Solidification and solubilization method for progesterone self-emulsifying liquid formulation and progesterone self-emulsifying solid formulation

Abstract

A solidification and solubilization method for a progesterone self-emulsifying liquid formulation and a progesterone self-emulsifying solid formulation. A curing agent is mixed with a progesterone self-emulsifying liquid formulation, wherein the curing agent comprises one or more of lauroyl polyoxyethylene-32 glyceride, polyoxyethylene-8 glyceryl behenate, polyethylene glycol-32 stearate and stearoyl polyoxyethylene glyceride. The melting point of the progesterone self-emulsifying liquid formulation is increased to above room temperature by means of a specific curing agent, such that the progesterone self-emulsifying liquid formulation is in a solid state at room temperature, thereby obtaining a progesterone self-emulsifying solid formulation; moreover, the drug loading capacity of progesterone is enhanced. The solidification and solubilization method can not only improve the solubility of the progesterone to avoid crystallization and precipitation, and improve the uniformity of the formulation, but also improve the self-emulsifying ability of the progesterone self-emulsifying formulation without affecting the release rate of progesterone in the self-emulsifying formulation.

Description

A method for solidifying and solubilizing a self-emulsifying liquid progesterone formulation and a self-emulsifying solid progesterone formulation.

[0001] This application claims priority to Chinese Patent Application No. 202410781129.4, filed on June 18, 2024, entitled "A solidification solubilization method for a self-emulsifying liquid progesterone preparation and a self-emulsifying solid progesterone preparation", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical formulation technology, and in particular to a solidification solubilization method for a self-emulsifying liquid progesterone formulation and a self-emulsifying solid progesterone formulation. Background Technology

[0003] Progesterone, also known as luteinizing hormone, is officially called pregnathione-4-ene-3,20-dione, with the chemical formula C. 21 H 30 O2 is an endogenous progesterone. Progesterone is a crucial intermediate in steroid synthesis, playing a role in the reproductive system, mammary glands, and metabolism. It is the main hormone for luteal support and pregnancy maintenance. Progesterone is a key factor influencing the transformation of the endometrium from the proliferative phase to the secretory phase, promoting endometrial maturation and shedding, and maintaining the female menstrual cycle. Simultaneously, progesterone affects endometrial thickness and blood flow, playing a role in stabilizing the endometrium and maintaining pregnancy in early pregnancy. As a natural progesterone, progesterone has no adverse effects on the fetus or the patient, making it the first-line and primary drug for obtaining luteal support and maintaining pregnancy. Clinically, it is mainly used to treat threatened miscarriage due to luteal insufficiency, menstrual disorders caused by ovulation disorders, and perimenopausal syndrome.

[0004] However, existing progesterone formulations have several drawbacks: injectable formulations are prone to adverse reactions and have poor patient compliance; vaginal sustained-release gels are inconvenient to use; oral formulations have better compliance, but low bioavailability and a higher incidence of side effects. Although many studies have been conducted on oral progesterone formulations, these studies lack the potential for clinical translation due to difficulties in manufacturing processes, difficulties in obtaining approval for excipients for clinical application, failure to demonstrate significant advantages compared to marketed products, or lack of in vivo validation through animal experiments. Therefore, this study aims to utilize self-emulsifying drug delivery technology, employ approved excipients, and design a manufacturing process that is easy to scale up, in order to improve bioavailability and enhance the clinical translation potential of oral progesterone formulations.

[0005] Self-emulsifying drug delivery systems (SEDDS) are thermodynamically stable homogeneous solutions composed of drugs, oils, surfactants, and co-surfactants, containing no aqueous phase. After oral administration, due to gastrointestinal motility, the SEDDS spontaneously forms an emulsion with a particle size of less than 5 μm in the aqueous phase. Because of their relatively simple preparation methods, high encapsulation efficiency for lipid-soluble drugs, and ease of administration, SEDDS have experienced rapid development, and several products are already on the market overseas, including... (Cyclosporine A), Norvir (ritonavir), Fortovase (saquinavir), and Agenerase (ampenavir), etc. Previous studies have found that the oral bioavailability of the invented self-emulsified liquid progesterone formulation is significantly higher than that of the existing oral progesterone formulation, Angelica. However, due to problems such as low drug loading and easy precipitation at low temperatures, the stability of the self-emulsified liquid progesterone formulation is poor, which limits its practical application.

