A dydrogesterone tablet and its preparation process and application

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a dydrogesterone tablet and its preparation process and application. A dydrogesterone tablet, in parts by weight, is composed as follows: 5 to 15 parts of dydrogesterone; 4 to 40 parts of polyvinyl pyrrolidone K30; 65 to 70 parts of lactose; 65 to 70 parts of modified microcrystalline cellulose; 2 to 4 parts of hypromellose; 2 to 4 parts of β-cyclodextrin; 4 to 40 parts of mannitol. The present invention improves the dissolution effect and bioavailability of dydrogesterone by improving the ingredients of dydrogesterone tablets.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and specifically relates to a dydrogesterone tablet and a preparation process and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Dydrogesterone is a synthetic progestin used to treat a variety of gynecological diseases related to luteal insufficiency or progesterone deficiency. Dydrogesterone tablets are mainly used to treat problems such as threatened abortion, habitual abortion, and menstrual disorders. It can also be used in assisted reproductive technology, such as supporting the luteal phase and early pregnancy during an in vitro fertilization (IVF) cycle. Dydrogesterone is poorly soluble in water, has poor dissolution in the human body, and has low bioavailability. Therefore, it is very necessary to provide a dydrogesterone tablet with high solubility. Microcrystalline cellulose is a commonly used additive in pharmaceuticals, but microcrystalline cellulose has limited effect in promoting drug dissolution. How to use microcrystalline cellulose to improve the dissolution performance of dydrogesterone remains to be studied. Summary of the invention

[0004] In order to solve the technical problems existing in the prior art, the present invention provides a dydrogesterone tablet and a preparation process and application thereof to solve the problems existing in the above-mentioned prior art. The present invention improves the ingredients of the dydrogesterone tablet to improve the dissolution effect and bioavailability of dydrogesterone.

[0005] Specifically, the technical solution of the present invention is as follows:

[0006] In a first aspect of the present invention, a dydrogesterone tablet is provided, which is composed of the following components in parts by weight:

[0007] Dydrogesterone 5-15 parts;

[0008] Polyvinylpyrrolidone K30 4-40 parts;

[0009] Lactose 65-70 parts;

[0010] 65-70 parts of modified microcrystalline cellulose;

[0011] Hydroxypropyl methylcellulose 2-4 parts;

[0012] β-cyclodextrin 2-4 parts;

[0013] Mannitol 4~30 parts.

[0014] In a specific embodiment, the dydrogesterone tablets are composed of the following components in parts by weight:

[0015] Dydrogesterone 5-10 parts;

[0016] Polyvinylpyrrolidone K30 4-35 parts;

[0017] Lactose 65-68 parts;

[0018] 65-70 parts of modified microcrystalline cellulose;

[0019] 2-3 parts of Hydroxypropyl Methylcellulose;

[0020] β-cyclodextrin 2-3 parts;

[0021] Mannitol 4~35 parts.

[0022] In a specific embodiment, the dydrogesterone tablets are composed of the following components in parts by weight:

[0023] Dydrogesterone 10-15 parts;

[0024] Polyvinylpyrrolidone K30 20-40 parts;

[0025] Lactose 67-70 parts;

[0026] 65-70 parts of modified microcrystalline cellulose;

[0027] 3-4 parts of Hydroxypropyl Methylcellulose;

[0028] β-cyclodextrin 3-4 parts;

[0029] Mannitol 20~40 parts.

[0030] In a specific embodiment, the dydrogesterone tablet further comprises a lubricant, and further, the lubricant is magnesium stearate.

[0031] In a specific embodiment, the particle size distribution of the dydrogesterone is D90≤40 μm.

[0032] In a specific embodiment, the preparation method of the modified microcrystalline cellulose is:

[0033] (1) adding water to microcrystalline cellulose to prepare a suspension, adding polyethylene glycol (PEG) to the suspension and mixing evenly to obtain a mixed slurry of microcrystalline cellulose and polyethylene glycol;

[0034] (2) adding sodium carboxymethyl cellulose to the mixed slurry of microcrystalline cellulose and polyethylene glycol obtained in step (1), and mixing them evenly to obtain a mixed slurry;

[0035] (3) Drying the mixed slurry obtained in step (2) to obtain modified microcrystalline cellulose.

