GB2595140A - Flupentixol/melitracen pharmaceutical composition and preparation thereof - Google Patents

Abstract

A flupentixol/melitracen pharmaceutical composition and a preparation thereof, in the technical field of pharmaceutical preparations. The flupentixol/melitracen pharmaceutical composition includes flupentixol dihydrochloride, melitracen hydrochloride and an antioxidant. By means of adding an antioxidant, it is possible to effectively strengthen stability of the flupentixol/melitracen compound preparation, and it is possible to effectively control contaminants such as Lu28-159 and trifluoromethylthioxanthenone produced by flupentixol degradation, decreasing contaminant levels and ensuring safety and efficacy of the product; compared with the original tablet Deanxit, the present invention has similar in vitro dissolution behavior and bioequivalence.

Description

FLUPENTIXOL (FPL)-MELITRACEN PHARMACEUTICAL COMPOSITION AND

PHARAMACEUTICAL PREPARATION THEREOF

TECHNICAL FIELD

[0001] The present disclosure relates to a flupentixol (FPL)-melitracen pharmaceutical composition and a pharmaceutical preparation thereof, and belongs to the technical field of pharmaceutical preparations.

BACKGROUND

100021 Generally, the stability of a pharmaceutical composition is a very important factor considered during the design, production, and storage of the pharmaceutical composition. A drug with poor stability may degrade into degradation products that cause unnecessary side reactions or reduces the efficacy or bioavailability of the drug itself, and thus makes it difficult to achieve a satisfactory result.

100031 FPL dihydrochloride is a hydrochloride form of the atypical antipsychotic drug FPL and is a thioxanthene derivative. It has a powerful dopamine receptor-blocking effect and exhibits anti-anxiety and anti-depressant effects at a small dosage. FPL dihydrocMoride has a chemical name of 2-14-13(EZ)-(2-trifluoromethylthioxanthen-9-ylidene)propyl] piperazin-l-yllethanol dihydrochloride, and a structural formula as follows:

H

[00041. 2HCI 100051 Melitracen hydrochloride is a tricyclic anti-bipolar disorder drug, and exhibits an excitative effect when used at a low dosage. Melitracen hydrochloride has a chemical name of 3-1 I 0,10-di methy1-9( I 0H)-anthracenyl idenel-N,N-di methyl-I -p ropylam ine hydrochloride, and a structural formula as follows: H3C NcH

HCI

100061 H3C CH3 [0007] FPL was marketed in 1966, and its pharmaceutical preparations include FPL tablets (0.5 mg and 5 mg) and FPL injections (1 mL: 20 mg). Melitracen was marketed in 1968, and its pharmaceutical preparation is in the form of a capsule. A compound preparation of FPL and melitracen has anti-depressant, anti-anxiety, and excitative effects. An FPL-melitracen tablet developed and marketed by Lundbeck Phanceutical Co., Ltd. in Denmark is traded as Deanxit, and each FPL-melitracen tablet includes 0.584 mg of FPL dihydrochloride (0.5 mg based on FPL) and 11.25 mg of melitracen hydrochloride (10 mg based on melitracen). Deanxit shows definite therapeutic effects on mild and moderate depression, anxiety, neurasthenia, psychogenic depression, and depressive psychoneurosis, with quick onset and small adverse reactions. Deanxit is one of the most-widely-used antidepressants in China.

100081 The FPL-melitracen compound preparation and a preparation method thereof have been disclosed in many documents.

[0009] Chinese Patent CN I 019 I 2397A discloses an FPL-melitracen tablet including adjuvants such as cyclodextrin, hydrogenated vegetable oil, lactose, starch, hydroxypropyl cellulose (HPC), and microcrystalline cellulose (MCC). In an example of the patent, an FPL premix is mixed with 13-cyclodextrin, lactose monohydrate, corn starch, and HPC, then purified water is added, and a resulting mixture is subjected to wet granulation to obtain FPL granules; melitracen, corn starch, lactose monohydmte, and HPC are mixed, then purified water is added, and a resulting mixture is subjected to wet granulation to obtain melitracen granules; the FPL granules are combined with the melitracen granules, resulting mixed granules are mixed with MCC, cross-linked sodium carboxymethyl cellulose (CMC), talcum powder, 11PC, hydrogenated vegetable oil, and magnesium stearate, and a resulting mixture is pressed into a tablet. This process uses [3-cyclodextrin as a stabilizer at a high dosage, so obtained tablets are easy to absorb moisture.

