Progesterone suspension as well as preparation method and application thereof

Abstract

The invention provides a progesterone suspension as well as a preparation method and application thereof, and belongs to the technical field of medicines. The preparation method comprises the following steps: dissolving a progesterone raw material medicine in hot vegetable oil, and cooling to separate out progesterone to obtain a progesterone oil suspension; the progesterone oil suspension is mixed with a surfactant, and a progesterone suspension is obtained; or mixing the vegetable oil with a surfactant to obtain a mixed oil phase; dissolving a progesterone raw material medicine in a hot mixed oil phase, and cooling to separate out progesterone, so as to obtain the progesterone suspension, the D90 particle size of progesterone in the progesterone suspension is 4 to 50 [mu] m. The progesterone is dissolved in hot vegetable oil or a mixed oil phase by adopting a hot dissolution and cold separation process, the progesterone can be uniformly separated out and uniformly dispersed in a system through cooling, and the progesterone in the progesterone suspension is uniform in particle size, loose in texture, not easy to agglomerate and relatively good in suspension effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a progesterone suspension, its preparation method, and its application. Background Technology

[0002] Progesterone, also known as luteinizing hormone or pregn-4-ene-3,20-dione, is a 21-carbon steroid hormone secreted by the luteal cells of the female ovary and plays an important role in menstruation and pregnancy. Exogenous progesterone was first successfully synthesized by researchers in the 1830s. The structural formula of progesterone is shown in Formula I.

[0003]

[0004] Currently, the most commonly used dosage forms and administration methods for progesterone include oral, intramuscular injection, and vaginal administration. Oral progesterone administration is convenient and provides accurate dosage, but it suffers from the first-pass effect in the liver, reducing bioavailability, irritating the gastrointestinal system, and producing complex metabolites. 80-90% of oral progesterone is eliminated by the liver (first-pass effect). Intramuscular injection of progesterone is widely used in clinical treatment. Intramuscular injection allows for faster and better absorption by the body, achieving higher blood concentrations, a longer onset of action, and is inexpensive. However, because injection is an invasive treatment, patient compliance is poor, and prolonged use can easily lead to redness, swelling, and lumps at the injection site, causing inconvenience to patients.

[0005] The vagina is very close to the uterus, and vaginal administration involves placing the medication inside the vagina, where it is absorbed through the vaginal mucosa and enters the body to produce a therapeutic effect, avoiding the first-pass effect of the liver. After progesterone is administered vaginally, it is rapidly absorbed by the vaginal epithelial cells and diffuses to the cervix and uterine body via local fluids, primarily the lymphatic system, before entering the systemic circulation—the "uterine first-pass effect." This portion of the drug reaches the target organ first before entering the systemic circulation, and its efficacy is not affected by hepatic metabolism. It also allows for a smaller dosage and avoids causing more systemic adverse reactions. Therefore, vaginal administration is the optimal method of progesterone administration.

[0006] There are reports of using progesterone suspension as the content to prepare progesterone vaginal soft capsules. However, when using this method to prepare progesterone suspension, in order to improve the suspension effect, the progesterone raw material needs to be micronized in advance, which is a complicated operation. Summary of the Invention

[0007] The purpose of this invention is to provide a progesterone suspension, its preparation method, and its application. The preparation method of the progesterone suspension in this invention is simple to operate, and the progesterone in the progesterone suspension has a good suspension effect.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] This invention provides a method for preparing a progesterone suspension, comprising method one or method two:

[0010] Method 1 includes the following steps: dissolving progesterone raw material in hot vegetable oil, cooling to precipitate progesterone, and obtaining a progesterone oil suspension; mixing the progesterone oil suspension with a surfactant to obtain the progesterone mixed suspension;

[0011] The second method includes the following steps: mixing vegetable oil with a surfactant to obtain a mixed oil phase; dissolving progesterone raw material in the hot mixed oil phase, and precipitating progesterone by cooling to obtain the progesterone suspension;

[0012] The progesterone in the progesterone suspension has a D90 particle size of 4–50 μm.

[0013] Preferably, the progesterone suspension comprises 5-15 parts progesterone, 10-95 parts vegetable oil, and 0.1-50 parts surfactant by weight.

[0014] Preferably, in method one, the temperature of the hot vegetable oil is ≥80℃, and the cooling rate is 1.0~3.0℃ / min;

[0015] In Method 2, the temperature of the hot mixed oil phase is ≥80℃, and the cooling rate is 1.0~3.0℃ / min.

[0016] Preferably, the vegetable oil includes one or more of the following: sesame oil, soybean oil, sunflower seed oil, olive oil, grape seed oil, corn oil, tea oil, peanut oil, castor oil, palm oil, flaxseed oil, rapeseed oil, blueberry seed oil, macadamia nut oil, litsea cubeba oil, rosemary oil, cottonseed oil, walnut oil, rapeseed oil, rice bran oil, aloe vera oil, and calendula oil.

[0017] The surfactant includes one or more of nonionic surfactants, anionic surfactants, and amphoteric surfactants.

[0018] Preferably, the nonionic surfactant comprises one or more of the following: fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ester, fatty amine polyoxyethylene ether, alkylolamide polyoxyethylene ether, squalene, squalane, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether, triethanolamine, polyglycerol-2 dihydroxystearate, polyglycerol-2 isostearate, PEG-30 dihydroxystearate, decanoic acid decanoic acid triglyceride, cetyl polyethylene glycol / polypropylene glycol-10 / 1 dimethylsiloxane, polyethylene glycol (40) stearate, polysorbate, Span, and poloxamer.

[0019] The anionic surfactant includes benzenesulfonate and / or sodium lauryl sulfate;

[0020] The amphoteric surfactant includes lecithin.

[0021] The present invention provides a progesterone suspension prepared by the preparation method described above, comprising progesterone, vegetable oil and surfactant, wherein the progesterone in the progesterone suspension is formed by hot dissolution and cold precipitation of progesterone raw material, and the D90 particle size of progesterone in the progesterone suspension is 4-50 μm.

[0022] This invention provides the application of the progesterone suspension described above in the preparation of progesterone vaginal administration formulations, wherein the progesterone vaginal administration formulations include progesterone foam, progesterone ointment, or progesterone suppositories.

[0023] This invention provides a progesterone foaming agent, comprising an intermediate and a propellant, wherein the intermediate comprises a hydrophobic component and the progesterone suspension described in the above technical solution; the mass percentage of progesterone in the progesterone foaming agent is <19% of the mass of the intermediate.

[0024] This invention provides a progesterone ointment, comprising an ointment base and the progesterone suspension described in the above technical solution.

[0025] This invention provides a progesterone suppository, comprising a suppository matrix and the progesterone suspension described in the above technical solution.

[0026] This invention provides a method for preparing a progesterone suspension, comprising either method one or method two: Method one includes the following steps: dissolving progesterone raw material in hot vegetable oil, cooling to precipitate progesterone, obtaining a progesterone oil suspension; mixing the progesterone oil suspension with a surfactant to obtain the progesterone suspension; Method two includes the following steps: mixing vegetable oil with a surfactant to obtain a mixed oil phase; dissolving progesterone raw material in the hot mixed oil phase, cooling to precipitate progesterone, obtaining the progesterone suspension; the D90 particle size of progesterone in the progesterone suspension is 4-50 μm. This invention employs a hot-dissolution and cold-precipitation process, dissolving progesterone in hot vegetable oil or a mixed oil phase, and cooling to achieve uniform precipitation and dispersion of progesterone in the system. The resulting progesterone suspension has uniform progesterone particle size and a loose texture, making it less prone to aggregation and exhibiting good suspension performance. The progesterone raw material used in the preparation of progesterone suspension in this invention does not require pre-micronization, and the operation is simple.