[0036] Preferably, the molecular weight of the polyethylene glycol is 1000-1500 Daltons.

[0037] Polyethylene glycol can improve the fluidity of microcrystalline cellulose powder by reducing the friction between particles and increase the wettability of microcrystalline cellulose particles. Polyethylene glycol-modified microcrystalline cellulose can accelerate the dispersion of drugs in medicines, improve the solubility of drugs, and thus accelerate the absorption of drugs in the body; in addition, when microcrystalline cellulose and polyethylene glycol are used in combination, the release rate of drugs can be adjusted. For example, high molecular weight PEG can delay the release of drugs, while lower molecular weight PEG can accelerate the release. In addition, the present application also adds sodium carboxymethyl cellulose when modifying microcrystalline cellulose. Sodium carboxymethyl cellulose can promote the disintegration of tablets in the moist environment provided by microcrystalline cellulose and polyethylene glycol, further accelerate the rapid dispersion of tablets, and thus promote the release of drugs.

[0038] In the second aspect of the present invention, a method for preparing the dydrogesterone tablets according to the first aspect is provided, comprising the following steps:

[0039] (1) Weighing raw materials;

[0040] (2) preparing a uniform solution of polyvinyl pyrrolidone K30, mannitol and water, adding dydrogesterone to the solution, and dispersing the solution by ultrasound to obtain a suspension;

[0041] (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0042] (4) granulating the mixture, drying it, adding magnesium stearate to the granules, mixing them evenly, and tableting them to obtain dydrogesterone tablets.

[0043] In a specific embodiment, in step (4), the temperature for drying the mixture is 40-50°C.

[0044] In the third aspect of the present invention, there is provided a use of the dydrogesterone tablets described in the first aspect in the preparation of a medicament for treating threatened abortion, habitual abortion and menstrual disorders.

[0045] The present invention has the following beneficial effects: in the present invention, dydrogesterone, polyvinyl pyrrolidone K30, lactose, modified microcrystalline cellulose, hydroxypropyl methylcellulose, beta-cyclodextrin, mannitol and magnesium stearate are combined to improve the dissolution rate of dydrogesterone tablets. DETAILED DESCRIPTION

[0046] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0047] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof. If the experimental methods of specific conditions are not indicated in the following specific embodiments, they are generally in accordance with conventional methods and conditions in the art, and such techniques and conditions are fully explained in the literature.

[0048] The present invention is further explained by the following examples, but they are not intended to limit the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0049] Example 1

[0050] A dydrogesterone tablet, in parts by weight, is composed as follows:

[0051] Dydrogesterone (particle size distribution D90 = 25 μm) 10 parts;

[0052] Polyvinylpyrrolidone K30 20 parts;

[0053] Lactose 67 parts;

[0054] Modified microcrystalline cellulose 67 parts;

[0055] 3 parts of hypromellose;

[0056] β-cyclodextrin 3 parts;

[0057] Mannitol 20 parts;

[0058] 0.7 parts of magnesium stearate.

[0059] Wherein, the preparation method of modified microcrystalline cellulose is:

[0060] (1) adding 5 times the mass of water to microcrystalline cellulose to prepare a suspension, adding polyethylene glycol with a molecular weight of 1000 Daltons to the suspension and mixing evenly, wherein the amount of polyethylene glycol added is 0.5% of the mass of the microcrystalline cellulose, to obtain a mixed slurry of microcrystalline cellulose and polyethylene glycol;

[0061] (2) adding sodium carboxymethyl cellulose to the mixed slurry of microcrystalline cellulose and polyethylene glycol obtained in step (1), wherein the amount of sodium carboxymethyl cellulose added is 15% of the mass of the microcrystalline cellulose, and mixing them evenly to obtain a mixed slurry;

[0062] (3) Drying the mixed slurry obtained in step (2) to obtain modified microcrystalline cellulose.

[0063] The preparation method comprises the following steps:

[0064] (1) Weighing raw materials;

[0065] (2) adding polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, adding dydrogesterone to the above solution, and ultrasonically treating for 8 minutes to fully disperse it to obtain a suspension;

[0066] (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0067] (4) granulating the mixture, drying at 50° C., adding magnesium stearate to the granules, mixing evenly, and tableting to obtain dydrogesterone tablets.