[0006] Summary of the Invention

[0007] In view of this, the purpose of this application is to provide a solidification solubilization method for a self-emulsifying liquid progesterone formulation and a self-emulsifying solid progesterone formulation. The solidification solubilization method provided by this application not only increases the drug loading of progesterone, but also makes progesterone less prone to precipitation at low temperatures and exhibits good stability.

[0008] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0009] This application provides a solidification solubilization method for a self-emulsifying liquid progesterone formulation, which involves mixing a curing agent with the self-emulsifying liquid progesterone formulation.

[0010] The curing agent includes one or more of lauroyl polyoxyethylene-32 glyceryl ester, polyoxyethylene-8 hesperidin glyceryl ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glyceryl ester, glyceryl stearate, glyceryl distearate, and mono- and di-stearate glyceryl esters.

[0011] Preferably, the curing agent accounts for 10-80% of the total mass of the curing agent and the progesterone self-emulsifying liquid preparation.

[0012] Preferably, the progesterone self-emulsifying liquid formulation comprises the following raw materials by mass fraction:

[0013] Progesterone 0.5%–20%, oily solvent 15%–80%, surfactant 30%–80%.

[0014] Preferably, the raw materials for preparing the progesterone self-emulsifying liquid formulation further include a co-surfactant; based on the mass fraction of the progesterone, the mass fraction of the co-surfactant is ≤30%.

[0015] Preferably, the oily solvent includes one or more of soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, linolenic acid oil, castor oil, perilla oil, corn oil, mono-linolenic acid glycerides, di-linolenic acid glycerides, tri-linolenic acid glycerides, mono-linolenic acid glycerides, di-olenic acid glycerides, tri-olenic acid glycerides, medium-chain triglycerides, caprylic / capric triglycerides, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate, and palmitic acid.

[0016] Preferably, the surfactant comprises one or more of polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil, Tween 20, Tween 60, Tween 80, vitamin E-TPGS, and polyethylene glycol glycerol octanoate-capric acid.

[0017] Preferably, the co-surfactant comprises one or more of diethylene glycol monoethyl ether, polyglycerol oleate, PEG400, isopropanol, propylene glycol laurate, ethanol, and 1,2-propanediol.

[0018] Preferably, after mixing, the mixture further includes sequentially stirring and allowing it to stand;

[0019] The stirring temperature is 35–80°C, and the stirring time is 0.5–4 hours.

[0020] Preferably, the settling temperature is ≤20℃ and the settling time is 1~48h.

[0021] This application also provides a progesterone self-emulsifying solid formulation obtained by the solidification solubilization method described in the above technical solution.

[0022] This application provides a solidification solubilization method for a self-emulsifying liquid progesterone formulation, comprising mixing a curing agent with the self-emulsifying liquid progesterone formulation; wherein the curing agent comprises one or more of lauroyl polyoxyethylene-32 glyceryl ester, polyoxyethylene-8 hesperidin glyceryl ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glyceryl ester, glyceryl stearate, glyceryl distearate, and mono- and di-stearate.

[0023] This application utilizes one or more specific curing agents, such as lauroyl polyoxyethylene-32 glyceryl ester, polyoxyethylene-8-hexanoate glyceryl ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glyceryl ester, glyceryl stearate, distearate, and mono- and di-stearate, to raise the melting point of a self-emulsifying liquid progesterone formulation above room temperature, thus solidifying the room-temperature self-emulsifying liquid progesterone formulation, resulting in a self-emulsifying solid progesterone formulation. Simultaneously, it increases the drug loading of progesterone. This solidification solubilization method not only improves progesterone solubility, preventing crystallization and precipitation, and increases drug loading and formulation uniformity, but also enhances the self-emulsifying ability of the self-emulsifying progesterone formulation without affecting the release rate of progesterone in the self-emulsifying formulation. This ensures that the dissolution rate and oral bioavailability of progesterone in the self-emulsifying solid progesterone formulation are consistent with those of the self-emulsifying liquid progesterone formulation. The solidification solubilization method provided in this application is simple and highly feasible for industrial production. Attached Figure Description