[0010] Chinese Patent CN I 05663062A discloses an FPL-melitracen tablet and a preparation method thereof In the preparation method, under opposed jet crushing, melitracen is evenly added to FPL in 2 to 5 batches for thorough mixing, a binder solution is added, and a resulting mixture is subjected to granulation; and the resulting granules are dried, screened, and then thoroughly mixed with a disintcgrant and a lubricant, and then pressed into a tablet. In this process, melitracen is added to FPL under opposed jet crushing. However, opposed jet crushing is an energy intensive process and gives an unstable yield. As a result, it is difficult to control and reproduce the process. Moreover, as FPL dihydrochloride and melitracen hydrochloride are highly irritant, dust during the production process will lead to low operation feasibility.

[0011] Chinese Patent CN104288153A discloses an FPL-melitracen tablet and a preparation method thereof In the preparation method, fine-grained FPL (with a particle size distribution D90 of less than 150 (un), melitracen, a filler, a disintegrant, a binder, and a lubricant are mixed, and a resulting mixture is directly tableted to obtain the FPL-melitracen tablet. The production process in this patent is simple, but the stability of the product during preparation and storage cannot be guaranteed as there is no stabilizer.

100121 Prescription ingredients are not selected based on the stability characteristics of FPL and melitracen in the prior art. According to a forced degradation test, FPL is very sensitive to oxidation and light and can mainly be degraded into Lu28-159 and trifluoromethyl thioxanthone, and melitracen will also be degraded under alkaline and oxidative conditions and can mainly be degraded into 10. I 0-dimethylthioxanthone The main degradation pathway and degradation product of FPL are as follows: Trifluoromethvl thioxanthone 10013] [0014] Therefore, for the compound preparation of FPL and melitracen, it is urgent to develop a preparation method of an FPL-melitracen composition that can ensure stable product quality and simple and feasible preparation

SUMMARY

[0015] The present disclosure is intended to overcome the above-mentioned shortcomings of the prior art and provide an FPL-melitracen pharmaceutical composition and a pharmaceutical preparation thereof The preparation including the pharmaceutical composition has excellent dissolution characteristics and stability and low related substance contents, which can better ensure the safety and effectiveness of the product.

100161 In order to achieve the above objective, the present disclosure adopts the following technical solutions: An FPL-melitracen pharmaceutical composition is provided, including FPL dihydrochloride, melitracen hydrochloride, and an antioxidant.

FPL dihydrochloride [0011 As a preferred implementation of the pharmaceutical composition according to the present disclosure, in the pharmaceutical composition, the FPL dihydrochloride may have a mass percentage of 0.3% to 1.0%, the melitracen hydrochloride may have a mass percentage of 5.78% to 19.26%, and the antioxidant may have a mass percentage of 0.01% to 10%.

[0018] As a preferred implementation of the pharmaceutical composition according to the present disclosure, the FPL dihydrochloride may have a mass percentage of 0.4% to 0.8%, the melitracen hydrochloride may have a mass percentage of 7.71% to 15.41%, and the antioxidant may have a mass percentage of 0.02% to 5%.

[0019] As a preferred implementation of the pharmaceutical composition according to the present disclosure, the antioxidant may be at least one from the group consisting of butylatcd hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium thiosulfate, L-cysteine, vitamin C or a sodium salt thereof, vitamin C palm 'tate, vitamin E. and a water-soluble organic weak acid.

[0020] As a preferred implementation of the pharmaceutical composition according to the present disclosure, the antioxidant may be at least one from the group consisting of BHA, BHT, PG, vitamin C, vitamin C palmitate, and the water-soluble organic weak acid.

[0021] As a preferred implementation of the pharmaceutical composition according to the present disclosure, the antioxidant may be at least one from the group consisting of BHA, BHT, and PG. 100221 As a preferred implementation of the pharmaceutical composition according to the present disclosure, the antioxidant may be BHT.

