CHIDAMIDE PHARMACEUTICAL COMPOSITION, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF

Abstract

A chidamide pharmaceutical composition, a preparation method therefor and an application thereof. The pharmaceutical composition comprises chidamide and a pharmaceutically acceptable enteric excipient that severe as a carrier. In the pharmaceutical composition, chidamide is used as a guest molecule, and the pharmaceutically acceptable enteric excipient is used as a carrier molecule. Oral pharmacokinetic testing on animal proves that the bioavailability of the composition comprising chidamide and the pharmaceutically acceptable enteric excipient is greatly improved, while adverse reactions caused by the drug in the gastrointestinal tract are reduced; in addition, the dosage may be reduced while maintaining the curative effect, thus having more important clinical significance than commercially available chidamide tablets.

Claims

1. A chidamide pharmaceutical composition, comprising chidamide and a pharmaceutically acceptable enteric excipient as a carrier.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable enteric excipient is selected from one or more than two of hypromellose acetate succinate, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hypromellose phthalate and acrylic resin.

3. The pharmaceutical composition according to claim 1, wherein the mass ratio of chidamide to the pharmaceutically acceptable enteric excipient ranges from 1:1 to 1:100.

4. A chidamide preparation, comprising the chidamide pharmaceutical composition according to claim 1.

5. The preparation according to claim 4, which is a tablet, capsule, pill, oral liquid preparation, granule, powder, plaster or dropping pill.

6. A method of preparing a chidamide preparation, comprising a step of using the pharmaceutical composition according to claim 1.

7. (canceled)

8. (canceled)

9. A method for preparing the pharmaceutical composition according to claim 1, comprising a step of preparing the pharmaceutical composition with chidamide and the pharmaceutically acceptable enteric excipient by a solvent evaporation method or hot melt extrusion method.

10. The method according to claim 9, wherein the solvent used in the solvent volatilization method is selected from a pharmaceutically acceptable alcohol, acetone, tetrahydrofuran or any combination thereof.

11. The method according to claim 10, wherein the alcohol is selected from at least one or two of methanol, ethanol, isopropanol, butanol, tert-butanol and propanol.

12. A method of treating a disease associated with the action mechanism of histone deacetylase, comprising a step of administering to a subject in need thereof an effective amount of the chidamide pharmaceutical composition according to claim 1.

13. The method according to claim 12, wherein the disease associated with the action mechanism of histone deacetylase is selected from cancer, viral disease, autoimmune disease and blood system disease.

14. A method of treating a disease associated with the action mechanism of histone deacetylase, comprising a step of administering to a subject in need thereof an effective amount of the chidamide preparation according to claim 4.

15. The method according to claim 14, wherein the disease associated with the action mechanism of histone deacetylase is selected from cancer, viral disease, autoimmune disease and blood system disease.

16. A method of inhibiting HDAC, comprising a step of administering to a subject in need thereof an effective amount of the chidamide pharmaceutical composition according to claim 1.

17. A method of inhibiting HDAC, comprising a step of administering to a subject in need thereof an effective amount of the chidamide preparation according to claim 4.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0103] FIG. 1 shows the results of the rat pharmacokinetic experiment of the chidamide pharmaceutical composition;

[0104] FIG. 2 shows the mean plasma concentration-time curves in dog plasma for commercially available chidamide tablet, Example 4 chidamide tablet, Example 6 chidamide capsule, and Example 8 chidamide capsule.

SPECIFIC MODES FOR CARRYING OUT THE INVENTION

[0105] The present invention discloses a chidamide pharmaceutical composition and a preparation method and application thereof, which can be achieved by those skilled in the art by learning from the content described herein and appropriately improving process parameters. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention. The pharmaceutical composition of the present invention and its preparation method and application have been described through the preferred examples, and relevant persons can obviously realize and apply the technology of the present invention by changing or making appropriate modification and combination of the pharmaceutical composition and its preparation method described herein without departing from the content, spirit and scope of the present invention.

[0106] The chidamide pharmaceutical composition, its preparation method and application provided by the present invention are further elucidated below.

