Pharmaceutical composition comprising allopregnanolone derivative and use thereof

Abstract

Provided are a pharmaceutical composition comprising an allopregnanolone derivative and the use thereof. The pharmaceutical composition comprises the following components in percentage by mass: 30% to 70% of allopregnanolone derivative, 15% to 62% of filler, 5% to 20% of binder, 1% to 2.5% of glidant, 0.2% to 1.2% of lubricant and 0 to 10% of disintegrant. The pharmaceutical composition has excellent stability and a rapid dissolution rate, and is suitable for preparing solid preparations such as quick-release capsules, granules, and tablets. Also provided is a method for preparing a capsule preparation by using the pharmaceutical composition.

Description

Pharmaceutical composition containing allopregnanolone derivatives and use thereof

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on September 27, 2023, with patent application number 2023112633786, entitled “Pharmaceutical Compositions Containing Allopregnanolone Derivatives and Uses Thereof.” The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing an allopregnanolone derivative and a use thereof. Background Art

[0003] It's reported that approximately 121 million people worldwide suffer from depression. Postpartum depression (PPD) refers to a significant depressive mood disorder that develops in women during the postpartum period. The global prevalence is approximately 13%, and in developing countries, it can be as high as 18.7%. PPD typically begins within four weeks of delivery. Symptoms include anxiety, panic, irritability, guilt, sadness, insomnia, fatigue, indifference toward the baby, family, and friends, fear of being alone with the baby, and even suicidal thoughts, causing significant distress and suffering for women and their families.

[0004] Allopregnanolone (Brexanolone, also known as allopregnanolone) is a natural positive allosteric modulator of endogenous γ-aminobutyric acid type A receptor (GABAA) in the human body. In March 2019, the U.S. FDA approved the marketing of allopregnanolone intravenous injection developed by SAGE. The trade name is For the treatment of PPD in adults, allopregnanolone has poor solubility in the body, low oral bioavailability, and rapid metabolism. Therefore, it must be administered by continuous intravenous infusion for 60 hours, which is extremely inconvenient for both patients and medical staff.

[0005] The applicant’s prior patent application WO2023040851A discloses a water-soluble pregnane alcohol derivative (Compound I) or a pharmaceutically acceptable salt thereof and a solvate thereof, and discloses a variety of representative compounds. Another prior application CN202310230221.7 discloses a variety of crystalline forms of one of the representative compounds, L-valine-3-deuterium, (3α, 5α)-3-hydroxy-pregnane-20-one ester hydrochloride (Compound II). These compounds have the characteristics of high oral bioavailability, rapid onset, long duration of action, low toxic and side effects, and good metabolic stability. They are suitable for making oral preparations, improving drug safety, and improving patient compliance and convenience of administration. The full text of the above two applications is incorporated into the present invention as recorded and disclosed in this application.

[0006] Summary of the Invention

[0007] The present invention provides a pharmaceutical composition containing a water-soluble pregnanolone derivative, particularly a pharmaceutical composition containing L-valine-3-deuterium (3α,5α)-3-hydroxy-pregnan-20-one ester hydrochloride (Compound II). The pharmaceutical composition exhibits excellent dissolution properties and stability and is suitable for formulation into solid preparations such as capsules, granules, and tablets.

[0008] The present invention provides the following technical solutions:

[0009] A pharmaceutical composition comprising the following components in percentage by weight:

[0010] Wherein: the allopregnanolone derivative is selected from the following compound (I), or its racemate, stereoisomer, tautomer, solvate, polymorph or pharmaceutically acceptable salt:

[0011] In compound (I), R2 and R4 are independently selected from H (hydrogen) or D (deuterium); R1 and R3 are independently selected from CH3, CH2D, CHD2 or CD3; provided that compound (I) contains at least one deuterium atom.

[0012] Preferably, the compound (I) is selected from the following compounds 1 to 5, or racemates, stereoisomers, tautomers, solvates, polymorphs or pharmaceutically acceptable salts of compounds 1 to 5:

[0013] The filler is selected from at least one of microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate, sucrose, glucose, and starch;

[0014] The binder is selected from at least one of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, hypromellose, and pregelatinized starch;

[0015] The glidant is selected from at least one of colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, talc, magnesium carbonate, calcium silicate, and polyethylene glycol;

[0016] The lubricant is selected from at least one of stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and talc;

[0017] The disintegrant is selected from at least one of cross-linked polyvinylpyrrolidone, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose.