[0024] Figure 1 shows the dissolution curves of progesterone self-emulsifying solid formulations containing different proportions of curing agent;

[0025] Figure 2 shows the progesterone drug-time curves after oral administration of self-emulsified solid and self-emulsified liquid progesterone formulations to beagles. Detailed Implementation

[0026] This application provides a solidification solubilization method for a self-emulsifying liquid progesterone formulation, which involves mixing a curing agent with the self-emulsifying liquid progesterone formulation.

[0027] The curing agent includes one or more of lauroyl polyoxyethylene-32 glyceryl ester, polyoxyethylene-8 hesperidin glyceryl ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glyceryl ester, glyceryl stearate, glyceryl distearate, and mono- and di-stearate glyceryl esters.

[0028] Unless otherwise specified, all raw materials used in this application are preferably commercially available products.

[0029] This application mixes a curing agent and a progesterone self-emulsifying liquid formulation.

[0030] In this application, the curing agent includes one or more of lauroyl polyoxyethylene-32 glyceryl ester, polyoxyethylene-8 hesperidin glyceryl ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glyceryl ester, glyceryl stearate, distearate glyceryl ester, and mono- and di-stearoyl glyceryl esters. Specifically, it can be a mixture of glyceryl stearate and lauroyl polyoxyethylene-32 glyceryl ester, a mixture of distearate glyceryl ester and stearoyl polyoxyethylene glyceryl ester, a mixture of mono- and di-stearoyl glyceryl esters and polyethylene glycol-32 stearate, or glyceryl stearate. In this application, the mass ratio of glyceryl stearate to lauroyl polyoxyethylene-32 glyceryl ester in the mixture of glyceryl stearate and lauroyl polyoxyethylene-32 glyceryl ester is preferably 1:2; the mass ratio of glyceryl distearate to glyceryl stearoyl polyoxyethylene ester in the mixture of glyceryl distearate and glyceryl stearoyl polyoxyethylene ester is preferably 1:1 to 2:3; and the mass ratio of glyceryl monostearate to glyceryl distearate and polyethylene glycol-32 stearate in the mixture of glyceryl monostearate and glyceryl distearate is preferably 1:2. In this application, the curing agent preferably accounts for 10-80% of the total mass of the curing agent and the progesterone self-emulsifying liquid formulation, more preferably 20-70%, more preferably 30-60%, and most preferably 40-50%, specifically preferably 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%.

[0031] In this application, the progesterone self-emulsifying liquid formulation preferably comprises the following raw materials by mass fraction:

[0032] Progesterone 0.5%–20%, oily solvent 15%–80%, surfactant 30%–80%.

[0033] In this application, the raw materials for preparing the progesterone self-emulsifying liquid formulation preferably include 0.5% to 20% progesterone by mass, more preferably 1% to 15%, more preferably 1% to 10%, and specifically preferably 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0034] In this application, the raw materials for preparing the progesterone self-emulsifying liquid formulation preferably include an oily solvent with a mass fraction of 15% to 80%, more preferably 19.2% to 50%, more preferably 20% to 40%, and specifically preferably 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%. In this application, the oily solvent preferably includes one or more of soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, linolenic acid oil, castor oil, perilla oil, corn oil, monolinoleic acid glyceride, dilinoleic acid glyceride, trilinoleic acid glyceride, monolinoleic acid glyceride, dioleic acid glyceride, trioleic acid glyceride, medium-chain triglycerides, caprylic / capric triglycerides, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate, and palmitic acid. More preferably, it includes one or more of monolinoleic acid glyceride, dilinoleic acid glyceride, trioleic acid glyceride, monolinoleic acid glyceride, dioleic acid glyceride, trioleic acid glyceride, medium-chain triglycerides, caprylic / capric triglycerides, oleic acid, linoleic acid, ethyl oleate, and ethyl linoleate.