[0023] As a preferred implementation of the pharmaceutical composition according to the present disclosure, the pharmaceutical composition may further include a pharmaceutically acceptable adjuvant, and the pharmaceutically acceptable adjuvant may be at least one from the group consisting of a filler, a disintegrant, a binder, and a lubricant.

100241 The present disclosure also provides a pharmaceutical preparation, and raw materials for preparing the pharmaceutical preparation include the pharmaceutical composition described above. [0025] As a preferred implementation of the pharmaceutical preparation according to the present disclosure, the pharmaceutical preparation may be in a dosage form of a tablet, granules, a capsule, or an injection.

[0026] Compared with the prior art, the present disclosure has the following beneficial effects: In the FPL-melitracen pharmaceutical composition according to the present disclosure, the antioxidant is added: as a result, the stability of the compound preparation of FPL and melitmcen can be effectively enhanced, and the impurity level can be lowered by effectively controlling the production of Lu28-159, trifluoromethyl thioxanthone, and other impurities from the degradation of FPL. Thus, the safety and effectiveness of the product can be guaranteed An FPL-melitracen tablet prepared according to the present disclosure has similar in vitro dissolution and bioequivalence to the original tablet Deanxit.

DETAILED DESCRIPTION

[0027] In order to well illustrate the objectives, technical solutions, and advantages of the present disclosure, the present disclosure will be further described below in conjunction with specific examples.

[0028] Example 1

100291 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.48%, 9.30%, and 0.08%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

[0030] A preparation method of the tablet in this example included: 100311 (1) Preparation of FPL granules 100321 FPL dihydrochloride and BHT were added to an 80% ethanol-water solution, and a resulting mixture was stirred until clear; anhydrous lactose, MCC, and HPC were added to a high-speed stirring granulator, then the 80% ethanol-water solution with FPL dihydrochloride and BHT was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

[0033] (2) Preparation of melitracen granules 100341 Mehtracen hydrochloride, anhydrous lactose, MCC, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules.

100351 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

100361 Table 1

Component Example Example Example 3 Example _ Example Example Exampl c 8

1 2 4 Example) 6 7

FPL FPL Mass 0.584 0.584 0.584 0.584 0.584 0.584 0.584 0.584 granule dihvdrochl (mg/tab s oride let) antioxidant substan BHT PG BHA BHT and vita min BHT and BHT vitamin vitamin cc C PG C C paimitat e mass 0.1 1.0 0.8 0.05 and 0.05 and 0A 0.006 22.5 tine/lab 10 0.7 let) filler substan a nhydro us a nhydro calcium hydrogen phospha le and MEG Lactose lactose and slarch anhydro us lactose anhydro ce lactose and MCC us lactose and MCC lactose and MEG and us and starch MCC lactose and

MCC

mass 30 aM 3028 and 25 and 33 15 and 33 30 and 28 20 and 8.1 and 25 and (mg/tab 28 40 16.2 75 let) binder substan HPC 1-WE hydroxypro povidone HPC I-1PC cc PY1 100 incthylcell ulose (11PMC) mass 1.8 1.8 1.8 3 1.8 1.35 King/tab let) lubricant substan magnesi magnesi CC UM 11111 stcaratc stearate mass 0.48 7.7 (mg/tab let) Melina mclitracen mass 11.25 11.25 11.25 11.25 11.25 11.25 11.25 11.25 unit hydrochlori (mg/tab granule de let) s filler substan a nhydro a nhydro calcium hydrogen phosphate and MCC lactose lactose and starch lactose lactose anhydro cc us us and MEG and and us laclose lactose MEG MEG lactose and and and MEG starch MEG mass 7 and 21 7 and 21 7 and 21 7 and 71 7 and 21 10 and Sand 16.48 (ingnab 20 11.2 and let) 49.44 binder substan HPC HPC 14PMC povidone K30 HPC HPC

CC

mass 1.7 1.7 1.2 2.4 1.7 1.01 (mg/lab let) lubricant substan rnagnesi magnesi cc UM um stearate stearate mass 0.32 2.03 (mg/tab let) Additio disintegran substan cross-lin cross-lin cross-hake crospovid one low-substil cross-lin cross-lin CMC nal t cc kcd ked d sodium uted had had adjuvan sodium sodium CMC hydroxypr sodium sodium t CMC CMC opyl CMC CMC cellulose (L-HPC) mass 1.8 2.4 2.4 3.6 3.6 3.6 0.28 13.5 King/tab let) filler ller substan MEG MEG MEG MEG MEG