[0018] According to an embodiment of the present invention, the filler is selected from a combination of mannitol and one or more of the following substances: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sucrose, glucose, and starch.

[0019] In some embodiments of the present invention, when the pharmaceutical composition contains mannitol, the pharmaceutical composition does not contain a disintegrant.

[0020] According to an embodiment of the present invention, the content of the filler mannitol is 30 wt % or less, for example, 5 to 30 wt %.

[0021] In one embodiment of the present invention, the filler is selected from a combination of mannitol and microcrystalline cellulose.

[0022] According to an embodiment of the present invention, when magnesium stearate is contained in the composition, its content is 0.2 to 1.2 wt %, preferably 0.2 to 1 wt %, for example 0.2 to 0.8 wt %.

[0023] According to an embodiment of the present invention, the allopregnanolone derivative shown in formula (I) is a compound disclosed in WO2023040851A and CN202211112060.3. Therefore, the full text of these two patents is incorporated into the present invention as a reference.

[0024] According to an embodiment of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, benzoate, p-toluenesulfonate, malate, acetate, benzenesulfonate and maleate.

[0025] According to an embodiment of the present invention, the allopregnanolone derivative may be compound (II) shown below:

[0026] In some embodiments, the pharmaceutical composition comprises the following components in percentage by weight:

[0027] In some embodiments, the pharmaceutical composition comprises the following components in percentage by weight:

[0028] In some preferred embodiments, the pharmaceutical composition comprises the following components in percentage by mass:

[0029] In some embodiments, the pharmaceutical composition comprises the following components in percentage by weight:

[0030] In some preferred embodiments, the pharmaceutical composition comprises the following components in percentage by mass:

[0031] In some preferred embodiments, the pharmaceutical composition comprises the following components in percentage by mass:

[0032] In some preferred embodiments, the pharmaceutical composition comprises the following components in percentage by mass:

[0033] According to an embodiment of the present invention, the allopregnanolone derivative may be the crystalline form I of compound (II). Patent document CN202310230221.7 discloses a method for preparing the crystalline form I of compound (II), and the entire text of the application is incorporated herein by reference.

[0034] According to an embodiment of the present invention, the X-ray powder diffraction of Compound (II) crystalline form I expressed in 2θ angles has an absorption peak at the following position:

[0035] Preferably, the crystalline Form I has an XRPD pattern substantially as shown in FIG1 ; or further has one or more of the following characteristics:

[0036] 1) The DSC spectrum of the crystalline form I has an endothermic peak in the range of about 156±2°C; 2) the crystalline form I has a DSC spectrum substantially as shown in Figure 2; 3) the crystalline form I has a TGA spectrum substantially as shown in Figure 3; 4) the crystalline form I has a DVS spectrum substantially as shown in Figure 4.

[0037] The pharmaceutical composition of the present invention may also include other excipients, such as disintegrants and flavoring agents. However, the present inventors have discovered that when mannitol is used as a filler, a disintegrant is not required to achieve a good dissolution rate. However, at the same dosage, the dissolution performance is poor when a disintegrant is used without mannitol.

[0038] The pharmaceutical composition of the present invention can be prepared into a quick-release solid preparation, such as a quick-release capsule, granules, tablets, etc., preferably a granule or a capsule containing these granules. The capsule can be prepared using capsule shells known in the art, including soft capsule shells and hard capsule shells. For example, the capsule shell is a hard capsule shell, such as a gelatin capsule shell or a plant-based hard capsule shell.

[0039] The pharmaceutical composition of the present invention can be prepared into different pharmaceutical specifications according to the different contents of the active ingredient in the unit preparation, for example, the unit preparation contains 25 mg, 50 mg, 200 mg of the active ingredient, etc.

[0040] Therefore, the present invention provides a capsule preparation comprising any one of the above pharmaceutical compositions.