[0035] In this application, the raw materials for preparing the progesterone self-emulsifying liquid formulation preferably include a surfactant with a mass fraction of 30% to 80%, more preferably 40% to 80%, and even more preferably 50% to 80%, specifically preferably 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%. In this application, the surfactant preferably includes one or more of polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil, Tween 20, Tween 60, Tween 80, vitamin E-TPGS, and polyethylene glycol glycerol caprylate / capric acid.

[0036] In this application, the raw materials for preparing the progesterone self-emulsifying liquid formulation preferably further include a co-surfactant; based on the mass fraction of the progesterone, the mass fraction of the co-surfactant is preferably ≤30%, more preferably ≤25%. In this application, the co-surfactant preferably includes one or more of diethylene glycol monoethyl ether, polyglycerol oleate, PEG400, isopropanol, propylene glycol laurate, ethanol, and 1,2-propanediol, more preferably one or more of diethylene glycol monoethyl ether, polyglycerol oleate, and propylene glycol laurate.

[0037] In this application, the method for preparing the progesterone self-emulsifying liquid formulation preferably includes the following steps:

[0038] Progesterone, an oily solvent, and a surfactant are mixed to obtain the self-emulsifying liquid progesterone formulation.

[0039] In this application, the mixing temperature is preferably 35-40°C, and the mixing time is preferably 30 min; the mixing is preferably carried out under stirring conditions, and the stirring speed is preferably 50-300 rpm.

[0040] After mixing the curing agent and the progesterone self-emulsifying liquid formulation, this application preferably includes sequential stirring and standing.

[0041] In this application, the stirring temperature is preferably 35–80°C, more preferably 40–60°C; the stirring time is preferably 0.5–4 hours. In this application, the stirring speed is preferably 50–300 rpm.

[0042] In this application, the settling temperature is preferably ≤20℃, more preferably -20~4℃; the settling time is preferably 1~48h.

[0043] This application also provides a progesterone self-emulsifying solid formulation obtained by the solidification solubilization method described in the above technical solution.

[0044] The following detailed description, in conjunction with embodiments, illustrates the solidification solubilization method for the self-emulsifying liquid progesterone formulation and the self-emulsifying solid progesterone formulation provided in this application. However, these descriptions should not be construed as limiting the scope of protection of this application.

[0045] Example 1

[0046] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0047] Weigh 7.0g of progesterone self-emulsifying liquid preparation, 1.0g of stearate and 2.0g of lauroyl polyoxyethylene-32 glyceryl ester into a round-bottom flask, stir magnetically at 200rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0048] The composition of the progesterone self-emulsifying liquid formulation is as follows: 4.0% progesterone, 38.4% glyceryl monolinoleate (an oily solvent), 52.8% glyceryl caprylate (a surfactant), and 4.8% polyglycerol oleate (a co-surfactant). The preparation method is as follows: 0.4g of progesterone, 3.84g of glyceryl monolinoleate, 5.28g of glyceryl caprylate (a surfactant), and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 200rpm for 30min at 40℃ to obtain the progesterone self-emulsifying liquid formulation.

[0049] Example 2

[0050] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0051] Weigh 8g of progesterone self-emulsifying liquid preparation, 1g of distearate glyceryl ester, and 1g of stearoyl polyoxyethylene glyceryl ester into a round-bottom flask. Stir magnetically at 200rpm for 90min at 35℃, and then let stand overnight at 25℃ to obtain progesterone self-emulsifying solid preparation.

[0052] The composition of the self-emulsifying liquid progesterone formulation is as follows: 4.0% progesterone, 19.2% glyceryl monolinoleate (an oily solvent), 67.2% Tween-20 (a surfactant), and 9.6% diethylene glycol monoethyl ether (a co-surfactant). The preparation method is as follows: 0.4g of progesterone, 1.92g of glyceryl monolinoleate, 6.72g of Tween-20, and 0.96g of diethylene glycol monoethyl ether are weighed into a round-bottom flask and magnetically stirred at 200rpm for 30min at 40°C to obtain the self-emulsifying liquid progesterone formulation.