[0068] Example 2

[0069] A dydrogesterone tablet, in parts by weight, is composed as follows:

[0070] Dydrogesterone (particle size distribution D90 = 25 μm) 5 parts;

[0071] 4 parts of polyvinylpyrrolidone K30;

[0072] Lactose 65 parts;

[0073] 65 parts of modified microcrystalline cellulose;

[0074] 2 parts of Hydroxypropyl Methylcellulose;

[0075] β-cyclodextrin 2 parts;

[0076] Mannitol 4 parts;

[0077] 0.5 parts of magnesium stearate.

[0078] The preparation method of modified microcrystalline cellulose is the same as that in Example 1.

[0079] The preparation method comprises the following steps:

[0080] (1) Weighing raw materials;

[0081] (2) adding polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, adding dydrogesterone to the above solution, and ultrasonically treating for 8 minutes to fully disperse it to obtain a suspension;

[0082] (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0083] (4) granulating the mixture, drying at 50° C., adding magnesium stearate to the granules, mixing evenly, and tableting to obtain dydrogesterone tablets.

[0084] Example 3

[0085] A dydrogesterone tablet, in parts by weight, is composed as follows:

[0086] Dydrogesterone (particle size distribution D90 = 25 μm) 15 parts;

[0087] Polyvinylpyrrolidone K30 40 parts;

[0088] Lactose 70 parts;

[0089] 70 parts of modified microcrystalline cellulose;

[0090] 4 parts of Hydroxypropyl Methylcellulose;

[0091] 4 parts of β-cyclodextrin;

[0092] Mannitol 30 parts;

[0093] 1 part of magnesium stearate.

[0094] The preparation method of modified microcrystalline cellulose is the same as that in Example 1.

[0095] The preparation method comprises the following steps:

[0096] (1) Weighing raw materials;

[0097] (2) Add polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, add dydrogesterone to the above solution, and perform ultrasonic treatment for 8 minutes to fully disperse it to obtain a suspension;

[0098] (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin to obtain a mixed excipient, spraying the suspension into the mixed excipient, and stirring to obtain a mixture;

[0099] (4) The mixture is granulated, dried at 50° C., magnesium stearate is added to the granules, mixed evenly, and tabletted to obtain dydrogesterone tablets.

[0100] Comparative Example 1

[0101] A dydrogesterone tablet, in parts by weight, is composed as follows:

[0102] Dydrogesterone (particle size distribution D90 = 25 μm) 10 parts;

[0103] Polyvinylpyrrolidone K30 20 parts;

[0104] Lactose 67 parts;

[0105] Modified microcrystalline cellulose 67 parts;

[0106] 3 parts of hypromellose;

[0107] Mannitol 20 parts;

[0108] 0.7 parts of magnesium stearate.

[0109] Wherein, the preparation method of modified microcrystalline cellulose is the same as that in Example 1.

[0110] The preparation method comprises the following steps:

[0111] (1) Weighing raw materials;

[0112] (2) Add polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, add dydrogesterone to the above solution, and disperse it fully by ultrasonication to obtain a suspension;

[0113] (3) mixing lactose, modified microcrystalline cellulose, and hypromellose uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0114] (4) The mixture is granulated, dried at 50° C., magnesium stearate is added to the granules, mixed evenly, and tabletted to obtain dydrogesterone tablets.

[0115] Comparative Example 2

[0116] A dydrogesterone tablet, in parts by weight, is composed as follows:

[0117] Dydrogesterone (particle size distribution D90 = 25 μm) 10 parts;

[0118] Polyvinylpyrrolidone K30 20 parts;

[0119] Lactose 67 parts;

[0120] 3 parts of hypromellose;

[0121] β-cyclodextrin 3 parts;

[0122] Mannitol 20 parts

[0123] 0.7 parts of magnesium stearate.

[0124] The preparation method comprises the following steps:

[0125] (1) Weighing raw materials;

[0126] (2) adding polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, adding dydrogesterone to the above solution, and ultrasonically treating for 8 minutes to fully disperse it to obtain a suspension;

[0127] (3) mixing lactose, hydroxypropyl methylcellulose and β-cyclodextrin uniformly to obtain a mixed auxiliary material, spraying the above suspension into the mixed auxiliary material, and stirring to obtain a mixture;

[0128] (4) granulating the mixture, drying at 50° C., adding magnesium stearate to the granules, mixing evenly, and tableting to obtain dydrogesterone tablets.