[0041] Furthermore, the present invention also provides a method for preparing the above-mentioned capsule preparation, comprising the following steps:

[0042] 1) Sieving: sieving the active ingredient compound (I) and the excipients separately to obtain sieved materials;

[0043] 2) Premixing: fully mixing the sieved compound (I), other fillers except mannitol, glidants, binders, and optionally a portion of mannitol to obtain a premixed material;

[0044] 3) Granulation: Granulate the premixed material to obtain compressed material;

[0045] 4) Total mixing: thoroughly mixing the compressed material with the lubricant and all or part of the mannitol to obtain a final mixture;

[0046] 5) Capsule filling: The final mixture is filled into capsule shells.

[0047] Wherein, in step 3), the granulation is dry granulation.

[0048] According to an embodiment of the present invention, when the content of mannitol is less than 15wt% of the pharmaceutical composition, the mannitol can be added in the total mixing in step 4); when the content of mannitol is more than 15wt%, it is added in steps 2) and 4) respectively; that is, in step 4), the amount of mannitol added is less than 15wt% of the pharmaceutical composition, preferably 5-10wt%.

[0049] Wherein, in step 4), the amount of mannitol added accounts for less than 15% by mass of the pharmaceutical composition, preferably 5 to 10%. According to different pharmaceutical specifications, as the content of the active ingredient compound changes, the content of the filler mannitol can be adjusted while maintaining the excellent dissolution rate and stability of the pharmaceutical composition or preparation. For example, in a larger-scale preparation (such as a unit preparation containing 50 mg or more of the active ingredient), the content of mannitol can account for 5 to 15% by mass of the pharmaceutical composition; in a smaller-scale preparation (such as a unit preparation containing 25 mg of the active ingredient), the content of mannitol can account for 20 to 30% by mass of the pharmaceutical composition.

[0050] However, the present inventors also found that during the preparation of solid (capsule) preparations, the amount of mannitol added affects the performance of the preparation particles.

[0051] When all of the mannitol is added to the premix in step 2), the dissolution rate of the active ingredient in the resulting preparation is significantly slower; preferably, when the content of mannitol in the pharmaceutical composition is less than 15 wt%, the addition of mannitol to the total mix in step 4) during capsule preparation can significantly increase the drug dissolution rate;

[0052] When the content of mannitol in the pharmaceutical composition is high (for example, reaching 15wt%, 20wt%, 25wt% or higher), if all the mannitol is added during the total mixing in step 4), the content uniformity of the resulting preparation is likely to exceed the acceptable standard in the content uniformity test method. The inventors have found that when the mannitol content is high, it is preferably added in two parts, one part added in the premixing step and the other part added in the total mixing step. In some specific embodiments of the present invention, the content of mannitol added in the total mixing step is less than 15% of the total mass of the pharmaceutical composition, preferably not more than 10% of the total mass of the pharmaceutical composition, and the remaining mannitol is added in the premixing step. This can solve the above-mentioned problem, significantly improve the uniformity of the drug particles, and improve the smoothness and controllability of the formulation process.

[0053] The present invention further provides the use of the pharmaceutical composition or solid preparation (such as capsules, granules, tablets, etc.) in preparing drugs for preventing or treating diseases related to the central nervous system, or in preparing drugs for sedation and hypnosis.

[0054] According to an embodiment of the present invention, the central nervous system-related diseases are, for example, traumatic brain injury, essential tremor, epilepsy (including refractory epilepsy, rare genetic epilepsy (such as Dravet syndrome and Rett syndrome)), depression (including postpartum depression) and Alzheimer's disease. For example, the central nervous system disease is selected from essential tremor, epilepsy, clinical depression, postpartum or postpartum depression, atypical depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideas or suicidal behavior.

[0055] In the pharmaceutical composition of the present invention, compound (I) as an active ingredient has excellent stability and dissolution properties. After oral administration, compound (I) is hydrolyzed and the active metabolite allopregnanolone is rapidly released. By means of a prodrug, oral administration of allopregnanolone is achieved. In comparison, the solid preparation of compound (I) can improve the convenience of clinical use, enhance patient compliance, reduce the risk of administration, and shorten the time of hospitalization while maintaining the efficacy, and is more in line with clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG1 is an XRPD pattern of Form I of Compound (II).