[0053] Example 3

[0054] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0055] Weigh 9.0g of progesterone self-emulsifying liquid preparation, 0.4g of distearate and 0.6g of stearoyl polyoxyethylene glycerol into a round-bottom flask. Stir magnetically at 150rpm for 60min at 45℃ and let stand overnight at room temperature to obtain progesterone self-emulsifying solid preparation.

[0056] The composition of the progesterone self-emulsifying liquid formulation is as follows: 3.9% progesterone, 19.2% oleic acid (an oily solvent), 67.3% Tween-80 (a surfactant), and 9.6% diethylene glycol monoethyl ether (a co-surfactant). The preparation method is as follows: 0.39g of progesterone, 1.92g of oleic acid, 6.73g of Tween-80, and 0.96g of diethylene glycol monoethyl ether are weighed into a round-bottom flask and magnetically stirred at 150rpm for 30min at 40°C to obtain the progesterone self-emulsifying formulation.

[0057] Example 4

[0058] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0059] Weigh 8.5g of progesterone self-emulsifying liquid preparation, 0.6g of distearate glyceryl ester, and 0.9g of stearoyl polyoxyethylene glyceryl ester into a round-bottom flask. Stir magnetically at 100rpm for 40min at 50℃, and then let stand overnight at -20℃ to obtain progesterone self-emulsifying solid preparation.

[0060] The composition of the self-emulsifying liquid progesterone formulation is as follows: 3.9% progesterone, 19.2% oleic acid (an oily solvent), 67.3% Tween-80 (a surfactant), and 9.6% ethanol (a co-surfactant). The preparation method is as follows: 0.39g of progesterone, 1.92g of oleic acid, 6.73g of Tween-80, and 0.96g of ethanol are weighed into a round-bottom flask and magnetically stirred at 100rpm for 30min at 40°C to obtain the self-emulsifying liquid progesterone formulation.

[0061] Example 5

[0062] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0063] Weigh 8.0g of progesterone self-emulsifying liquid preparation, 0.8g of distearate glyceryl ester, and 1.2g of stearoyl polyoxyethylene glyceryl ester into a round-bottom flask. Stir magnetically at 150rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0064] The composition of the self-emulsifying liquid progesterone formulation is as follows: 3.0% progesterone, 39.4% peanut oil (an oily solvent), 52.8% PEG-glycerol octanoate (a surfactant), and 4.8% polyglycerol oleate (a co-surfactant). The preparation method is as follows: 0.3g of progesterone, 3.94g of peanut oil, 5.28g of PEG-glycerol octanoate, and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 150rpm for 30min at 40°C to obtain the self-emulsifying liquid progesterone formulation.

[0065] Example 6

[0066] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0067] Weigh 7.5g of progesterone self-emulsifying liquid preparation, 1.0g of distearate glyceryl ester, and 1.5g of stearoyl polyoxyethylene glyceryl ester into a round-bottom flask. Stir magnetically at 200rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0068] The composition of the progesterone self-emulsifying liquid formulation is as follows: 3.0% progesterone, 39.4% ethyl oleate (oil solvent), 52.8% PEG-glycerol octanoate (surfactant), and 4.8% polyglycerol oleate (co-surfactant). The preparation method is as follows: 0.3g of progesterone, 3.94g of ethyl oleate, 5.28g of PEG-glycerol octanoate, and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 200rpm for 30min at 40°C to obtain the progesterone self-emulsifying liquid formulation.

[0069] Example 7

[0070] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0071] Weigh 7.0g of progesterone self-emulsifying liquid preparation, 1.2g of distearate, and 1.8g of stearoyl polyoxyethylene glycerol into a round-bottom flask. Stir magnetically at 200rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0072] The composition of the self-emulsifying liquid progesterone formulation is as follows: 5.0% progesterone, 36.4% ethyl linoleate, 51.8% PEG-glycerol octanoate / capric acid, and 4.8% polyglycerol oleate. The preparation method is as follows: 0.5g of progesterone, 3.64g of ethyl linoleate, 5.18g of PEG-glycerol octanoate / capric acid, and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 200rpm for 30min at 35°C to obtain the self-emulsifying liquid progesterone formulation.

