple times into a steel cup with a jacket, and coolingThe ring assembly was cooled to 9 ℃;
sample preparation: the shearing head was placed in the precipitation solvent and the rotational speed was adjusted to 6000 rpm. The diameter of the liquid outlet is adjusted to 0.51mm, so that the progesterone solution is pumped into the precipitated solvent at the speed of 100 mL/min. After the progesterone solution was added completely, the filtration was carried out, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 3g of mannitol and 100mL of water), and the resulting suspension was lyophilized after stirring at 500rpm for 30min (the same lyophilization conditions as in example 1).
Particle size test results: particle size was measured using a Malvern MasterSizer 3000 (water as the assay vehicle), average particle size D [4,3]]＝8.450μm。
Example 10 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: and (3) putting the shearing head into the precipitated solvent, adjusting the rotating speed to 8000rpm, adjusting the diameter of a liquid outlet to 0.51mm, and pumping the progesterone solution into the precipitated solvent at the speed of 50 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay vehicle) and the average particle size D [4,3] ═ 6.653 μm.
Example 11 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: and (3) putting the shearing head into the precipitated solvent, adjusting the rotating speed to 8000rpm, adjusting the diameter of a liquid outlet to 0.51mm, and pumping the progesterone solution into the precipitated solvent at the speed of 20 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay support) and the average particle size D [4,3] was 3.386 μm.
Example 12 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: putting the shearing head into the precipitated solvent, adjusting the rotating speed to 15000rpm, adjusting the diameter of a liquid outlet to 0.16mm, and pumping the progesterone solution into the precipitated solvent at the speed of 20 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay support) and the average particle size D [4,3] was 0.538 μm.
Example 13 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: putting the shearing head into the precipitated solvent, adjusting the rotating speed to 15000rpm, adjusting the diameter of a liquid outlet to 0.16mm, and pumping the progesterone solution into the precipitated solvent at the speed of 6 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water as the assay vehicle) and the average particle size D [4,3] was 0.356 μm.
Example 14 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 600mL of 95% ethanol, and stirring to dissolve;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: placing the precipitated solvent on a magnetic stirrer, adjusting the rotating speed to 2000rpm, adjusting the diameter of a liquid outlet to 0.16mm, and pumping the progesterone solution into the precipitated solvent at the speed of 6 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay vehicle) and the average particle size D [4,3] ═ 15.425 μm.
Example 15 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 100mL of absolute ethyl alcohol, and stirring to dissolve the progesterone;
preparation of a precipitated solvent: weighing 15g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 3000mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: putting the shearing head into the precipitated solvent, adjusting the rotating speed to 15000rpm, adjusting the diameter of a liquid outlet to 0.16mm, and pumping the progesterone solution into the precipitated solvent at the speed of 20 mL/min. After the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay vehicle) and the average particle size D [4,3] ═ 1.447 μm.
Example 16 preparation of progesterone powder
Preparing a progesterone solution: weighing 20g of progesterone, adding 65mL of absolute ethyl alcohol, and stirring at 60 ℃ to dissolve the progesterone;
preparation of a precipitated solvent: weighing 2.5g of Tween 20, washing the Tween 20 into a steel cup with a jacket by 1500mL of water for multiple times, and cooling the Tween to 9 ℃ by using a cooling circulation device;
sample preparation: placing the precipitated solvent on a magnetic stirrer, adjusting the rotating speed to 2000rpm to precipitate the solvent, adjusting the diameter of a liquid outlet to be 0.90mm, and pumping the progesterone solution into the precipitated solvent at the speed of 100 mL/min. When the progesterone solution was added completely, it was filtered with suction, the obtained filter cake was washed with 3000mL of purified water, the solid precipitate was transferred to a mannitol solution (containing 4g of mannitol and 130mL of water), and after stirring at 500rpm for 30min, the resulting suspension was lyophilized (lyophilization conditions as in example 1).
Particle size test results: the particle size was measured using a malvern MasterSizer 3000 (water was the assay vehicle) and the average particle size D [4,3] ═ 58.162 μm.
Example 17 in vivo metabolism of progesterone suspensions
Experimental animals: SD female rats (ovariectomized) 16 (220g to 300g) were randomly divided into 4 groups (A, B, C, D groups in turn), with 4 per group.
The reference formulation was a commercially available oily injection of progesterone (50 mg/mL).
Administration mode and dose: intramuscular injection to the outer thigh; group A: 6mg/Kg of oily progesterone injection sold on the market is continuously administered for 5 days; group B: progesterone suspension from example 4, administered at 30 mg/Kg; group C: the progesterone suspension of example 2, administered at 30 mg/Kg; group D: 30mg/Kg of the progesterone suspension of example 7 was administered.
Sampling and detecting: after administration, 0.3ml of venous blood was taken from B, C, D groups at 6 days (144h) before (0h), 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 1d (24h), 2d (48h), 3d (72h), 4d (96h), 5d (120h) before administration, respectively in heparinized EP tubes; group A was bled 0.3ml into heparinized EP tubes on day 1 pre-dose (0h), post-dose (0d)0.5h, 1h, 2h, 3h, 4h, 6h, 8h, day 2, 3, 4 pre-dose (0h of day) and post-dose 3h, day 5 pre-dose (0h of day) and day 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 24h and 48 h. The collected whole blood was centrifuged at 4000rpm for 10min to separate plasma, which was stored in a refrigerator at-80 ℃ to be assayed.