[0057] Figure 2 is the DSC spectrum of Form I of Compound (II).

[0058] FIG3 is a TGA spectrum of Form I of Compound (II).

[0059] Figure 4 is a DVS spectrum of Form I of Compound (II).

[0060] FIG5 is a DSC spectrum of the granules of Example 10 (dry granulation).

[0061] FIG6 is a DSC spectrum of the granules of Comparative Example 8 (wet granulation).

[0062] FIG7 is a DSC spectrum of the granules of Comparative Example 9 (wet granulation). DETAILED DESCRIPTION

[0063] The following examples illustrate the technical solutions of the present invention in detail using compound (II) as a representative compound. The examples should not be construed as limiting the present invention in any way. Unless otherwise specified, the materials used in the examples are commercially available, and all experimental procedures are performed using methods or instruments known or conventional in the art.

[0064] Compound (II) sample: Compound (II) Form I can be prepared with reference to the method described in patent document CN202310230221.7. About 5.0 g of compound (II) was added to 50 ml of isopropyl acetate, stirred and slurried at 50 ° C, filtered, the filter cake was washed with 10 ml of isopropyl acetate, and vacuum dried at 50 ° C to obtain Form I of compound (II). The Form I has an XRPD pattern substantially as shown in Figure 1; its DSC spectrum has an endothermic peak in the range of about 156 ± 2 ° C; its DSC spectrum is specifically shown in Figure 2. Its TGA spectrum is shown in Figure 3. The Form I also has a DVS spectrum substantially as shown in Figure 4.

[0065] Preparation of capsules: In the following examples, capsules were prepared according to the formulations shown in the table, with a batch size of 1200 capsules per batch.

[0066] Stability tests: 1) Samples were stored at 40°C, 75% RH; 2) Samples were stored at 60°C, in a dry environment. HPLC detection conditions for related substances: Mobile phase A: 10 mmol / L diammonium hydrogen phosphate solution, mobile phase B: acetonitrile; diluent: 70% methanol solution; detection wavelength: 205 nm.

[0067] Dissolution study: 0.01N hydrochloric acid medium; paddle method (sinking basket); rotation speed: 50 rpm; volume: 900 ml; temperature: 37±0.5°C; sampling time points: 10, 15, 20, 30, and 45 min.

[0068] Mixing uniformity inspection: At the end of mixing, samples are taken from 11 locations, including the top of the mixing barrel, the corner edge, and the discharge port, to test the content. The single value of the mixing uniformity sample content should be within ±10% (absolute) of the mean, and the RSD value should be ≤5.0%.

[0069] Content uniformity test: Take 10 tablets of the preparation sample, transfer the contents accurately to a volumetric flask, add an appropriate amount of diluent and ultrasonically dissolve, shake while ultrasonicating, let cool, dilute to the scale with diluent, shake well, filter with a filter membrane, and take the filtrate. According to the 2020 edition of the Chinese Pharmacopoeia Part IV General Rules <0941> Test the product's content uniformity. Calculate the mean and standard deviation, S, as well as the absolute value, A, of the difference between the labeled amount and the mean. Judge the results based on the acceptance criteria. The criteria are: if A + 2.2S ≤ L, the product's content uniformity meets the requirements; if A + S > L, it does not meet the requirements; L = 15.0.

[0070] DSC test parameters: The sample was placed in an alumina crucible for DSC test, and the parameters were set as follows: heating range: 25-200°C; heating rate: 10°C / min; nitrogen purge gas: 50 ml / min.

[0071] Examples 1-2 and Comparative Example 1: Preparation of capsule preparations from the pharmaceutical composition of the present invention

[0072] Example 1, Example 2, and Comparative Example 1 show the effects of different contents of components, especially mannitol, on the pharmaceutical composition of the present invention. The formulation is shown in Table 2 below.

[0073] Preparation method: 1) Screening: The prescribed amount of compound (II) and excipients are sieved separately (40 mesh standard sieve, the same below) to obtain a screened material; 2) Premixing: The screened microcrystalline cellulose, colloidal silicon dioxide, compound (II), and ethyl cellulose are thoroughly mixed to obtain a premixed material; 3) Granulation: The premixed material is roller-pressed using a dry granulator to obtain a compressed material; 4) Total mixing: The compressed material is thoroughly mixed with other excipients, magnesium stearate and mannitol, to obtain a final mixture; 5) Capsule filling: The final mixture is filled into gelatin capsule shells.