Example 1: Chidamide Solid Dispersion Preparation as Control

[0107] Chidamide solid dispersion was prepared by taking polyvinylpyrrolidone K30 as a carrier, wherein the ratio of chidamide to polyvinylpyrrolidone K30 was 1:5, and the preparation method of chidamide solid dispersion was as follows:

[0108] prescription:

[0109] chidamide 2 g

[0110] polyvinylpyrrolidone K30 10 g

[0111] ethanol an appropriate amount

[0112] the preparation method was as follows:

[0113] (1) chidamide and polyvinylpyrrolidone K30 were accurately weighed, dissolved in an appropriate amount of ethanol in a 90° C. water bath to form a transparent solution;

[0114] (2) the solution formed in step (1) was rotary-evaporated at 90° C. and dried to form a solid dispersion;

[0115] (3) the solid dispersion obtained in step (2) was taken out and pulverized to prepare a chidamide solid dispersion powder.

Example 2: Chidamide Pharmaceutical Composition of the Present Invention

[0116] Chidamide pharmaceutical composition was prepared by using hypromellose acetate succinate as a carrier, wherein the ratio of chidamide to hypromellose acetate succinate was 1:3, and the preparation method of the chidamide pharmaceutical composition was as follows:

[0117] prescription:

[0118] chidamide 2 g

[0119] hypromellose acetate succinate 6 g

[0120] ethanol an appropriate amount

[0121] the preparation method was as follows:

[0122] (1) chidamide and hypromellose acetate succinate were accurately weighed, dissolved in an appropriate amount of ethanol in a 90° C. water bath to form a transparent solution;

[0123] (2) the solution formed in step (1) was rotary-evaporated at 90° C. and dried to form a solid dispersion;

[0124] (3) the solid dispersion obtained in step (2) was taken out and pulverized to prepare a chidamide pharmaceutical composition powder.

Example 3: Rat Pharmacokinetic Experiment

[0125] 12 healthy rats were selected and randomly divided into 2 groups, 6 rats in each group (3 females and 3 males), namely Chidamide solid dispersion group, Chidamide-Hypromellose acetate succinate (1:3) group. During the experiment, the rats were fasted overnight before administration, and blood was collected from the orbit before administration, and the plasma was separated, which was taken as the plasma concentration sample at 0 h. Chidamide solid dispersion prepared in Example 1 and Chidamide-Hypromellose acetate succinate (1:3) prepared in Example 2 were dispersed with purified water respectively to give gavage solution , the concentration of Chidamide in each gavage solution was 2 mg/ml, and each rat was administered with chidamide 20 mg/kg respectively. After administration, blood samples were collected at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h, and each sample collected was about 0.5 ml; the samples were anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma which was then stored at −80° C. for later testing. The drug concentration in plasma was measured by LC-MS/MS. The test results were shown in Table 1 and FIG. 1.

TABLE-US-00001 TABLE 1 Comparison of pharmacokinetic data in rats Parameter (ng/ml) Example 1 Example 2 AUC(0-t) 2271.4 3716.4 Cmax 836.1 2059.9

[0126] According to the test results in Table 1 and FIG. 1, compared with the chidamide solid dispersion tablet, the chidamide pharmaceutical composition comprising hypromellose acetate succinate showed a significantly improved bioavailability of chidamide.

Example 4: Tablet Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0127] Chidamide pharmaceutical composition was prepared by using hypromellose phthalate as a carrier, wherein the ratio of chidamide to hypromellose phthalate was 1:5, and the chidamide tablet preparation and the preparation method thereof were as follows:

[0128] prescription:

[0129] chidamide 5 g

[0130] hypromellose phthalate 25 g

[0131] mannitol 40 g

[0132] microcrystalline cellulose 51 g

[0133] sodium carboxymethyl starch 5 g

[0134] polyvinylpyrrolidone 3 g

[0135] magnesium stearate 1 g

[0136] ethanol an appropriate amount

[0137] water an appropriate amount

[0138] made into 1000 tablets (pills)

[0139] preparation method:

[0140] (1) chidamide and hypromellose phthalate were accurately weighed and dissolved in ethanol to form a transparent solution;

[0141] (2) the solution obtained in step (1) was spray-dried to obtain a chidamide-hypromellose phthalate composition;

[0142] (3) the composition obtained in step (2) was uniformly mixed with mannitol, microcrystalline cellulose, sodium carboxymethyl starch, and polyvinylpyrrolidone, added with water and subjected to wet granulation to obtain a soft material;

[0143] (4) the soft material obtained in step (3) was dried to obtain dry particles;

[0144] (5) the dry particles obtained in step (4) were added with magnesium stearate to perform total mixing;

[0145] (6) the material of total mixing obtained in step (5) was subjected to tableting to obtain the tablet preparation.