[0027] Furthermore, the progesterone suspension described in this invention can be applied to foam formulations. These foam formulations exhibit good compliance, uniform progesterone dispersion, precise particle size control, and are less prone to caking. They provide accurate progesterone dosage, are convenient to use, offer a wide contact area within the vagina, and provide stable release. They can also meet different release requirements, balancing rapid early release with sustained subsequent release. Simultaneously, the progesterone suspension described in this invention can also be applied to vaginal suppositories and ointments, achieving good results. Attached Figure Description

[0028] Figure 1 A diagram showing the dispersion at each stage when evaluating the dispersion of the active pharmaceutical ingredient;

[0029] Figure 2 Foam property diagrams at different levels for evaluating foam properties;

[0030] Figure 3 The mean CT curves are for the tested foam sample (Example 3) and a commercially available progesterone gel. Detailed Implementation

[0031] This invention provides a method for preparing a progesterone suspension, comprising method one or method two:

[0032] Method 1 includes the following steps: dissolving progesterone raw material in hot vegetable oil, cooling to precipitate progesterone, and obtaining a progesterone oil suspension; mixing the progesterone oil suspension with a surfactant to obtain the progesterone mixed suspension;

[0033] The second method includes the following steps: mixing vegetable oil with a surfactant to obtain a mixed oil phase; dissolving progesterone raw material in the hot mixed oil phase, and precipitating progesterone by cooling to obtain the progesterone suspension;

[0034] The progesterone in the progesterone suspension has a D90 particle size of 4–50 μm.

[0035] In this invention, unless otherwise specified, all raw materials used are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0036] The composition of the progesterone suspension described in this invention will be explained in detail below.

[0037] In one embodiment of the present invention, the progesterone suspension comprises, by weight, 5-15 parts progesterone, 10-95 parts vegetable oil, and 0.1-50 parts surfactant. The present invention limits the amounts of each component within the above ranges. When progesterone is dissolved in hot vegetable oil or a mixed oil phase, it facilitates the formation of a supersaturated solution. Subsequently, cooling allows the progesterone to precipitate uniformly and disperse evenly in the system.

[0038] In one embodiment of the present invention, the progesterone suspension comprises 5 to 15 parts of progesterone by mass, specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 parts. The progesterone suspension of the present invention has a D90 particle size of 4-50 μm, specifically 4 μm, 6 μm, 8 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, or 50 μm. This invention can directly prepare the progesterone suspension using progesterone raw material without the need for micronization or other pretreatments. The operation is simple, and progesterone with a D90 particle size of 4-50 μm and in a suspended state is formed through hot dissolution and cold precipitation. The final progesterone suspension has a good suspension effect.

[0039] As one embodiment of the present invention, based on the mass fraction of progesterone, the progesterone suspension includes 10 to 95 parts of vegetable oil, specifically 10, 20, 30, 40, 50, 56, 60, 63, 66, 67, 70, 74, 76, 80, 82, 85, 90, or 95 parts. In one embodiment of the present invention, the vegetable oil may include one or more of the following: sesame oil, soybean oil, sunflower seed oil, olive oil, grape seed oil, corn oil, tea oil, peanut oil, castor oil, palm oil, flaxseed oil, rapeseed oil, blueberry seed oil, macadamia nut oil, litsea cubeba oil, rosemary oil, cottonseed oil, walnut oil, canola seed oil, rice bran oil, aloe vera oil, and calendula oil; furthermore, it may be one or more of the following: sesame oil, soybean oil, sunflower seed oil, olive oil, grape seed oil, corn oil, and tea oil; even further, it may be one or more of the following: sesame oil, soybean oil, grape seed oil, olive oil, and corn oil; specifically, it may be sesame oil, soybean oil, grape seed oil, olive oil, or corn oil; it may also be a soybean oil-corn oil blend, a sesame oil-soybean oil blend, a sesame oil-olive oil blend, a sesame oil-corn oil blend, a soybean oil-olive oil blend, or a soybean oil-grape seed oil blend; or it may be a sesame oil-soybean oil-corn oil blend or a sesame oil-soybean oil-olive oil blend. In one embodiment of the present invention, the mass ratio of soybean oil to corn oil in the soybean oil-corn oil blend can be 35-60:15-25, specifically 51:15.65, 52:15.65, 40:16.65, 47:16.65, 50:16.65, 54:16.65, or 60:25; the mass ratio of sesame oil to soybean oil in the sesame oil-soybean oil blend can be 50-60:30-50, specifically 55:35; the mass ratio of sesame oil to olive oil in the sesame oil-olive oil blend can be 40-50:25-40, specifically 45:35; and the mass ratio of sesame oil to corn oil in the sesame oil-corn oil blend can be 40-55:30-40. Specifically, the ratio can be 50:35 or 42:32; the mass ratio of soybean oil to grapeseed oil in the soybean oil-grapeseed oil blend can be 45-55:20-30, and more specifically, 50:25; the mass ratio of soybean oil to olive oil in the soybean oil-olive oil blend can be 45-55:30-40, and specifically, 50:35; the mass ratio of sesame oil, soybean oil, and corn oil in the sesame oil-soybean oil-corn oil blend can be 35-45:5-25:15-35, and specifically, 40:10:30; the mass ratio of sesame oil, soybean oil, and olive oil in the sesame oil-soybean oil-olive oil blend can be 20-30:30-40:10-20, and specifically, 25:36:15.

[0040] In one embodiment of the present invention, based on the mass fraction of progesterone, the progesterone suspension includes 0.1 to 50 parts of surfactant, more specifically 0.5 to 20 parts, and more specifically 0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 parts. In another embodiment of the present invention, the surfactant may include one or more of nonionic surfactants, anionic surfactants, and amphoteric surfactants. In one embodiment of the present invention, the nonionic surfactant may include fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ester, fatty amine polyoxyethylene ether, alkylolamide polyoxyethylene ether, squalene, squalane, fatty acid monoglycerides, fatty acid diglycerides, sucrose fatty acid esters, polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether, triethanolamine, polyglycerol-2-dimeric hydroxystearate (PGPH), polyglycerol-2-isostearate (IS-201P), PEG-30-dimeric hydroxystearate (D... PHS), decanoic acid triglyceride (GTCC), cetyl polyethylene glycol / polypropylene glycol-10 / 1 dimethylsiloxane (EM90), polyethylene glycol (40) stearate, polysorbate (Tween), Span, and poloxamer, further comprising one or more of fatty alcohol polyoxyethylene ether, polyoxyethylene stearate, squalane, lecithin, fatty acid monoglycerides, fatty acid diglycerides, sucrose fatty acid esters, Tween, poloxamer, triethanolamine, and Span; wherein the Tween may be Tween 20 and / or Tween 60, and the Span may be Span 40. As one embodiment of the invention, the anionic surfactant may include benzenesulfonate and / or sodium lauryl sulfate; the amphoteric surfactant may include lecithin. In one embodiment of the present invention, the surfactant may be one or more of Tween, Span, squalane, lecithin, triethanolamine, sodium lauryl sulfate, and polyethylene glycol (40) stearate; specifically, it may be Tween, Span, squalane, lecithin, triethanolamine, sodium lauryl sulfate, or polyethylene glycol (40) stearate; it may also be a Tween-Span complex, a squalane-lecithin complex, a Tween-squalane complex, a Span-triethanolamine complex, or a squalane-triethanolamine complex; or it may be a Tween-Span-triethanolamine complex.In one embodiment of the present invention, the mass ratio of Tween to Span in the Tween-Span compound can be 1-4:0.5-2.5, specifically 3:2 or 2:1; the mass ratio of squalane to lecithin in the squalane-lecithin compound can be 3-5:1-3, specifically 4:2; the mass ratio of Tween to squalane in the Tween-squalane compound can be 4-6:2-4, specifically 5:3; the mass ratio of Span to triethanolamine in the Span-triethanolamine compound can be 1-3:7-9, specifically 2:8; the mass ratio of squalane to triethanolamine in the squalane-triethanolamine compound can be 2-4:5-7, specifically 3:6; and the mass ratio of Tween, Span, and triethanolamine in the Tween-Span-triethanolamine compound can be 6-8:2-4:3-5, specifically 7:3:4.