[0074] Table 2

[0075] The dissolution test results are shown in Table 3.

[0076] Table 3

[0077] The stability test results are shown in Table 4 below.

[0078] Table 4

[0079] The results showed that the dissolution rate of the formulation in Comparative Example 1 was approximately 85% in 30 minutes and reached approximately 93% in 45 minutes. However, the formulations in Examples 1 and 2 achieved dissolution rates exceeding 80% in 20 minutes and exceeding 97% in 30 minutes, significantly higher than those in Comparative Example 1. This indicates that the addition of mannitol facilitates rapid dissolution and release of the API compared to the formulation without mannitol. Furthermore, under conditions of 40°C / 75% RH and a high temperature of 60°C, the formulations in Examples 1 and 2 exhibited excellent stability. Furthermore, the mixing uniformity and content uniformity of the samples in Examples 1 and 2 met the standards.

[0080] Examples 3-4 and Comparative Example 2: Preparation of capsule preparations from the pharmaceutical composition of the present invention

[0081] Examples 3, 4 and Comparative Example 2 show the effects of filler mannitol and disintegrant crospovidone on the pharmaceutical composition. The formulation is shown in Table 5.

[0082] Preparation method: same as Example 1.

[0083] Table 5

[0084] The dissolution test results are shown in Table 6.

[0085] Table 6

[0086] The results of the stability study are shown in Table 7 below.

[0087] Table 7

[0088] The experimental results show that the prescriptions of Examples 3 and 4 both contain mannitol, and the dissolution rate can reach more than 95% in 30 minutes. Example 4 also contains a disintegrant cross-linked polyvinylpyrrolidone, and there is no significant difference in the dissolution rate compared with Example 3. The prescription of Comparative Example 2 does not contain mannitol, but only contains cross-linked polyvinylpyrrolidone, and the dissolution rate in 30 minutes is significantly lower than that of Examples 3 and 4. The above results show that mannitol can promote the rapid dissolution of the API in the pharmaceutical composition of the present invention. Although the disintegrant cross-linked polyvinylpyrrolidone can promote the dissolution of the API, the effect is significantly inferior to that of mannitol. When mannitol is added, there is no need to add the disintegrant cross-linked polyvinylpyrrolidone. In addition, the prescriptions of Examples 3 and 4 both have good stability; the mixing uniformity and content uniformity tests all meet the standards.

[0089] Examples 5-6 and Comparative Example 3: Pharmaceutical Compositions

[0090] Examples 5, 6 and Comparative Example 3 show the effects of different filler contents on the pharmaceutical composition. The formulation is shown in Table 8.

[0091] Preparation method: Same as Example 1.

[0092] Table 8

[0093] The dissolution test results are shown in Table 9.

[0094] Table 9

[0095] The results of the stability study are shown in Table 10 below.

[0096] Table 10

[0097] The experimental results show that the prescription of Example 5 contains fillers microcrystalline cellulose and mannitol, the prescription of Example 6 contains fillers microcrystalline cellulose, mannitol and anhydrous calcium hydrogen phosphate, and the prescription of Comparative Example 3 contains fillers silicified microcrystalline cellulose and lactose, and the 30-min dissolution rate reaches about 96% to 98%. In comparison, there is no significant difference in the dissolution rate of the three. However, the stability of Comparative Example 3 under 40°C / 75%RH and high temperature 60°C is poor, and the stability of Examples 5 and 6 is significantly better than that of Comparative Example 3. Therefore, silicified microcrystalline cellulose and lactose are not suitable as fillers for the pharmaceutical composition of the present invention. The fillers of the pharmaceutical composition of the present invention can be selected from microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate, more preferably microcrystalline cellulose and mannitol. In addition, the mixing uniformity and content uniformity of the prescriptions of Examples 5 and 6 meet the standards.

[0098] Examples 7-8 and Comparative Example 4

[0099] Examples 7, 8, and Comparative Example 4 demonstrate the effects of different preparation methods (particularly the addition of mannitol) on the preparation of capsule particles from a pharmaceutical composition. The formulation is shown in Table 11 below.