[0129] Comparative Example 3

[0130] Dydrogesterone (particle size distribution D90 = 25 μm) 10 parts;

[0131] Polyvinylpyrrolidone K30 20 parts;

[0132] Lactose 67 parts;

[0133] Microcrystalline cellulose 67 parts;

[0134] 3 parts of hypromellose;

[0135] β-cyclodextrin 3 parts;

[0136] Mannitol 20 parts;

[0137] 0.7 parts of magnesium stearate.

[0138] The preparation method comprises the following steps:

[0139] (1) Weighing raw materials;

[0140] (2) adding polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, adding dydrogesterone to the above solution, and ultrasonically treating for 8 minutes to fully disperse it to obtain a suspension;

[0141] (3) mixing lactose, microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0142] (4) granulating the mixture, drying at 50° C., adding magnesium stearate to the granules, mixing evenly, and tableting to obtain dydrogesterone tablets.

[0143] Comparative Example 4

[0144] Dydrogesterone (particle size distribution D90 = 25 μm) 10 parts;

[0145] Polyvinylpyrrolidone K30 20 parts;

[0146] Lactose 67 parts;

[0147] Modified microcrystalline cellulose 67 parts;

[0148] 3 parts of hypromellose;

[0149] β-cyclodextrin 3 parts;

[0150] Mannitol 20 parts;

[0151] 0.7 parts of magnesium stearate.

[0152] Wherein, the preparation method of modified microcrystalline cellulose is:

[0153] (1) adding 5 times the mass of water to microcrystalline cellulose to prepare a suspension, adding sodium carboxymethyl cellulose to the suspension, wherein the amount of sodium carboxymethyl cellulose added is 15% of the mass of the microcrystalline cellulose, and mixing well to obtain a mixed slurry;

[0154] (2) Drying the mixed slurry obtained in step (1) to obtain modified microcrystalline cellulose.

[0155] The preparation method comprises the following steps:

[0156] (1) Weighing raw materials;

[0157] (2) adding polyvinyl pyrrolidone K30 and mannitol to 400 ml of water to prepare a uniform solution, adding dydrogesterone to the above solution, and ultrasonically treating for 8 minutes to fully disperse it to obtain a suspension;

[0158] (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture;

[0159] (4) granulating the mixture, drying at 50° C., adding magnesium stearate to the granules, mixing evenly, and tableting to obtain dydrogesterone tablets.

[0160] Dissolution determination:

[0161] Take the dydrogesterone tablet samples prepared in Examples 1-3 and Comparative Examples 1-4, use pH 6.8 phosphate buffer as the dissolution medium, and follow the dissolution method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules 0931, Method 2), the speed is 50 revolutions per minute, and the dissolution solution is taken at 5, 10, 20, 30, and 60 minutes for HPLC determination. The experimental results are as follows:

[0162] Table 1 Dissolution results of dydrogesterone in dydrogesterone tablets of Examples 1-3 and Comparative Examples 1-4

[0163]

[0164] It can be seen from the above experimental results that in the embodiment of the present invention, dydrogesterone, polyvinyl pyrrolidone K30, lactose, hydroxypropyl methylcellulose, β-cyclodextrin, mannitol and magnesium stearate are combined to improve the solubility of dydrogesterone tablets. In Comparative Example 1, β-cyclodextrin is not added, so that the solubility of dydrogesterone tablets is lower than that of Examples 1-3; in Comparative Example 2, modified microcrystalline cellulose is not added, so that the solubility of dydrogesterone tablets is further reduced; in Comparative Example 3, the existing microcrystalline cellulose is used to replace the modified microcrystalline cellulose prepared in Example 1 of the present application, so that the solubility of dydrogesterone tablets is also poorer than that of Examples 1-3; in Comparative Example 4, only sodium carboxymethyl cellulose is used to modify microcrystalline cellulose when preparing modified microcrystalline cellulose, so that the solubility of dydrogesterone tablets is also poorer than that of Examples 1-3. Therefore, the combination of polyvinyl pyrrolidone K30, lactose, modified microcrystalline cellulose, hypromellose, β-cyclodextrin, mannitol and magnesium stearate in the present application can improve the dissolution rate of dydrogesterone tablets, and the combination of these ingredients is indispensable.