[0041] The progesterone suspension described in this invention can be prepared using either method one or method two. Progesterone is a white, odorless powder or crystal with a melting point of 121–131°C and is very stable in air. It is almost insoluble in water but soluble in solvents such as chloroform and acetone, exhibiting good lipid solubility. This invention employs a hot-dissolution and cold-precipitation process, dissolving progesterone in hot vegetable oil or a mixed oil phase. Cooling allows for the uniform precipitation and dispersion of progesterone throughout the system. The resulting progesterone suspension contains uniformly sized and loosely aggregated progesterone particles, demonstrating good suspension performance. The two methods of this invention are described in detail below.

[0042] In this invention, method one includes the following steps: dissolving progesterone raw material in hot vegetable oil, cooling to precipitate progesterone, and obtaining a progesterone oil suspension; mixing the progesterone oil suspension with a surfactant to obtain the progesterone mixed suspension. As one embodiment of this invention, the temperature of the hot vegetable oil can be ≥80℃, more preferably 80~105℃, specifically 80℃, 85℃, 90℃, 95℃, 100℃, or 105℃; the cooling rate can be 1.0~3.0℃ / min, specifically 1.0℃ / min, 1.5℃ / min, 2.0℃ / min, 2.5℃ / min, or 3.0℃ / min; preferably, the temperature is reduced to ≤50℃ after cooling, more preferably 20~50℃, specifically 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, or 50℃. This invention controls the cooling rate and temperature within the aforementioned range, which is beneficial for the uniform precipitation and dispersion of progesterone in the system. As one embodiment of this invention, cooling can be achieved using condensate; preferably, the cooling process is accompanied by stirring. This invention does not impose any particular limitation on the stirring rate; any stirring rate well-known to those skilled in the art can be used.

[0043] As one embodiment of the present invention, after dissolving the progesterone raw material in hot vegetable oil, a suspension stabilization treatment may be included; the suspension stabilization treatment may include homogenization and / or grinding, the homogenization may include one or more of high pressure homogenization, microfluidic homogenization and high shear homogenization, and the grinding may be wet grinding; the suspension stabilization treatment may be performed once or multiple times, and the present invention does not have any particular limitation on this. In one embodiment of the present invention, the conditions for high-pressure homogenization include: a pressure of 500–2500 bar, specifically 500 bar, 1000 bar, 1500 bar, 2000 bar, or 2500 bar; a rotational speed of 6000–12000 rpm, specifically 6000 rpm, 8000 rpm, 10000 rpm, or 12000 rpm; and a high-shear homogenization rotational speed of 4000–12000 rpm, specifically 4000 rpm, 4500 rpm, 5000 rpm, 5500 rpm, 6000 rpm, 6500 rpm, 7000 rpm, 8000 rpm, 10000 rpm, or 12000 rpm. The present invention does not specifically limit the timing of the suspension stabilization treatment. For example, after dissolving the progesterone raw material in hot vegetable oil, the suspension stabilization treatment can be started when cooling begins, and stopped when cooling to room temperature. The present invention employs a suspension stabilization treatment, which helps to prevent progesterone particles in the progesterone suspension from growing larger and can break some of the already grown progesterone particles back into smaller particles, thereby improving the stability of the progesterone suspension.

[0044] In this invention, method two includes the following steps: mixing vegetable oil with a surfactant to obtain a mixed oil phase; dissolving progesterone raw material in the hot mixed oil phase, and precipitating progesterone by cooling to obtain the progesterone suspension. As one embodiment of this invention, the temperature of the hot mixed oil phase can be ≥80℃, more preferably 80~105℃, specifically 80℃, 85℃, 90℃, 95℃, 100℃, or 105℃; the cooling rate can be 1.0~3.0℃ / min, specifically 1.0℃ / min, 1.5℃ / min, 1.6℃ / min, 2.0℃ / min, 2.5℃ / min, or 3.0℃ / min; preferably, the temperature is reduced to ≤50℃ by cooling, more preferably 20~50℃, specifically 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, or 50℃. This invention controls the cooling rate and temperature within the aforementioned range, which is beneficial for the uniform precipitation and dispersion of progesterone in the system. As one embodiment of this invention, cooling can be achieved using condensate; preferably, the cooling process is accompanied by stirring. This invention does not impose any particular limitation on the stirring rate; any stirring rate well-known to those skilled in the art can be used.

[0045] As one embodiment of the present invention, after dissolving the progesterone raw material in a hot mixed oil phase, a suspension stabilization treatment may be included; the method and number of suspension stabilization treatments are the same as those described above, and will not be repeated here.

[0046] This invention provides a progesterone suspension prepared by the method described in the above technical solution, comprising progesterone, vegetable oil, and a surfactant. The progesterone in the suspension is formed from progesterone raw material through hot dissolution and cold precipitation. The D90 particle size of the progesterone in the suspension is 4–50 μm. The composition of the progesterone suspension of this invention is consistent with the above technical solution and will not be repeated here.

[0047] This invention provides the application of the progesterone suspension described in the above-mentioned technical solution in the preparation of progesterone vaginal delivery formulations, which include progesterone foam, progesterone ointment, or progesterone suppositories. In the embodiments of this invention, the progesterone vaginal delivery formulation can specifically be a progesterone foam, progesterone ointment, or progesterone suppositories. Traditional vaginal progesterone dosage forms, such as vaginal tablets, capsules, suppositories, and solutions, fail to meet the actual needs of clinical use due to inconvenience, easy dislodgement restricting freedom of movement, slow release preventing timely efficacy, or lack of adhesion ensuring sufficient medication duration. Sustained-release gels are currently common progesterone vaginal delivery formulations, but to ensure sufficient and rapid efficacy, careful application using a vaginal speculum and application tools is usually required, which is inconvenient and leads to waste of active ingredients; moreover, some sustained-release gels use excipients such as polycarbofil and carbomer to improve adhesion, making the preparation process of sustained-release gels using these excipients relatively complex. In this embodiment of the invention, a progesterone foam is used. During use, the foam spontaneously expands in the vagina, filling the entire cavity. This ensures comprehensive, all-around coverage of the medication at the application site, and the large contact area guarantees that the drug quickly reaches its effective concentration. Simultaneously, after the foam fully expands, it forms a thin, uniform film that adheres to the inner surface of the vagina. This film is uniform and prevents leakage, ensuring sufficient medication duration. Furthermore, the progesterone suspension described in this invention can also be applied to vaginal suppositories and ointments, achieving good results. These will be described in detail below.

[0048] In this embodiment of the invention, the progesterone suspension is an anhydrous suspension, and the progesterone vaginal administration preparation prepared using the progesterone suspension is an anhydrous preparation. However, an appropriate amount of water may be added when preparing the progesterone suspension and the progesterone vaginal administration preparation. This invention does not have any special limitations on this.

[0049] This invention provides a progesterone foaming agent, comprising an intermediate and a propellant. The intermediate includes a hydrophobic component and the progesterone suspension described in the above-mentioned technical solution. The mass percentage of progesterone in the progesterone foaming agent is <19% of the mass of the intermediate. The progesterone foaming agent provided by this invention is a non-aqueous foaming agent.