CC

mass 14 14 14 12 14 King/tab let) binder substan IIPC I1PC IIPMC UPC I1PC IIPC I1PC ce mass 3 2.4 2.4 3 3.6 1.02 4.5 (ing/tab Id) lubricant substan magnesi stearic glyceryl nu-iglu:sill In mannesiu magnesi um magnesi um magmsi um ce IFM acid behenaie m slearate stearate stearate stearate stearate stearate mass 1.2 1.8 1.8 1.0 1.2 0.8 0.28 2.02 (mg/tab let)

[0037] Example 2

[0038] An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.48%, 9.19%, and 0.82%, respectively Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

[0039] A preparation method of the tablet in this example included: 100401 ( I) Preparation of FPL granules 100411 FPL dihydrochloride and PG were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; anhydrous lactose, starch, and HPC were added to a high-speed stirring granulator, then the 75% ethanol-water solution with FPL dihydrochloride and PG was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

100421 (2) Preparation of melitracen granules 100431 Melitracen hydrochloride, anhydrous lactose, starch, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules.

100441 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

100451 Example 3

[0046] An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.48%, 9.20%, and 0.65%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

100471 A preparation method of the tablet in this example included: 100481 (1) Preparation of FPL granules 100491 FPL dihydrochloride and BHA were added to a 75% ethanol-water solution and a resulting mixture was stirred until clear; calcium hydrogen phosphate. MCC, and HPMC were added to a high-speed stirring granulator, then the 75% ethanol-water solution with FPL dihydrochloride and BHA was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

100501 (2) Preparation of melitracen granules 100511 Mclitracen hydrochloride, calcium hydrogen phosphate, MCC, and HPMC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules.

[0052] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

[0053] Example 4

100541 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.49%, 9.38%, and 8.38%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

[0055] A preparation method of the tablet in this example included: 100561 (1) Preparation of FPL granules 100571 FPL dihydrochloride, BHT, vitamin C, and povidone K30 were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; lactose and MCC were added to a fluidized granulator, then the 75% ethanol-water solution with FPL dihydrochloride, BHT, vitamin C, and povidone K30 was added, and fluidized granulation was conducted; and a resulting product was dried and screened to obtain FPL granules.

[0058] (2) Preparation of melitracen granules 100591 Melitracen hydrochloride, lactose, and MCC were added to a fluidized granulator, then a povidone K30 aqueous solution was sprayed, and fluidized granulation was conducted; and a resulting product was dried and screened to obtain melitracen granules.

100601 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

[0061] Example 5

100621 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.47%, 9.12%, and 0.61%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

100631 A preparation method of the tablet in this example included: 100641 (1) Preparation of FPL granules 100651 BHT and PG were added to an 80% ethanol-water solution, and a resulting mixture was stirred until clear; FPL dihydrochloride and lactose were thoroughly mixed in an equal incremental manner, then mixed with starch and HPC, and added to a high-speed stirring granulator, then the 80% ethanol-water solution with BHT and PG was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

[0066] (2) Preparation of melitracen granules 100671 Melitracen hydrochloride, lactose, starch, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

100681 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

[0069] Example 6

100701 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.53%, 10.16%, and 0.09%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

100711 A preparation method of the tablet in this example included: 100721 (1) Preparation of FPL granules [0073] FPL dihydrochloride and BHT were thoroughly mixed with lactose in an equal incremental manner, and then thoroughly mixed with lactose. MCC, and magnesium stearate, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain FPL granules.

100741 (2) Preparation of melitracen granules 100751 Melitracen hydrochloride, lactose. MCC, and magnesium stearate were thoroughly mixed, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain melitracen granules.