[0100] The preparation method of Example 7 is the same as that of Example 1. Mannitol is added during the total mixing in step 4).

[0101] The preparation method of Example 8 is basically the same as that of Example 7, except that the prescribed amount of mannitol is divided into two equal parts, one part is added to the premix in step 2), and the other part is added to the total mix in step 4).

[0102] The preparation method of Comparative Example 4 is basically the same as that of Example 7, except that all the prescribed amount of mannitol is added to the premix in step 2).

[0103] Table 11

[0104] The dissolution test results are shown in Table 12.

[0105] Table 12

[0106] The experimental results show that in Example 7, mannitol was added in the total mixing step, and the 30-minute dissolution rate reached 97.6%, the fastest dissolution rate. In Example 8, part of the mannitol (3.7wt%) was added in the premixing step, and the remaining part (3.7wt%) was added in the total mixing step. The dissolution rate in the first 20 minutes was significantly slower than that of Example 7, and the 30-minute dissolution rate reached 90.6%, which was lower than that of Example 7. The mannitol in Comparative Example 4 was all added in the premixing step, and the dissolution rate was the slowest. It can be seen that the addition method of mannitol has a certain influence on the dissolution rate. It is preferred that mannitol be added in the total mixing step. The mixing uniformity and content uniformity of each prescription were found to meet the standards.

[0107] Example 9 and Comparative Examples 5 and 6

[0108] Example 9 and Comparative Examples 5, 6, and 7 show the effects of different preparation methods on the preparation of capsule particles from a pharmaceutical composition. The formulation is shown in Table 13 below.

[0109] Preparation method of Example 9: 1) Screening: The prescribed amount of Compound (II) and other excipients are sieved separately to obtain a sieved material; 2) Premixing: The sieved microcrystalline cellulose, a portion of mannitol (accounting for 19.7 wt% of the weight of the pharmaceutical composition), colloidal silicon dioxide, Compound (II), and ethyl cellulose are thoroughly mixed to obtain a premixed material; 3) Dry granulation: The premixed material is roller-compacted using a dry granulator to obtain a compressed material; 4) Total mixing: The compressed material is mixed with other excipients [the remaining mannitol (accounting for 10 wt% of the weight of the pharmaceutical composition), magnesium stearate] to obtain a final mixture; 5) Capsule filling: The final mixture is filled into gelatin capsule shells.

[0110] The preparation method of Comparative Example 5 is basically the same as that of Example 9, except that part of the mannitol (accounting for 9.7 wt% of the weight of the pharmaceutical composition) is added in the premixing step 2), and the remaining mannitol (accounting for 20 wt% of the weight of the pharmaceutical composition) is added in the total mixing step 4).

[0111] The preparation method of Comparative Example 6 is basically the same as that of Example 9, except that all mannitol is added during the total mixing in step 4). The preparation method of Comparative Example 7 is basically the same as that of Example 9, except that all mannitol is added during the premixing in step 2).

[0112] Table 13

[0113] The dissolution test results are shown in Table 14.

[0114] Table 14

[0115] The results of the mixing uniformity and content uniformity inspection are shown in Table 15 below.

[0116] Table 15

[0117] The results of the stability study are shown in Table 16 below.

[0118] Table 16

[0119] The results show that the content of API in Example 9 and Comparative Examples 5-7 is small, the content of mannitol is high, and the dissolution rate of API is fast, with no significant difference. However, the way of adding mannitol affects the mixing uniformity and content uniformity of the composition. When mannitol accounts for 29.7wt% of the weight of the pharmaceutical composition, if the amount added in the total mixing step is 10wt%, good uniformity can be obtained during the roller granulation process, the material does not stick to the roller, and the process is smooth (Example 9), while when the mannitol added in the total mixing step is 20wt%, the mixing uniformity of the total mixed material and the content uniformity of the preparation do not comply with the 2020 edition of the Chinese Pharmacopoeia Part Four General Rules <0941> Acceptance criteria in the content uniformity test method (Comparative Example 5).