[0050] In one embodiment of the present invention, the propellant may include one or more of dimethyl ether, chlorofluorocarbons, hydrofluorocarbons, and short-chain aliphatic alkanes, specifically dimethyl ether, chlorofluorocarbons, hydrofluorocarbons, or short-chain aliphatic alkanes; the short-chain aliphatic alkanes may include one or more of ethane, propane, butane, pentane, and hexane; the hydrofluorocarbons may include one or more of tetrafluoroethane, heptafluoropropane, and difluoroethane, specifically tetrafluoroethane, heptafluoropropane, or difluoroethane. The use of the above-mentioned propellants in this invention is beneficial for obtaining a progesterone foam with good properties. Especially when the progesterone foam is used as a vaginal administration preparation, hydrofluorocarbons are preferably used as the propellant, as their suitable spreadability helps improve patient compliance.

[0051] As one embodiment of the present invention, based on the amount of the intermediate being 10-100g / bottle, the amount of the propellant is 4-8g / bottle; specifically, the amount of the intermediate can be 10g / bottle, 20g / bottle, 30g / bottle, 40g / bottle, 50g / bottle, 60g / bottle, 70g / bottle, 80g / bottle, 90g / bottle or 100g / bottle; the amount of the propellant can be 4g / bottle, 4.5g / bottle, 5g / bottle, 5.5g / bottle, 6g / bottle, 6.5g / bottle, 7g / bottle, 7.5g / bottle or 8g / bottle.

[0052] In one embodiment of the present invention, the hydrophobic component may include one or more of the following: liquid fatty acid ester compounds, C12-C22 solid fatty acid ester compounds, C12-C22 fatty alcohol compounds, C12-C22 fatty acid compounds, and mineral oil; specifically, it may be a compound of liquid fatty acid ester compounds, C12-C22 solid fatty acid ester compounds, C12-C22 fatty alcohol compounds, C12-C22 fatty acid compounds, and mineral oil; wherein the compound contains... The mass ratio of liquid fatty acid esters, C12-C22 solid fatty acid esters, C12-C22 fatty alcohols to C12-C22 fatty acids is 10-13:2-5:0.4-0.8:0.8-1.2, specifically 11.75:3-4:0.6:1; the mass ratio of mineral oil to C12-C22 solid fatty acid esters in the compound can be 3-5:2-5, specifically 3:5, 4:4, 5:3 or 5:2. In one embodiment of the present invention, the liquid fatty acid ester compound may include one or more of isopropyl myristate, isopropyl palmitate, ethyl oleate, glyceryl oleate, and isopropyl laurate, specifically isopropyl myristate; the C12-C22 solid fatty acid ester compound may include one or more of glyceryl monostearate, glyceryl distearate, glyceryl monostearate and glyceryl distearate, glyceryl laurate, and glyceryl palmitate, specifically glyceryl monostearate; the C12-C22 fatty alcohol compound may include dodecyl alcohol, tetradecyl alcohol, etc. The mineral oil may include one or more of hexadecyl alcohol, octadecyl alcohol, eicosyl alcohol, and dioctyl alcohol, and may further include hexadecyl alcohol and / or octadecyl alcohol, specifically a hexadecyl alcohol-octadecyl alcohol complex, wherein the mass ratio of hexadecyl alcohol to octadecyl alcohol in the hexadecyl alcohol-octadecyl alcohol complex may be 0.1-0.3:0.3-0.5, specifically 0.2:0.4; the C12-C22 fatty acid compound may include one or more of lauric acid, myristic acid, palmitic acid, stearic acid, ferulic acid, behenic acid, oleic acid, and linoleic acid, specifically stearic acid; the mineral oil may include petrolatum. In this embodiment of the invention, the hydrophobic component may be a compound of isopropyl myristate, glyceryl monostearate, cetyl alcohol, octadecyl alcohol, stearic acid, and petrolatum. The mass ratio of isopropyl myristate, glyceryl monostearate, cetyl alcohol, octadecyl alcohol, and stearic acid in the compound may be 10-13:2-5:0.1-0.3:0.3-0.5:0.8-1.2, specifically 11.75:3-4:0.2:0.4:1. The mass ratio of petrolatum to glyceryl monostearate in the compound may be 3-5:2-5, specifically 3:5, 4:4, 5:3, or 5:2.

[0053] The percentage of progesterone in the progesterone foam agent of the present invention is <19%, and can be further 5% to 12%, specifically 5%, 6%, 7%, 8%, 9%, 10%, 11% or 12%.

[0054] In one embodiment of the present invention, the preparation method of the intermediate may include the following steps: mixing all components except progesterone to obtain a mixture; dissolving progesterone in the hot mixture, and precipitating progesterone by cooling to obtain the intermediate. In one embodiment of the present invention, the temperature of the hot mixture can be ≥80°C, more preferably 80–105°C, specifically 80°C, 85°C, 90°C, 95°C, 100°C, or 105°C; the cooling rate can be 1.0–3.0°C / min, specifically 1.0°C / min, 1.5°C / min, 2.0°C / min, 2.5°C / min, or 3.0°C / min; preferably, the temperature is reduced to ≤50°C by cooling, more preferably 20–50°C, specifically 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C.

[0055] In one embodiment of the present invention, the intermediate is a non-Newtonian fluid; when the rotor used is HA4, the temperature is room temperature (25.4~25.8℃) and the rotation speed is 20~200rpm, the viscosity of the intermediate can be 200~2500mPa·s, further can be 300~2100mPa·s, and even further can be 370~2040mPa·s; in one embodiment of the present invention, the rotation speed can be 20rpm, 30rpm, 40rpm, 50rpm, 60rpm, 70rpm, 80rpm, 90rpm, 100rpm, 110rpm, 120rpm, 130rpm, 140rpm, 150rpm, 160rpm, 170rpm, 180rpm, etc. The intermediate can have a viscosity of 2040.00 mPa·s, 1440.00 mPa·s, 1130.00 mPa·s, 952.00 mPa·s, 833.33 mPa·s, 737.14 mPa·s, 665.00 mPa·s, 608.89 mPa·s, 568.00 mPa·s, 534.55 mPa·s, 506.67 mPa·s, 480.00 mPa·s, 462.86 mPa·s, 437.33 mPa·s, 417.50 mPa·s, 402.35 mPa·s, 393.33 mPa·s, 381.05 mPa·s, or 370.00 mPa·s, at 190 rpm or 200 rpm.

[0056] In one embodiment of the present invention, the preparation method of the progesterone foam agent may include the following steps: filling an intermediate with a propellant to obtain the progesterone foam agent. The present invention does not specifically limit the specific operation method for filling the intermediate with the propellant; any method well known to those skilled in the art can be used. In this embodiment, specifically, the intermediate is placed in an aluminum can, a metering valve (1.35 mL) is pressed, the propellant is added, and then a protective sleeve and metering cap are added to obtain the progesterone foam agent.

[0057] This invention provides a progesterone ointment, comprising an ointment base and the progesterone suspension described in the above technical solution.