[0073] Example 8

[0074] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0075] Weigh 7.0g of progesterone self-emulsifying liquid preparation, 1.0g of mono- and di-stearate glyceryl esters, and 2.0g of polyethylene glycol-32 stearate into a round-bottom flask. Stir magnetically at 150rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0076] The composition of the self-emulsifying liquid progesterone formulation is as follows: 5.0% progesterone, 36.4% ethyl linoleate, 53.8% PEG-glycerol ester (caprylic / capric acid), and 4.8% polyglycerol oleate. The preparation method is as follows: 0.5g of progesterone, 3.64g of linoleic acid, 5.38g of PEG-glycerol ester, and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 150rpm for 30min at 35°C to obtain the self-emulsifying liquid progesterone formulation.

[0077] Example 9

[0078] Solidification solubilization methods for self-emulsified progesterone liquid formulations include:

[0079] Weigh 7.0g of progesterone self-emulsifying liquid preparation and 3.0g of glyceryl stearate into a round-bottom flask, stir magnetically at 150rpm for 60min at 40℃, and then let stand overnight at 4℃ to obtain progesterone self-emulsifying solid preparation.

[0080] The composition of the progesterone self-emulsifying liquid formulation is as follows: 4.0% progesterone, 38.4% monolinoleic acid glyceride, 52.8% caprylic / capric acid PEG-glycerol ester, and 4.8% polyglycerol oleate. The preparation method is as follows: 0.4g of progesterone, 3.84g of monolinoleic acid glyceride, 5.28g of caprylic / capric acid PEG-glycerol ester, and 0.48g of polyglycerol oleate are weighed into a round-bottom flask and magnetically stirred at 150rpm for 30min at 40℃ to obtain the progesterone self-emulsifying liquid formulation.

[0081] Experimental Example 1

[0082] Long-term observation revealed that crystal precipitation occurred in the self-emulsified liquid formulation containing 25 mg / g progesterone when placed at 4°C. This is likely due to a significant decrease in the solubility of progesterone in the self-emulsified liquid formulation at low temperatures. To mitigate the impact of low temperatures on the transportation and storage of the formulation, the effects of low-temperature conditions on both the solid and liquid self-emulsified progesterone formulations were investigated.

[0083] Taking the progesterone self-emulsifying solid formulations obtained in different embodiments as examples, progesterone self-emulsifying solid formulations and progesterone self-emulsifying liquid formulations containing different progesterone contents were prepared and placed in a refrigerator at 4°C. The precipitation of progesterone crystals in different formulations was observed daily, and the results are shown in Table 1.

[0084] Table 1. Precipitation of progesterone crystals in different formulations

[0085] Table 1 shows that for self-emulsified liquid progesterone formulations, progesterone tends to precipitate as crystals at concentrations of 40 mg / g and 30 mg / g, which is detrimental to later transportation and long-term storage. A self-emulsified liquid progesterone formulation with a concentration of 20 mg / g can be stored stably, but the low drug loading may limit its clinical translation. For self-emulsified solid progesterone formulations, crystal precipitation also occurred around 15 days at concentrations of 50 mg / g and 40 mg / g, but no precipitation occurred for an extended period at a concentration of 30 mg / g. Compared to the liquid progesterone formulation, the solid progesterone formulation exhibits a higher drug loading at low temperatures.

[0086] Experimental Example 2

[0087] Experimental method: Take 1g of progesterone self-emulsifying solid preparation containing different proportions of curing agent and add it to 1L of distilled water. Use the stirring paddle of the dissolution apparatus at 200rpm until the progesterone self-emulsifying solid preparation is completely self-emulsified. Filter through a 0.22μm microporous membrane. Take the filtrate and use a dynamic light scattering instrument to determine the particle size and polydispersity index.