Example 5: Granule Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0146] Chidamide pharmaceutical composition was prepared by using polyvinyl alcohol phthalate as a carrier, wherein the ratio of chidamide to polyvinyl alcohol phthalate was 1:50, and the chidamide granule preparation and the preparation method thereof were as follows:

[0147] prescription:

[0148] chidamide 5 g

[0149] polyvinyl alcohol phthalate 250 g

[0150] lactose 200 g

[0151] hydroxypropyl cellulose 10 g

[0152] Low-substituted hydroxypropyl cellulose sodium 5 g

[0153] silica 2 g

[0154] tetrahydrofuran/ethanol (1:1) an appropriate amount

[0155] water an appropriate amount

[0156] made into 1000 tablets (pills)

[0157] preparation method:

[0158] (1) chidamide and polyvinyl alcohol phthalate were accurately weighed and dissolved in tetrahydrofuran/ethanol (1:1) to form a solution;

[0159] (2) the solution obtained in step (1) was spray-dried to obtain a chidamide-polyvinyl alcohol phthalate composition;

[0160] (3) the composition obtained in step (2) was uniformly mixed with lactose, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose sodium, added with water to obtain a soft material, and subjected to a shaking method to obtain particles;

[0161] (4) the particles obtained in step (3) were dried to obtain dry particles;

[0162] (5) the dry particles obtained in step (4) were added with silica, and mixed uniformly;

[0163] (6) the mixture obtained in step (5) was bagged to obtain the granule preparation.

Example 6: Capsule Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0164] Chidamide pharmaceutical composition was prepared by using acrylic resin L100-55 as a carrier, wherein the ratio of chidamide to acrylic resin L100-55 was 1:3, and the chidamide capsule preparation and the preparation method thereof were as follows:

[0165] prescription:

[0166] chidamide 5 g

[0167] acrylic resin L100-55 15 g

[0168] mannitol 20 g

[0169] microcrystalline cellulose 35 g

[0170] croscarmellose sodium 2 g

[0171] hypromellose 2 g

[0172] magnesium stearate 1 g

[0173] acetone an appropriate amount

[0174] water an appropriate amount

[0175] made into 1000 tablets (pills)

[0176] preparation method:

[0177] (1) chidamide and acrylic resin L100-55 were accurately weighed, and dissolved in acetone to form a transparent solution;

[0178] (2) the solution obtained in step (1) was subjected to vacuum rotary-evaporation to obtain a chidamide-acrylic resin L100-55 composition;

[0179] (3) the composition obtained in step (2) was mixed with mannitol, microcrystalline cellulose, croscarmellose sodium, and hypromellose uniformly, added with water to obtain a soft material, and subjected to a shaking method to obtain particles;

[0180] (4) the particles obtained in step (3) were dried to obtain dry particles;

[0181] (5) the dry particles obtained in step (4) were added with magnesium stearate, and subjected to total mixing;

[0182] (6) the material of the total mixing obtained in step (5) was filled into capsules to obtain the capsule preparation.

Example 7: Dry Suspension Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0183] Chidamide pharmaceutical composition was prepared by using cellulose acetate phthalate as a carrier, wherein the ratio of chidamide to cellulose acetate phthalate was 1:100, and the chidamide dry suspension preparation and the preparation method thereof were as follows:

[0184] prescription:

[0185] chidamide 5 g

[0186] cellulose acetate phthalate 500 g

[0187] mannitol 500 g

[0188] sodium carboxymethyl cellulose 5 g

[0189] xanthan gum 5 g

[0190] silica 5 g

[0191] acetone an appropriate amount

[0192] water an appropriate amount

[0193] made into 1000 tablets (pills)

[0194] preparation method:

[0195] (1) chidamide and cellulose acetate phthalate were accurately weighed and dissolved in ethanol to form a transparent solution;

[0196] (2) the solution obtained in step (1) was spray-dried to obtain a chidamide-cellulose acetate phthalate composition;

[0197] (3) under stirring conditions, sodium carboxymethyl cellulose was added into purified water, and continuously stirred until completely dissolved;

[0198] (4) the composition obtained in step (2) was mixed uniformly with mannitol, then added into the sodium carboxymethyl cellulose solution obtained in step (3), and subjected to wet granulation;

[0199] (5) the particles obtained in step (4) were dried to obtain dry particles;

[0200] (6) the dry particles obtained in step (5) were added with xanthan gum and silica, and mixed for breaking;

[0201] (7) the dry suspension powder obtained in step (6) was subjected to subpackaging.