[0058] In one embodiment of the present invention, the ointment base may include one or more of petrolatum, lanolin, paraffin, lard, beeswax, cetyl alcohol, octadecanol, stearic acid, and glyceryl stearate; the paraffin may be liquid paraffin or solid paraffin; the glyceryl stearate may be glyceryl monostearate; specifically, the ointment base may be one or more of stearic acid, cetyl alcohol, octadecanol, liquid paraffin, and glyceryl monostearate; for example, the ointment base may be stearic acid or cetyl alcohol. The ointment base can be a compound of liquid paraffin and glyceryl monostearate, wherein the mass ratio of stearic acid, hexadecyl alcohol, liquid paraffin, and glyceryl monostearate in the compound can be 5-7:5-7:10-15:5-7, specifically 6:6:12:6; or the ointment base can be a compound of hexadecyl alcohol, octadecyl alcohol, and glyceryl monostearate, wherein the mass ratio of hexadecyl alcohol, octadecyl alcohol, and glyceryl monostearate in the compound can be 7-9:5-6:9-10, specifically 8:5.5:9.5. As one embodiment of the invention, the mass ratio of progesterone suspension to ointment base in the progesterone ointment can be 1:0.8-10, specifically 1:0.8, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. In one embodiment of the present invention, the raw materials for preparing the progesterone ointment may further include preservatives and / or humectants; the preservative may be sodium benzoate; the humectant may be glycerin; the mass content of the preservative in the raw materials for preparing the progesterone ointment may be 0.1-1.0%, specifically 0.5%; the mass content of the humectant may be 5-20%, specifically 16.5%. In another embodiment of the present invention, the raw materials for preparing the progesterone ointment may further include a solvent, the solvent may be an alcohol solvent and / or water, and the alcohol solvent may be propylene glycol.

[0059] As one embodiment of the present invention, the preparation method of the progesterone ointment may include the following steps: mixing an ointment base with vegetable oil and heating for a first time to obtain a hot mixture; dissolving progesterone raw material in the hot mixture to obtain an oil phase; mixing a surfactant, water, and the remaining raw materials and heating for a second time to obtain an aqueous phase; mixing the oil phase and the aqueous phase and emulsifying and homogenizing them sequentially, followed by vacuum degassing to form an ointment, thereby obtaining the progesterone ointment. As one embodiment of the present invention, the temperatures of the first heating and the second heating can be independently ≥80℃, and more specifically 80~85℃; the emulsification can be carried out under stirring conditions, and the emulsification time can be 10~20 min, specifically 15 min; the homogenization speed can be 4500~5500 rpm, specifically 5000 rpm, and the time can be 4~8 min, specifically 6 min.

[0060] This invention provides a progesterone suppository, comprising a suppository matrix and the progesterone suspension described in the above technical solution.

[0061] In one embodiment of the present invention, the suppository matrix may include one or more of solid polyethylene glycol, polyoxyethylene stearate, and hexadecyl alcohol, specifically hexadecyl alcohol. In another embodiment of the present invention, the mass ratio of progesterone suspension to suppository matrix in the progesterone ointment may be 1:0.1 to 10, specifically 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0062] In one embodiment of the present invention, the preparation method of the progesterone suppository may include the following steps: mixing a suppository matrix with vegetable oil and heating to obtain a hot mixture; dissolving progesterone raw material in the hot mixture; then, while still hot, pouring the mixture into a suppository mold coated with paraffin oil; solidifying and smoothing the mixture before demolding to obtain the progesterone suppository. In one embodiment of the present invention, the temperatures of the first heating and the second heating can be independently ≥80℃, and more specifically 80–85℃.

[0063] The following examples and comparative examples involve progesterone foaming agents that include intermediates and propellants. The intermediates specifically refer to the components in the progesterone foaming agent other than the propellant. The total mass of the intermediates in each bottle of progesterone foaming agent is 40g. The amount of each component added in the intermediates is a percentage of the total mass of the intermediates (i.e., the total amount of each component added in the intermediates is 100%). The amount of the propellant added is the mass of the propellant added in each bottle of progesterone foaming agent.

[0064] The particle size distribution of the intermediates involved in the following embodiments was evaluated. Specifically, the intermediates were evenly spread on a glass slide, covered with a coverslip, and observed and recorded under a 10x eyepiece and a 20x objective lens. The quality of the formulation was evaluated based on the dispersion of the active pharmaceutical ingredient. Figure 1 The dispersion diagrams for evaluating the dispersion of active pharmaceutical ingredients (APIs) are shown from left to right as Grade A, Grade B, Grade C, and Grade D. Grade A indicates excellent dispersion of the API with no aggregation; Grade B indicates good dispersion of the API with no aggregation, but the particle size is relatively large; Grade C indicates average dispersion of the API with slight aggregation; and Grade D indicates poor dispersion of the API with obvious aggregation.

[0065] The foam properties of the progesterone foaming agents involved in the following examples and comparative examples were evaluated, specifically the quality of the formulation was assessed based on the characteristics of the sprayed foam. Figure 2 The foam properties diagrams for evaluating foam characteristics at different levels are shown from left to right as A, B, C, and D. Grade A indicates that the foam is well-formed, fine, soft, and has good support; Grade B indicates that the foam is well-formed but not fine, with slightly larger pores and slightly weaker support; Grade C indicates that the foam is in a foamy state but has no support and is a network-like foam; and Grade D indicates that the foam is not in a foamy state and exists in liquid form.

[0066] The particle size of progesterone suspensions and progesterone foams involved in the following examples and comparative examples was evaluated using a wet method with a laser particle size analyzer. The steps are as follows: Weigh 0.2g of the test sample into a 50mL beaker, add 20mL of water, then add 10 drops of a 5wt% Tween 80 aqueous solution. Shake the beaker a few times, place it in an ultrasonic cleaner, and sonicate for 10 minutes to disperse the particles. Remove the beaker and shake well. Slowly pour the treated sample into a prepared wet disperser. When the sample reaches a light-blocking degree of 10% to 20%, wait for the sample to disperse and stabilize before measuring the sample. Finally, obtain the particle size distribution results.

[0067] The relative density of the progesterone foam in the following examples and comparative examples was tested using the following method: Three samples were placed at 25°C for 24 hours. The containers were shaken thoroughly but not heated, and 5-10 mL of foam was discarded. A flat weighing bottle with a volume of approximately 100 mL and a height of approximately 35 mm was prepared and its mass was accurately weighed and recorded as W. The nozzle was then placed at the bottom corner of the flat weighing bottle, and the metering cap was pressed down. The bottle was filled evenly in a circular motion. After the foam had fully expanded, excess foam was scraped off along the top edge of the bottle and cleaned. Its mass was accurately weighed and recorded as W2. The bottle was then filled with purified water at 25°C and its mass was accurately weighed and recorded as W1. The relative density was calculated using the following formula: ρ = (W2 - W) / (W1 - W).

[0068] The high and low temperature physical stability of the progesterone foam agent in the following examples was investigated. The specific method is as follows: it was placed at low temperature (2-8℃) for 20h, then restored to room temperature (25℃) for 4h, then placed at high temperature (30℃) for 20h, and then restored to room temperature for 4h. This was taken as one cycle, and five consecutive cycles were conducted.

[0069] The viscosity of the intermediate of progesterone foam agent in the following examples and comparative examples was tested. The specific method is as follows: the intermediate sample was taken and the viscosity was tested at room temperature. The intermediate sample needed to be stirred before the test. The test was conducted using an HA4 rotor at a speed of 100 rpm and the data was recorded.

[0070] In Comparative Examples 1 and 2 below, micronized active pharmaceutical ingredient (API) was used, i.e., progesterone API was used after micronization; in the following examples and other comparative examples, non-micronized API was used, i.e., progesterone API was used directly without micronization.

[0071] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0072] Example 1

[0073] According to Table 1, the prescribed amount of vegetable oil was heated to 80℃, 90℃, and 100℃ respectively. The prescribed amount of progesterone (unmicronized raw material) was added to the heated vegetable oil to dissolve it completely. Then, the temperature was lowered to 40±5℃ at a shearing speed of 5500 rpm and a cooling rate of 1.5℃ / min (cooling rate controlled by purging with condensate). The shearing was stopped, and the precipitation and dispersion of progesterone were observed.