[0088] Experimental Results: The self-emulsifying ability of progesterone self-emulsifying solid formulations is crucial to their emulsification and absorption in vivo. Generally, the smaller the particle size, the better the progesterone in the formulation is absorbed. To investigate whether the addition of a curing agent affects the self-emulsifying ability of the progesterone self-emulsifying solid formulation, the particle size distribution of the emulsion was measured, and the results are shown in Table 2. Table 2 shows that the curing agent of this application has little effect on the self-emulsifying ability of the progesterone self-emulsifying solid formulation.

[0089] Table 2. Particle size distribution of emulsions obtained after emulsification of progesterone self-emulsifying solid formulations.

[0090] Experimental Example 3

[0091] Experimental Method: The dissolution rate of the drug was determined using the basket method from the Chinese Pharmacopoeia. 1L of pH 6.8 phosphate buffer containing 3% sodium dodecyl sulfate was used as the dissolution medium. Before the test, the instrument setup needed to be calibrated, ensuring the distance between the bottom of the rotating basket and the inner bottom of the dissolution vessel was 25±2mm. 1L of dissolution medium was measured and placed into each dissolution vessel, with the actual measured volume deviating from the specified volume within ±1%. After the temperature of the dissolution medium stabilized at 37±0.5℃, samples of progesterone self-emulsified solid preparations and progesterone self-emulsified liquid preparations containing different proportions of curing agent were placed in the dry rotating basket, which was then lowered into the dissolution vessel. The instrument was started, the rotation speed was set to 100rpm, and the time was recorded. At 10, 20, and 30min and 1, 2, and 3h, 5mL of the dissolution solution was collected, 3mL was filtered off, and the filtrate was used as the test solution. 5mL of dissolution medium was added immediately after each sampling point. The test solution was diluted with one part methanol and the content was determined by HPLC. The amount of drug dissolved was calculated. The results are shown in Figure 1.

[0092] Figure 1 shows the dissolution curves of progesterone self-emulsifying solid formulations containing different proportions of curing agent. As can be seen from Figure 1, the dissolution curves of the progesterone self-emulsifying solid formulations containing different proportions of curing agent are basically consistent (i.e., Examples 4-7), all reaching a dissolution plateau at approximately 20 minutes. Furthermore, compared to the progesterone self-emulsifying liquid formulation, the dissolution curves after the addition of the curing agent did not show significant changes. Simultaneously, the dissolution rates of both the progesterone liquid self-emulsifying formulation and the progesterone self-emulsifying solid formulation are significantly higher than those of the commercially available progesterone formulation, Angelicine.

[0093] Experiment Example 4

[0094] Experimental Methods: Six male beagle dogs, weighing 9.66±0.78 kg, were divided into two groups for a crossover experiment. The dogs were kept clean for one week, and fasted for 12 hours prior to the experiment, but allowed free access to water. One group was administered two tablets of the self-emulsified solid progesterone formulation described in Example 7 (83.80 mg progesterone, Example 7), while the other group was administered two tablets of the self-emulsified liquid progesterone formulation described in Example 7 (94.65 mg progesterone, the self-emulsified liquid progesterone formulation described in Example 7). Approximately 1 mL of blood was collected from the forelimb vein before administration and at 5, 10, 20, 30, 45 min and 1, 1.5, 2, 3, 4, 6, and 8 h after administration, and analyzed by LC-MS / MS.

[0095] Pharmacokinetic data were analyzed using DRUG AND STATISTIC (DAS2.0) software, and pharmacokinetic parameters were calculated using the statistical moment model.

[0096] The pharmacokinetic curves for different formulations are shown in Figure 2, and the specific pharmacokinetic parameters are shown in Table 3.

[0097] Table 3 Pharmacokinetic parameters of different formulations Note: The above data are statistical moment parameters obtained from DAS2.0 analysis. max Peak concentration; T max Peak time; t 1 / 2 Half-life; AUC: Area under the curve; MRT: Mean residence time. AUC is dose-normalized.