Example 8: Capsule Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0202] The chidamide pharmaceutical composition was prepared by using hypromellose acetate succinate as a carrier, wherein the ratio of chidamide to hypromellose acetate succinate was 1:8, and the chidamide capsule preparation and the preparation method thereof were as follows:

[0203] prescription:

[0204] chidamide 5 g

[0205] hypromellose acetate succinate 40 g

[0206] microcrystalline cellulose blank pellets 100 g

[0207] made into 1000 tablets (pills)

[0208] preparation method:

[0209] (1) chidamide and hypromellose acetate succinate were accurately weighed, and dissolved in ethanol to form a transparent solution;

[0210] (2) the solution obtained in step (1) was loaded on the microcrystalline cellulose blank pellets by using a fluidized bed to obtain chidamide-containing pellets;

[0211] (3) the pellets obtained in step (2) were filled into capsules to obtain the capsule preparation.

Example 9: Tablet Preparation Comprising the Chidamide Pharmaceutical Composition of the Present Invention

[0212] Chidamide pharmaceutical composition was prepared by using cellulose acetate trimellitate as a carrier, wherein the ratio of chidamide to cellulose acetate trimellitate was 1:10, and the chidamide tablet preparation and the preparation method thereof were as follows:

[0213] prescription:

[0214] chidamide 5 g

[0215] cellulose acetate trimellitate 50 g

[0216] calcium hydrogen phosphate 15 g

[0217] corn starch 40 g

[0218] crospovidone 5 g

[0219] hydroxyethyl cellulose 3 g

[0220] sodium stearyl fumarate 1 g

[0221] Eudragit L100-55 4.5 g

[0222] triethyl citrate 0.45 g

[0223] talc powder 1.1 g

[0224] ethanol an appropriate amount

[0225] water an appropriate amount

[0226] made into 1000 tablets (pills)

[0227] preparation method:

[0228] (1) chidamide and cellulose acetate trimellitate were accurately weighed, and mixed evenly;

[0229] (2) the mixture obtained in step (1) was subjected to hot-melt extrusion to prepare a chidamide-cellulose acetate trimellitate composition;

[0230] (3) the composition obtained in step (2) was uniformly mixed with calcium hydrogen phosphate, corn starch, crospovidone, and hydroxyethyl cellulose, and added with water to carry out wet granulation to obtain a soft material;

[0231] (4) the soft material obtained in step (3) was dried to obtain dry particles;

[0232] (5) the dry particles obtained in step (4) were added with sodium stearyl fumarate, and subjected to total mixing;

[0233] (6) the material of the total mixing obtained in step (5) was subjected to tabletting to obtain a tablet preparation;

[0234] (7) Eudragit L100-55, triethyl citrate and talc powder were added into an appropriate amount of ethanol, and stirred well to prepare an enteric coating solution;

[0235] (8) the tablet preparation obtained in step (6) was coated by the enteric coating solution obtained in step (7) to obtain chidamide enteric-coated tablets.

Example 10: Pharmacokinetic Study in Beagle Dogs

[0236] Twelve healthy beagle dogs were selected and randomly divided into four groups, three dogs in each group, namely Commercially available chidamide tablet group, Example 4 chidamide tablet group, Example 6 chidamide capsule group and Example 8 chidamide capsule group. During the experiment, beagle dogs were fasted overnight before administration, and venous blood was collected before administration, and plasma was separated as the plasma concentration sample at Oh. Each dog was administered with chidamide 20 mg (4 pills, 5 mg/pill). After administration, blood samples were collected at 15 min, 0.5 h, 1 h, 2 h, 4 h, and 8 h respectively, each sample collected was about 0.5 ml, the samples were anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma which was then measured by LC-MS/MS to determine drug concentration in plasma. The test results were shown in Table 2 and FIG. 2.

TABLE-US-00002 TABLE 2 LC-MS/MS determination of drug concentrations (ng/ml) in dog plasma for each group at different time points Commercially Example 4 Example 6 Example 8 Time (h) available tablet tablet capsule capsule 0.25 110.291 754.028 555.006 655.453 0.50 222.878 953.046 1021.364 1036.435 1.00 416.646 1461.740 1236.307 1332.347 2.00 213.347 1049.735 891.904 966.674 4.00 50.908 298.286 336.756 327.331 8.00 19.411 95.123 71.706 74.923

[0237] According to the test results in Table 2 and FIG. 2, compared with the commercially available chidamide solid dispersion tablet (registered trademark: Epidaza), after chidamide and the pharmaceutically acceptable excipient of the present invention formed a composition, the bioavailability of chidamide in vivo was effectively improved.

[0238] The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should be regarded as falling within the scope of the present invention.