[0074] Table 1 shows the solubility and precipitation of progesterone in different vegetable oils in Example 1. The ratio of progesterone to vegetable oil in each formulation is by mass. The results show that progesterone can dissolve in hot vegetable oils, and the higher the temperature, the faster the dissolution rate. In the formulations containing sesame oil and / or soybean oil, the progesterone precipitates after cooling have smaller particle sizes and are more evenly distributed.

[0075] Table 1. Solubility and precipitation of progesterone in different vegetable oils

[0076]

[0077] Example 2: Preparation of progesterone suspension

[0078] Solution preparation: According to Table 2, heat the prescribed amount of vegetable oil and surfactant to 85±5℃ to completely melt and mix the components evenly, then add the prescribed amount of progesterone (unmicronized raw material) to dissolve it completely, and keep it warm for later use.

[0079] Cooling precipitation: The solution was cooled to 40±5℃ at a cooling rate of 1.0℃ / min (cooling rate controlled by purging with cooling water) under a shearing speed of 6500 rpm, and the shearing was stopped to obtain a progesterone suspension.

[0080] Table 2 shows the formulation of the progesterone suspension in Example 2, wherein the ratio of progesterone to vegetable oil and surfactant is by mass.

[0081] Table 2. Formulation of progesterone suspension in Example 2

[0082] Components Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 progesterone 5 9 12 15 5 9 12 15 sesame oil 55 / 45 40 50 / 42 25 soybean oil 35 60 / 10 / 50 / 36 olive oil / / 35 / / 35 / 15 corn oil / 25 / 30 35 / 32 / Twain 60 3 / 5 / / / 7 / Span 40 2 / / / 2 / 3 / squalane / 4 3 / / / / 3 Lecithin / 2 / 5 / 6 / / Triethanolamine / / / / 8 / 4 6

[0083] The quality of the composition was evaluated by the particle size distribution of progesterone. Three parallel experiments were conducted, and the specific test results are shown in Table 3. The results show that the D90 particle size range of progesterone in the composition is 4 to 30 μm.

[0084] Table 3. Progesterone particle size range (μm) in the progesterone suspension of Example 2.

[0085] Progesterone D90 particle size Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 1 21.62 23.65 23.63 25.68 25.68 23.68 22.56 24.63 2 22.36 22.96 22.65 24.62 25.61 23.48 25.64 23.56 3 22.45 23.76 21.68 24.96 22.57 24.63 22.96 24.62 average value 22.14 23.46 22.65 25.09 24.62 23.93 23.72 24.27

[0086] Example 3: Preparation of foaming agent

[0087] Solution preparation: According to Table 4, weigh out the prescribed amounts of petrolatum, isopropyl myristate, glyceryl monostearate, stearic acid, soybean oil, corn oil, cetyl alcohol, octadecanol, Span 40, and Tween 60, mix them, stir and heat to 80±5℃ to completely melt and mix the components evenly, then add the prescribed amount of progesterone (unmicronized raw material) to dissolve it completely, and keep it warm for later use;

[0088] Cooling precipitation: The solution was cooled to 40±5℃ at a cooling rate of 1.6℃ / min (cooling rate controlled by purging with cooling water) under a shearing speed of 4500 rpm, and the shearing was stopped to obtain the intermediate.

[0089] Filling: The intermediate is placed into an aluminum can, the metering valve (1.35 mL) is pressed, tetrafluoroethane is added, and then a protective cover and metering cap are added.

[0090] Comparative Example 1: Preparation of Foaming Agent

[0091] Oil phase preparation: According to Table 4, weigh out the prescribed amounts of isopropyl myristate, glyceryl monostearate, stearic acid, cetyl alcohol and octadecanol, mix them, stir and heat to 70±5℃ to completely melt the components, and keep warm for later use.

[0092] Aqueous phase preparation: Weigh out the prescribed amount of Tween 60 and glycerin and mix with water. Then add the prescribed amount of progesterone (micronized raw material). Heat to 70±5℃ and stir to mix the components evenly. Keep warm for later use.

[0093] Mixing: The oil phase is added to the aqueous phase. After the addition is complete, the mixture is stirred for 10 minutes at 70±5℃. Then, the resulting solution is stirred and cooled to room temperature at room temperature (25℃) to obtain the intermediate.

[0094] Filling: The intermediate is placed into an aluminum can, the metering valve (1.35 mL) is pressed, tetrafluoroethane is added, and then a protective cover and metering cap are added.

[0095] Comparative Example 2: Preparation of Foaming Agent

[0096] Oil phase preparation: According to Table 4, weigh out the prescribed amounts of petrolatum, isopropyl myristate, glyceryl monostearate, stearic acid, soybean oil, corn oil, cetyl alcohol, octadecanol, Span 40 and Tween 60, mix them, stir and heat to 70±5℃ to completely melt the components, and keep warm for later use.

[0097] Adding active pharmaceutical ingredient (API): Add the prescribed amount of progesterone (micronized API) to the oil phase and stir until the API is evenly dispersed to obtain the intermediate;

[0098] Filling: The intermediate is placed into an aluminum can, the metering valve (1.35 mL) is pressed, tetrafluoroethane is added, and then a protective cover and metering cap are added.

[0099] Table 4. Formulations of foaming agents in Example 3 and Comparative Examples 1-2

[0100]

[0101] The formulation's quality was evaluated based on intermediate viscosity, progesterone dispersion, progesterone particle size distribution, and the characteristics of the sprayed foam. Specific test results are shown in Table 5, and Table 6 shows the viscosity test results of the intermediate used in the foaming agent of Example 3 under different rotation speeds. The results show that in Example 3, the progesterone was uniformly dispersed after precipitation without aggregation, indicating a good intermediate state. The product formed good, fine, and complete foam. In contrast, in Comparative Examples 1 and 2, the progesterone D90 particles were larger, the progesterone dispersion was poor, aggregation occurred, and the foam spraying continuity was poor, easily clogging the conduit.

[0102] Table 5 Evaluation results of foaming agents in Example 3 and Comparative Examples 1-2

[0103]

[0104] Table 6 shows the viscosity test results of the intermediate used in the foaming agent in Example 3 under different rotation speed conditions.

[0105] Rotational speed / rpm (rotor HA4, temperature 25.8℃) Viscosity / mPa·s 20.00 2040.00 30.00 1440.00 40.00 1130.00 50.00 952.00 60.00 833.33 70.00 737.14 80.00 665.00 90.00 608.89 100.00 568.00 110.00 534.55 120.00 506.67 130.00 480.00 140.00 462.86 150.00 437.33 160.00 417.50 170.00 402.35 180.00 393.33 190.00 381.05 200.00 370.00

[0106] Preparation of foaming agents in Examples 4-6 and Comparative Example 3

[0107] The procedure is performed according to the method in Example 3, wherein the formulations of each foaming agent are shown in Table 7.

[0108] Table 7 shows the formulations of the foaming agents in Examples 4-6 and Comparative Example 3.

[0109]

[0110]

[0111] The quality of the formulation was evaluated based on intermediate viscosity, progesterone dispersion, progesterone particle size distribution, and the characteristics of the sprayed foam. The relative density of the foam from well-formed formulations was also measured. Specific test results are shown in Table 8. The results indicate that when the mass percentage of progesterone in the formulation is within the range of 5% to 19%, the progesterone can be uniformly dispersed after precipitation, the intermediate state is good, and the product can form good foam. The foam is fine and complete, and can persist in a sprayed state. However, if the mass percentage of progesterone in the formulation exceeds 19%, the progesterone D90 particle size is larger, the progesterone dispersion is poor, agglomeration occurs, and the foam spraying continuity is poor, easily clogging the conduit.