[0098] As shown in Figure 2 and Table 3, the AUC of progesterone in the self-emulsified solid progesterone formulation after dose normalization adjustment is: 0-t The AUC of progesterone in the self-emulsified liquid progesterone formulation was 118.76 ± 66.99 ng / mL·h. 0-t The concentration was 96.92 ± 43.97 ng / mL·h, with no significant difference between the two groups. Their oral bioavailability was almost identical. (C) max There were no significant differences in pharmacokinetic parameters. This result indicates that the progesterone self-emulsifying solid formulation prepared by solidifying the progesterone self-emulsifying liquid formulation can promote the oral absorption of progesterone, and the oral bioavailability of progesterone in the progesterone self-emulsifying solid formulation is similar to that in the progesterone self-emulsifying liquid formulation.

[0099] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. A solidification solubilization method of a progesterone self-emulsifying liquid formulation, characterized by, Mixing the solidifying agent and the progesterone self-emulsifying liquid preparation; The solidifying agent comprises one or more of lauroyl polyoxyl-32 glycerides, polyoxyl-8 glycerides ricinoleate, polyethylene glycol-32 stearate, polyoxyl stearates, glyceryl stearate, glyceryl distearate and glyceryl monodistearate.

2. The solidification-solubilization method according to claim 1, wherein, The solidifying agent accounts for 10-80% of the total mass of the solidifying agent and the progesterone self-emulsifying liquid preparation.

3. The solidification-solubilization method of claim 2, wherein, The solidifying agent accounts for 20-70% of the total mass of the solidifying agent and the progesterone self-emulsifying liquid preparation.

4. The solidification-solubilization method of claim 1, wherein The progesterone self-emulsifying liquid preparation comprises the following mass fractions of raw materials: Progesterone 0.5%-20%, oily solvent 15%-80%, surfactant 30%-80%.

5. The solidification-solubilization method according to claim 4, wherein The raw materials further comprise a co-surfactant; the mass fraction of the co-surfactant is ≤30%.

6. The solidification-solubilization method of claim 4, wherein The oily solvent comprises one or more of soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, flaxseed oil, castor oil, perilla oil, corn oil, monolinolein, dilinolein, trilinolein, monoolein, diolein, triolein, medium-chain triglyceride, caprylocapryl triglyceride, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate and palmitic acid.

7. The solidification-solubilization method of claim 4, wherein The surfactant comprises one or more of polyoxyl castor oil, hydrogenated polyoxyl castor oil, Tween 20, Tween 60, Tween 80, vitamin E-TPGS and caprylocapryl polyoxylglycerol.

8. The solidification-solubilization method of claim 5, wherein, The co-surfactant comprises one or more of diethylene glycol monoethyl ether, polyglyceryl oleate, PEG400, isopropyl alcohol, propylene glycol laurate, ethanol and 1,2-propanediol.

9. The solidification-solubilization method of claim 1, wherein, After the mixing, stirring and standing are further performed in sequence. The temperature of the stirring is 35-80°C, and the time is 0.5-4h.

10. The solidification-solubilization method of claim 9, wherein, The temperature of the standing is ≤20°C, and the time is 1-48h.

11. The solid self-microemulsifying formulation of progesterone obtained by the solid solubilization method according to any one of claims 1 to 10, characterized in that, The progesterone self-emulsifying liquid preparation comprises the following mass fractions of raw materials: Progesterone 0.5%-20%, oily solvent 15%-80%, surfactant 30%-80%. The raw materials further comprise a co-surfactant; the mass fraction of the co-surfactant is ≤30%. The oily solvent comprises one or more of soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, flaxseed oil, castor oil, perilla oil, corn oil, monolinolein, dilinolein, trilinolein, monoolein, diolein, triolein, medium-chain triglyceride, caprylocapryl triglyceride, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate and palmitic acid. The surfactant comprises one or more of polyoxyl castor oil, hydrogenated polyoxyl castor oil, Tween 20, Tween 60, Tween 80, vitamin E-TPGS and caprylocapryl polyoxylglycerol. The co-surfactant comprises one or more of diethylene glycol monoethyl ether, polyglyceryl oleate, PEG400, isopropyl alcohol, propylene glycol laurate, ethanol and 1,2-propanediol. After the mixing, stirring and standing are further performed in sequence. The temperature of the stirring is 35-80°C, and the time is 0.5-4h. The temperature of the standing is ≤20°C, and the time is 1-48h.

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