[0120] Furthermore, when the content of mannitol in the pharmaceutical composition reaches 43.5wt% and all of it is added in the total mixing step, the mixing uniformity of the total mixed material and the content uniformity of the preparation do not comply with the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia <0941> Acceptable criteria in the content uniformity test method (Comparative Example 6); when all mannitol is added in the premixing step, the mixture tends to stick to the roller during roller granulation, resulting in excessive fine powder in the granules and poor granulation uniformity, affecting the smoothness of the process and the uniformity of capsule filling (Comparative Example 7).

[0121] Therefore, when the composition contains a high amount of mannitol, it is preferably added in two portions: one portion in the premixing step and the other portion in the final mixing step. The mannitol content in the final mixing step is less than 15% of the total mass of the pharmaceutical composition, preferably not more than 10% of the total mass of the pharmaceutical composition, while the remaining mannitol is added in the premixing step. This can improve the uniformity of the drug particles and enhance the smoothness and controllability of the formulation process.

[0122] In addition, the stability study results show that the stability of Comparative Example 7 at high temperatures is poor, which is further analyzed to be due to the high content of magnesium stearate. Screening by the content of magnesium stearate found that in the prescription using the same ingredients, when the content of magnesium stearate is higher than 1.2wt% of the total weight of the prescription, the stability of the pharmaceutical composition will decrease. Preferably, the content of magnesium stearate in the present invention should not exceed 1.2wt%, more preferably not more than 1wt%, for example 0.2 to 0.8wt%.

[0123] Example 10 and Comparative Examples 8 and 9

[0124] Example 10 and Comparative Examples 8 and 9 respectively adopted the formulations shown in Table 17 below and used different granulation methods to prepare capsule granules to investigate the effects of different preparation processes on the pharmaceutical compositions.

[0125] Preparation method of Example 10 (dry granulation): same as Example 1.

[0126] Preparation method of Comparative Example 8 (wet granulation): 1) Screening: The prescribed amount of compound (II) and excipients are sieved separately to obtain a sieved material; 2) Premixing: The sieved microcrystalline cellulose, mannitol, colloidal silicon dioxide, compound (II), and ethyl cellulose are mixed to obtain a premixed material; 3) Wet granulation: A soft material is prepared using a wet granulator, an appropriate amount of water is used as a wetting agent, and granulation is performed using a swing granulator. After granulation, the material is dried in an oven; 4) Granulation and total mixing: The dried material is granulated using a granulator, and the granulated material is mixed with another pharmaceutically acceptable excipient (magnesium stearate) to obtain a final mixture; 5) Capsule filling: The final mixture is filled into gelatin capsule shells.

[0127] The preparation method of Comparative Example 9 (wet granulation) is basically the same as that of Comparative Example 8, except that 40% ethanol aqueous solution is used as the wetting agent.

[0128] Table 17

[0129] Differential scanning calorimetry (DSC) was used to measure the crystal form of Compound (II) raw material and the granulated and dried capsule granules to investigate whether the active ingredient Compound (II) undergoes a crystal transformation before and after granulation. The DSC spectrum of the raw Compound (II) is shown in Figure 2. The DSC spectra of the capsule granules of Example 10, Comparative Example 8, and Comparative Example 9 are shown in Figures 5 to 7, respectively.

[0130] The experimental results show that the raw material compound (II) is crystalline form I, and the DSC spectrum has an endothermic peak at about 156.05°C. Example 10 uses dry granulation, and the crystal form of the API in the obtained granules has an endothermic peak at 150.06°C, and no other endothermic peaks are newly added, indicating that the crystal form of compound (II) has not changed (the small difference in the endothermic peak compared with the spectrum of the raw material is due to the interference of the excipients in the pharmaceutical composition); Comparative Example 8 uses water as a binder for wet granulation, and new crystal form endothermic peaks (about 79.94°C, 164.09°C) appear in the DSC spectrum, indicating that the crystal form I of the API in the granules has partially transformed; Comparative Example 9 uses 40% ethanol aqueous solution as a binder for wet granulation, and the melting point endothermic peak of crystal form I disappears in the DSC spectrum, and only new endothermic peaks (at about 84.10°C, 163.40°C) exist, indicating that all the API in the granules has transformed. The above experiments indicate that wet granulation can cause the active ingredient's crystalline form to change, making the preparation unstable. Therefore, wet granulation is not suitable for the preparation of this product. Therefore, dry granulation is preferred for preparing solid preparations of the pharmaceutical composition of the present invention.