[0112] Table 8 Evaluation results of foaming agents in Examples 4-6 and Comparative Example 3

[0113]

[0114] Preparation of foaming agents in Examples 7-10 and Comparative Examples 4-5

[0115] The procedure is performed according to the method in Example 3, wherein the formulations of each foaming agent are shown in Table 9.

[0116] Table 9 shows the formulations of the foaming agents in Examples 7-10 and Comparative Examples 4-5.

[0117]

[0118]

[0119] The quality of the formulation was evaluated based on progesterone dissolution time, intermediate viscosity, progesterone dispersion state, progesterone particle size distribution, and the characteristics of the sprayed foam. Specific test results are shown in Table 10. The results indicate that when the mass ratio of petrolatum to glyceryl monostearate is 3–5:2–5, the progesterone dissolution time is shortened, and the precipitated progesterone disperses evenly without aggregation. The intermediate state is good, and the product forms good, fine, and complete foam. However, if the proportion of petrolatum is too high or too low, the foam cannot be sprayed smoothly.

[0120] Table 10 Evaluation results of foaming agents in Examples 7-10 and Comparative Examples 4-5

[0121]

[0122] The high and low temperature physical stability of the foaming agents in Examples 3 and 7-10 was investigated, and the specific test results are shown in Table 11. The results show that the foaming agents in Examples 3 and 7-10 have excellent high and low temperature physical stability.

[0123] Table 11 Results of high and low temperature physical stability tests of the foaming agents in Examples 3 and 7-10

[0124]

[0125]

[0126] The delivery performance of each spray was evaluated based on the amount of foam extruded, primarily examining the delivery uniformity of each spray. Specifically, one sample can was taken, shaken, the metering cap was pressed, the can was inverted vertically for 10 seconds, the can was then upright, the metering cap was released, and the first spray was discarded. Ten delivery doses were recorded: the initial three doses, the middle four doses, and the last three doses. The RSD value was calculated, and the specific test results are shown in Table 12. The results show that the RSD of the foam agent delivery uniformity in Examples 3 and 7-10 is <2%.

[0127] Table 12 Results (%) of foam agent delivery uniformity test in Examples 3 and 7-10

[0128]

[0129] Example 11 Preparation of Ointment

[0130] 1) According to Table 13, mix the prescribed amounts of stearic acid, cetyl alcohol, soybean oil, liquid paraffin and glyceryl monostearate, heat to 80°C to completely melt the components and maintain the temperature, add the prescribed amount of progesterone (unmicronized raw material) to dissolve it completely and mix it evenly to obtain the oil phase;

[0131] 2) Add sodium lauryl sulfate and propylene glycol to distilled water, heat to 80°C to completely dissolve the components and mix them evenly to obtain an aqueous phase;

[0132] 3) Under stirring conditions, the oil phase is added to the aqueous phase. After the oil phase is added, stirring is continued for 15 minutes to emulsify and form a primary emulsion. Then, homogenization is performed (homogenization speed is 5000 rpm, homogenization time is 6 minutes). During the homogenization process, the temperature is lowered to achieve cold precipitation of progesterone. Afterward, vacuum degassing is performed to form an ointment, thus obtaining progesterone ointment.

[0133] Table 13 Formulation of the ointment in Example 11

[0134] Components Dosage (g / 100g) progesterone 9 Propylene glycol 8 stearic acid 6 Cetyl alcohol 6 soybean oil 20 liquid paraffin 12 Glyceryl monostearate 6 Sodium lauryl sulfate 1 distilled water 32

[0135] Example 12 Preparation of Ointment

[0136] 1) According to Table 14, mix the prescribed amounts of soybean oil, cetyl alcohol, octadecanol and glyceryl monostearate, heat to 80°C to completely melt the components and maintain the temperature, add the prescribed amount of progesterone (unmicronized raw material) to dissolve it completely and mix it evenly to obtain the oil phase;

[0137] 2) Add sodium benzoate, Tween 20 and glycerol to distilled water in sequence, stir well, and heat to 80°C to obtain the aqueous phase;

[0138] 3) Under stirring conditions, the oil phase is added to the aqueous phase. After the oil phase is added, stirring is continued for 15 minutes to emulsify and form a primary emulsion. Then, homogenization is performed (homogenization speed is 5000 rpm, homogenization time is 6 minutes). During the homogenization process, the temperature is lowered to achieve progesterone cold precipitation. After the progesterone cold precipitation is complete, vacuum degassing is performed to form an ointment, thus obtaining progesterone ointment.

[0139] Table 14 Formulation of the ointment in Example 12

[0140] Components Dosage (g / 100g) progesterone 9 soybean oil 10 Cetyl alcohol 8 Octadecanol 5.5 Glyceryl monostearate 9.5 Twain 20 4.2 glycerin 16.5 Sodium benzoate 0.5 distilled water 36.8

[0141] Example 13 Preparation of Suppositories

[0142] 1) According to Table 15, soybean oil, polyethylene glycol (40) stearate and cetyl alcohol are mixed, heated to 80°C to completely melt the components and maintain the temperature, and the prescribed amount of progesterone (unmicronized raw material) is added to dissolve it completely and mix it evenly to obtain the mixture.

[0143] 2) While still hot, pour the mixture into a mold coated with paraffin oil, let it solidify (cooling down during solidification to achieve progesterone precipitation), scrape it smooth, and then demold to obtain progesterone suppositories.

[0144] Table 15 Formulation of the suppositories in Example 13

[0145] Components Dosage (g / 100g) progesterone 9 soybean oil 30 Polyethylene glycol (40) stearate 50 Cetyl alcohol 11

[0146] Test Example 1

[0147] The stability of the foaming agents in Examples 3 and 7-10 at 40°C was investigated to examine the influencing factors. Specifically, the foaming agents were placed at 40°C, and samples were tested at 0, 10, and 30 days to examine changes in foam properties, content, and related substances. The suitability of the packaging materials was also observed at different stages of the investigation. Comparative studies were also conducted with commercially available progesterone gel and the foaming agents in Comparative Examples 1-2. Specific test methods and conditions are as follows:

[0148] The testing methods for content and related substances are as follows:

[0149] Content determination method: determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512); chromatographic conditions: octadecylsilane-bonded silica gel was used as the stationary phase; methanol-water (methanol to water volume ratio of 75:25) was used as the mobile phase; the detection wavelength was 254 nm; the flow rate was 1.0 mL / min; the column temperature was 40 ℃; and the injection volume was 20 μL.

[0150] The determination of related substances was carried out according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512); chromatographic conditions: octadecylsilane-bonded silica gel was used as the stationary phase; methanol-water (methanol to water volume ratio of 65:35) was used as the mobile phase; the detection wavelength was 254 nm; the flow rate was 1.0 mL / min; the column temperature was 40 ℃; and the injection volume was 5 μL.

[0151] Table 16 shows the stability test results at 40°C for the foaming agents in Examples 3 and 7-10, Comparative Examples 1-2, and the commercially available progesterone gel. The results show that, compared to the initial 0 days, the foaming agents in Examples 3 and 7-10, after being placed at 40°C for 10 days, exhibited a supportive foam appearance, accurate foam dosage, and a smooth, fine texture. Related substances showed no significant changes compared to the initial 0 days, indicating good stability. The foaming agents in Examples 3 and 7-10, after being placed at 40°C for 30 days, showed no significant changes in content and related substances compared to the initial 0 days. They also showed good compatibility with the propellant and the metering device for the foaming agent. Upon cutting open the pressure-resistant aluminum can, no delamination of the coating was observed on the inner wall. Although the foaming agents in Comparative Examples 1-2 exhibited foam characteristics A and B respectively, the progesterone dispersion was poor, with agglomeration, and the foam spraying continuity was poor, easily clogging the delivery tube, resulting in fluctuating content values.