[0165] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A dydrogesterone tablet, characterized in that: In parts by weight, the composition is as follows: 5 to 15 parts of dydrogesterone; 4 to 40 parts of polyvinylpyrrolidone K30; 65 to 70 parts of lactose; 65 to 70 parts of modified microcrystalline cellulose; 2 to 4 parts of hypromellose; 2 to 4 parts of β-cyclodextrin; 4 to 40 parts of mannitol; The preparation method of the modified microcrystalline cellulose is: (1) adding water to microcrystalline cellulose to prepare a suspension, adding polyethylene glycol to the suspension and mixing evenly to obtain a mixed slurry of microcrystalline cellulose and polyethylene glycol; (2) adding sodium carboxymethyl cellulose to the mixed slurry of microcrystalline cellulose and polyethylene glycol obtained in step (1), and mixing them evenly to obtain a mixed slurry; (3) Drying the mixed slurry obtained in step (2) to obtain modified microcrystalline cellulose; the molecular weight of the polyethylene glycol is 1000-1500 Daltons.

2. The dydrogesterone tablet according to claim 1, characterized in that The dydrogesterone tablets are composed of the following components in parts by weight: 5-10 parts of dydrogesterone; 4-35 parts of polyvinylpyrrolidone K30; 65-68 parts of lactose; 65-70 parts of modified microcrystalline cellulose; 2-3 parts of hypromellose; 2-3 parts of β-cyclodextrin; and 4-35 parts of mannitol.

3. The dydrogesterone tablet according to claim 1, characterized in that The dydrogesterone tablets are composed of the following components in parts by weight: 10-15 parts of dydrogesterone; 20-40 parts of polyvinyl pyrrolidone K30; 67-70 parts of lactose; 65-70 parts of modified microcrystalline cellulose; 3-4 parts of hypromellose; 3-4 parts of β-cyclodextrin; and 20-40 parts of mannitol.

4. The dydrogesterone tablet according to claim 1, characterized in that The particle size distribution of the dydrogesterone is D90≤40 μm.

5. A dydrogesterone tablet, characterized in that: The composition is as follows, in parts by weight: 5-15 parts of dydrogesterone; 4-40 parts of polyvinylpyrrolidone K30; 65-70 parts of lactose; 65-70 parts of modified microcrystalline cellulose; 2-4 parts of hypromellose; 2-4 parts of β-cyclodextrin; 4-40 parts of mannitol; and a lubricant; The preparation method of the modified microcrystalline cellulose is: (1) adding water to microcrystalline cellulose to prepare a suspension, adding polyethylene glycol to the suspension and mixing evenly to obtain a mixed slurry of microcrystalline cellulose and polyethylene glycol; (2) adding sodium carboxymethyl cellulose to the mixed slurry of microcrystalline cellulose and polyethylene glycol obtained in step (1), and mixing them evenly to obtain a mixed slurry; (3) Drying the mixed slurry obtained in step (2) to obtain modified microcrystalline cellulose; the molecular weight of the polyethylene glycol is 1000-1500 Daltons.

6. The dydrogesterone tablet according to claim 5, characterized in that The lubricant is magnesium stearate.

7. The method for preparing the dydrogesterone tablets according to claim 6, characterized in that: The following steps are involved: (1) Weighing raw materials; (2) preparing a uniform solution of polyvinyl pyrrolidone K30, mannitol and water, adding dydrogesterone to the solution, and dispersing the solution by ultrasound to obtain a suspension; (3) mixing lactose, modified microcrystalline cellulose, hypromellose and β-cyclodextrin uniformly to obtain a mixed excipient, spraying the above suspension into the mixed excipient, and stirring to obtain a mixture; (4) granulating the mixture, drying it, adding magnesium stearate to the granules, mixing them evenly, and tableting them to obtain dydrogesterone tablets.

8. Use of the dydrogesterone tablets according to any one of claims 1 to 6 in the preparation of a medicament for treating threatened abortion, habitual abortion and menstrual disorders.

Images