[0131] In summary, the pharmaceutical composition of the present invention has excellent dissolution performance and stability. Moreover, when the pharmaceutical composition is prepared into solid tablets such as capsules by the preparation method of the present invention, the active ingredient does not undergo crystal transformation, the preparation process is simple and smooth, and the phenomenon of sticking to the roller and excessive fine powder does not occur, and uniform and stable capsule particles can be obtained.

[0132] The above embodiments are used as examples to explain the technical solutions of the present invention. Those skilled in the art may make modifications based on the disclosure of the present invention. As long as they do not deviate from the concept of the present invention, the modified technical solutions should fall within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The following components are included in mass percentage: Wherein: the allopregnanolone derivative is selected from compound (I), or its racemate, stereoisomer, tautomer, solvate, polymorph or pharmaceutically acceptable salt: In compound (I), R2 and R4 are independently selected from H (hydrogen) or D (deuterium); R1 and R3 are independently selected from CH3, CH2D, CHD2 or CD3; provided that compound (I) contains at least one deuterium atom.

2. The pharmaceutical composition according to claim 1, characterized in that The allopregnanolone derivative is selected from the following compounds 1 to 5, or one or more of the racemates, stereoisomers, tautomers, solvates, polymorphs or pharmaceutically acceptable salts of compounds 1 to 5: Preferably, the allopregnanolone derivative is selected from the following compound (II):

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The filler is selected from one or more of microcrystalline cellulose, mannitol, sucrose, glucose, and starch; and / or, The binder is selected from one or more of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and pregelatinized starch; and / or, The glidant is selected from one or more of colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, talc, magnesium carbonate, calcium silicate, and polyethylene glycol; and / or, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and talc; and / or, The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose; Preferably, the filler is selected from the group consisting of mannitol and a combination of one or more of the following substances: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sucrose, glucose, and starch. Preferably, when the pharmaceutical composition contains mannitol, the pharmaceutical composition does not contain a disintegrant.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The following components are included in mass percentage: Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Preferably, the pharmaceutical composition comprises the following components in percentage by weight: Preferably, the pharmaceutical composition comprises the following components in percentage by weight:

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The allopregnanolone derivative is selected from the crystalline form I of compound (II); the crystalline form I has an absorption peak at the following positions in X-ray powder diffraction expressed at 2θ angles:

6. A rapid-release solid preparation, characterized in that: A pharmaceutical composition comprising any one of claims 1 to 5; Preferably, the immediate-release solid preparation is a capsule, a granule or a tablet.

7. A method for preparing the immediate-release solid preparation according to claim 6 using the pharmaceutical composition according to any one of claims 1 to 5, characterized in that: The following steps are involved: 1) Sieving: Sieving the active ingredient compound (I) and the excipients separately to obtain sieved materials; 2) premixing: fully mixing the sieved compound (I), other fillers except mannitol, glidants, binders, optional disintegrants and optionally part of mannitol to obtain a premixed material; 3) Granulation: granulating the premixed material to obtain a compressed material; 4) Total mixing: fully mixing the compressed material with the lubricant and all or part of the mannitol to obtain a final mixture; 5) Capsule filling: Fill the final mixture into capsule shells.

8. The method according to claim 7, wherein in step 3), the granulation is dry granulation; and in step 4), the amount of mannitol added is less than 15% by weight of the pharmaceutical composition.

9. The method according to claim 7 or 8, wherein in step 3), the granulation is dry granulation; and in step 4), the amount of mannitol added is 5-10% by weight of the pharmaceutical composition.

10. Use of the pharmaceutical composition according to any one of claims 1 to 5 or the immediate-release solid preparation according to claim 6 in the preparation of a medicament for preventing or treating a disease related to the central nervous system, or in the preparation of a sedative and hypnotic medicament; the disease related to the central nervous system is, for example, Alzheimer's disease, epilepsy, depression, especially postpartum depression, traumatic brain injury, and essential tremor.

Images