[0152] Table 16 Results of stability tests at 40°C for foaming agents and commercially available progesterone gels in the examples and comparative examples.

[0153]

[0154]

[0155] Test Example 2

[0156] The in vitro dissolution rate of the foaming agent in Example 3 was evaluated using the rotating basket method, and its dissolution rate was compared with that of a commercially available progesterone gel. The cumulative dissolution amount was determined by the content assay method. The specific test conditions were as follows: the medium was 1000 mL of methanol-water (methanol to water volume ratio of 20:80), the rotation speed was 100 rpm, and the sampling times were 2 h, 4 h, 24 h, and 72 h.

[0157] The results of the in vitro dissolution test are shown in Table 17. The results show that the in vitro release rate of the foaming agent in Example 3 is faster than that of the commercially available progesterone gel.

[0158] Table 17 Results of in vitro dissolution test

[0159]

[0160]

[0161] Test Example 3: Animal PK Experiment

[0162] In the animal pharmacokinetic (PK) experiment, 14 SPF-grade New Zealand female rabbits (not in their estrous cycle) weighing 2.0–2.5 kg were divided into three groups (A, R, and P) according to a (6+6+2) formula. Group A was the test foaming agent (specifically, the foaming agent in Example 3), R was the commercially available progesterone gel, and P was the control. Group A received one puff of the drug, and Group R received one unit (one vial). 0.8 mL of ear vein blood was collected before administration and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. The blood samples were placed in heparinized plastic tubes, centrifuged at 3000 rpm for 5 min, and approximately 0.3 mL of plasma was transferred to PE tubes and stored at -20°C for testing.

[0163] The operating procedure is as follows:

[0164] R. Administration of commercially available progesterone gel: Connect a blunt-tipped tubing about 3 cm long to a 10 mL syringe, inject the commercially available progesterone gel into the syringe for later use. Fix the animal, expose the vaginal opening, moisten the tubing with lubricant and gently insert it into the vagina (3-4 cm), and slowly inject the sample from the syringe. After completion, remove the catheter.

[0165] A. Administration of the test foam sample: Connect the administration catheter, which is about 3 cm long, to the administration nozzle on the protective sleeve, shake it several times, invert it for 10 seconds, fix the animal at the same time, expose the vaginal opening, gently insert the administration catheter into the vagina (3-4 cm), release the fingers, inject the foam, and then remove the administration catheter.

[0166] In Group A, the drug and the applicator connected well during administration, the drug delivery was smooth, the interface was well sealed, and no drug leakage was observed after administration. The animals accepted the drug well. After administration to both Group A and Group R, the experimental animals were in good condition and no obvious adverse reactions were observed.

[0167] After pretreatment, the progesterone content in the plasma was determined by LC-MS analysis. Pharmacokinetic parameters of groups A and R were calculated using the statistical software DAS3.3.1.

[0168] Table 18 shows the results of animal pharmacokinetic (PK) studies of the tested foam sample (Example 3) and a commercially available progesterone gel. The results indicate that the average AUC0-t values ​​of the tested foam sample and the commercially available progesterone gel were 745.5 and 588.0, respectively, with a ratio of 1.27, indicating that their in vivo exposure levels were comparable within 0–24 h. The tested foam sample was absorbed more rapidly than the commercially available progesterone gel within 0–4 h. The average Cmax values ​​of the tested foam sample and the commercially available progesterone gel were 124.8 and 86.5, respectively, with an F value of 1.44, indicating that the tested foam sample and the commercially available progesterone gel had the same safety profile. The average T1 / 2 values ​​of the tested foam sample and the commercially available progesterone gel were 1.4 h and 1.0 h, respectively. Based on the mean CT curves, they should have consistent elimination rates, indicating that the tested foam sample in this invention has a sustained-release effect similar to the commercially available progesterone gel (specifically as shown in the figure). Figure 3 As shown, Figure 3 R-drug indicates administration of commercially available progesterone gel, while A-drug indicates administration of the tested foam formulation.

[0169] Table 18 Results of animal pharmacokinetic (PK) tests on the tested foam sample (Example 3) and commercially available progesterone gel.

[0170]

[0171] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a progesterone suspension, comprising method one or method two: The first method includes the following steps: Progesterone raw material is dissolved in hot vegetable oil, and progesterone is precipitated by cooling to obtain progesterone oil suspension; the progesterone oil suspension is mixed with a surfactant to obtain progesterone mixed suspension. The second method includes the following steps: mixing vegetable oil with a surfactant to obtain a mixed oil phase; dissolving progesterone raw material in the hot mixed oil phase, and precipitating progesterone by cooling to obtain the progesterone suspension; The progesterone in the progesterone suspension has a D90 particle size of 4–50 μm.

2. The preparation method according to claim 1, characterized in that, The progesterone suspension comprises, by weight, 5-15 parts progesterone, 10-95 parts vegetable oil, and 0.1-50 parts surfactant.

3. The preparation method according to claim 1 or 2, characterized in that, In Method 1, the temperature of the hot vegetable oil is ≥80℃, and the cooling rate is 1.0~3.0℃ / min; In Method 2, the temperature of the hot mixed oil phase is ≥80℃, and the cooling rate is 1.0~3.0℃ / min.

4. The preparation method according to claim 1 or 2, characterized in that, The vegetable oils include one or more of the following: sesame oil, soybean oil, sunflower seed oil, olive oil, grape seed oil, corn oil, tea oil, peanut oil, castor oil, palm oil, flaxseed oil, rapeseed oil, blueberry seed oil, macadamia nut oil, litsea cubeba oil, rosemary oil, cottonseed oil, walnut oil, rapeseed oil, rice bran oil, aloe vera oil, and calendula oil. The surfactant includes one or more of nonionic surfactants, anionic surfactants, and amphoteric surfactants.

5. The preparation method according to claim 4, characterized in that, The nonionic surfactants include one or more of the following: fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ester, fatty amine polyoxyethylene ether, alkylolamide polyoxyethylene ether, squalene, squalane, fatty acid monoglycerides, fatty acid diglycerides, sucrose fatty acid esters, polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether, triethanolamine, polyglycerol-2 dihydroxystearate, polyglycerol-2 isostearate, PEG-30 dihydroxystearate, decanoic acid decanoic acid triglyceride, cetyl polyethylene glycol / polypropylene glycol-10 / 1 dimethylsiloxane, polyethylene glycol (40) stearate, polysorbate, Span, and poloxamer. The anionic surfactant includes benzenesulfonate and / or sodium lauryl sulfate; The amphoteric surfactant includes lecithin.

6. The progesterone suspension prepared by the preparation method according to any one of claims 1 to 5 comprises progesterone, vegetable oil and surfactant, wherein the progesterone in the progesterone suspension is formed by hot dissolution and cold precipitation of progesterone raw material, and the D90 particle size of the progesterone in the progesterone suspension is 4 to 50 μm.

7. The use of the progesterone suspension of claim 6 in the preparation of a progesterone vaginal administration formulation, wherein the progesterone vaginal administration formulation comprises a progesterone foam, a progesterone ointment, or a progesterone suppository.

8. A progesterone foaming agent, comprising an intermediate and a propellant, wherein the intermediate comprises a hydrophobic component and the progesterone suspension of claim 6; the mass percentage of progesterone in the progesterone foaming agent is <19% of the mass of the intermediate.

9. A progesterone ointment comprising an ointment base and the progesterone suspension of claim 6.

10. A progesterone suppository comprising a suppository matrix and the progesterone suspension of claim 6.

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