The detection method comprises the following steps: the content of progesterone in the plasma of rats was measured by HPLC-MS/MS method to show the change in plasma concentration of progesterone after intramuscular injection of progesterone suspension in SD rats.
Fig. 13 shows the time-dependent progesterone concentration in rat plasma, and it can be seen that the samples prepared in example 2 (mixed crystal form), example 4 (alpha crystal form) and example 7 (beta crystal form) all achieve the 5-day sustained release effect.
Claims (15)
- A method of preparing progesterone particles comprising:step 1, dissolving progesterone in a solvent to provide a progesterone solution;step 2, pumping the progesterone solution into a precipitation solvent of progesterone which is sheared at a high speed or stirred vigorously at a preset speed so as to precipitate the progesterone; andstep 3, separating precipitates and drying to obtain the progesterone particles;wherein the progesterone particles are progesterone crystals or progesterone powder.
- The method of claim 1, wherein step 2 is further: pumping the progesterone solution into a cooled high shear or vigorously stirred eluting solvent at a predetermined rate to elute progesterone; the precipitation solvent is water, an organic solvent or a mixture of water and the organic solvent;the drying in step 3 is preferably freeze-drying.
- The method of 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.
- The method of any one of claims 1 to 3, wherein the temperature of the eluting solvent is from-20 ℃ to 25 ℃; preferably, when water is used as the eluting solvent, the temperature is 1 ℃ to 25 ℃; when an organic solvent is used as a precipitation solvent, the temperature of the precipitation solvent is-20 ℃ to 0 ℃; when a mixture of water and an organic solvent is used as the eluting solvent, the temperature of the eluting solvent is-10 ℃ to 25 ℃.
- The method according to any one of claims 1 to 4, wherein the rotational speed of the vigorous stirring is 500 to 2000rpm, preferably 700 to 2000rpm, or preferably 700 to 1000 rpm; the high speed shearing is achieved by a shear apparatus with a rotation speed of 3000rpm to 20000rpm, preferably 5000rpm to 20000rmp or preferably 7000rpm to 20000 rpm.
- The method according to any one of claims 1 to 5, wherein the solvent used to dissolve progesterone is a water-miscible organic solvent; preferably, the solvent used for dissolving the progesterone in the step 1 is one or a mixture of methanol, absolute ethyl alcohol, ethylene glycol, isopropanol and acetone, or an aqueous solution of the above alcohols; further preferably, the solvent used for dissolving the progesterone in the step 1 is one or a mixture of methanol, absolute ethanol, isopropanol and acetone, or an aqueous solution of the above alcohols.
- The method of any one of claims 1 to 6, wherein the pumping rate of the progesterone solution is from 6 to 500 mL/min.
- The method of any one of claims 1 to 7, wherein the concentration of the progesterone solution is from 10mg/mL to 500 mg/mL.
- The method of any one of claims 2 to 8, wherein the freeze-drying comprises: re-dispersing the separated progesterone in 2-4 wt% mannitol water solution; then, lyophilization was performed.
- The method according to any one of claims 1 to 9, wherein a surfactant is added to the progesterone solution such that the progesterone solution further comprises, based on the mass of the progesterone solution, from 0.5 to 3 wt%, preferably from 1 to 2 wt% of a surfactant; or adding a surfactant to the precipitation solvent of the progesterone so that the precipitation solvent further contains 0.1 to 2 wt%, preferably 0.3 to 0.8 wt%, of the surfactant based on the mass of the precipitation solvent.
- Process according to any one of claims 1 to 10, preferably ethanol as the precipitation solvent, obtaining progesterone in the alpha crystalline form;or, preferably, water is used as a precipitation solvent, and methanol is used as an organic solvent for dissolving the progesterone to obtain the progesterone with the beta crystal form.
- The method of any one of claims 1 to 11, wherein the method further comprises: before adding the progesterone solution to the eluting solvent, seed crystals of a predetermined crystalline form are added to the eluting solvent to more stably obtain the corresponding crystalline form of progesterone.
- The method according to any one of claims 1 to 12, wherein the volume ratio of the pumped progesterone solution to the eluting solvent is 1.5:1 to 1: 30.
- A progesterone crystal or powder prepared by the method of any one of claims 1-13 having a particle size D [4,3] of 0.3 to 60 μ ι η.
- A progesterone injection wherein said injection comprises an effective amount of progesterone crystals or powder of claim 14.
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| PCT/CN2019/127555 WO2020135352A1 (en) | 2018-12-28 | 2019-12-23 | Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof |
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| 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 |
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| 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 |
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| DOAA RAGAB等: "Crystallization of Progesterone for Pulmonary Drug Delivery", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 99, no. 3, pages 1123 - 1137, XP055714431, DOI: 10.1002/jps.21896 * |
| EUNBI CHO等: "Enhanced dissolution of megestrol acetate microcrystals prepared by antisolvent precipitation process using hydrophilic additives", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 396, no. 1, pages 91 - 98, XP027169576, DOI: 10.1016/j.ijpharm.2010.06.016 * |
| JAVIER A.FALCON等: "In Situ Monitoring of Antisolvent Addition Crystallization with Principal Components Analysis of Raman Spectra", CRYSTAL GROWTH & DESIGN, vol. 4, no. 5, pages 457 - 463, XP055714436, DOI: 10.1021/cg034206y * |
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