100761 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

[0077] Example 7

100781 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition, FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of I.04%, I 9.99%, and 0.01%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

[0079] A preparation method of the tablet in this example included: 100801 ( I) Preparation of FPL granules [0081] FPL dihydrochloride and vitamin C palmitate were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; lactose. MCC, and HPC were added to a high-speed stirring granulator, then the 75% ethanol-water solution with FPL dihydrochloride and vitamin C palmitate was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

100821 (2) Preparation of melitracen granules 100831 Melitracen hydrochloride, lactose, MCC, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules. [0084] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

[0085] Example 8

[0086] An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition, FPL dihydrochloride, melitracen hydrochloride, and an antioxidant had mass percentages of 0.26%, 5%, and 10%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 1.

100871 A preparation method of the tablet in this example included: [0088] ( I) Preparation of FPL granules 100891 FPL dihydrochloride was thoroughly mixed with anhydrous lactose in an equal incremental manner, and then thoroughly mixed with anhydrous lactose, vitamin C, MCC, and magnesium stearate, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain FPL granules.

[0090] (2) Preparation of melitracen granules 100911 Melitracen hydrochloride, anhydrous lactose, MCC, and magnesium stearate were thoroughly mixed, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain melitracen granules.

[0092] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

100931 Comparative Example 1 100941 An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride and melitracen hydrochloride had mass percentages of 0.49% and 9.31%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 2.

[0095] A preparation method of the tablet in this comparative exampleincluded: [0096] (1) Preparation of FPL granules 100971 FPL dihydrochloride was added to an 80% ethanol-water solution and a resulting mixture was stirred until clear; anhydrous lactose. MCC, and HPC were added to a high-speed stirring granulator, then the drug solution was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules. [0098] (2) Preparation of melitracen granules 100991 Mclitracen hydrochloride, anhydrous lactose. MCC, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

1001001(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen pharmaceutical tablet.

100101] Comparative Example 2 [00102] An FPL-melitracen pharmaceutical composition was provided, and in the pharmaceutical composition. FPL dihydrochloride and melitracen hydrochloride had mass percentages of 0.53% arid 10.17%, respectively. Components in a tablet prepared from the pharmaceutical composition had contents shown in Table 2.

1001031A preparation method of the tablet in this comparative example included: 1001041(1) Preparation of FPL granules 100105]FPL dihydrochloride was thoroughly mixed with lactose in an equal incremental manner, and then thoroughly mixed with lactose, MCC, and magnesium stearate, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain FPL granules.

1001061(2) Preparation of melitracen granules [00107] Melitracen hydrochloride, lactose, and MCC were thoroughly mixed, and a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain melitracen granules.

1001081(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-mehtracen pharmaceutical tablet.

001091 Table 2

Component Comparative Example I Comparative Example 2 FPL granules FPL mass 0.584 0.584 dihydrouldoride (mg/tablet) filler substance anhydrous I aclose and MCC lactose and MCC mass 30 and 2R 20 and 40

(mg/tablet)

binder substance HPC mass 1.8

(mg/tablet)

lubricant substance magnesium slearale mass 0.48

(mg/tablet)

Mefitracen granules mehtracen mass 11.25 11.25 hydrochloride (mg/tablet) filler substance anhydrous lactose Tmd MCC lactose and MCC mass 7 arid 21 10 and 20

(mg/tablet)

binder substance HPC mass 1.2

(mg/tablet)

lubricant substance magnesium stearate mass 0.32

(me/tablet)

disintegrant substance cross-linked sodium CMC cross-linked sodium CMC mass 1.8 3.6

(mg/tablet)

filler substance MCC mass (/tabl et) mg 14 Additional adjuvant substance UPC UPC binder mass 3.6

(mg/tablet)

lubricant substa nce magnesium stea rate magnesium stea rate mass 1.2 0.8

(mg/tablet)

1001101Effect Example 1 1001111Dissolution test for Examples 1 to 8 and Comparative Examples 1 to 2 of thc present disclosure 1001121According to the dissolution rate determination method (the second method in the fourth general rule 0931 of the Chinese Pharmacopoeia, 2015 edition), dissolution rates of Examples 1 to 8 and Comparative Examples 1 to 2 were determined. 900 mL of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium to dissolve a sample, the resulting solution was stirred at a rotational speed of 75 rpm for 30 min and then filtered, and a subsequent filtrate was collected as a test solution. The test solution was subjected to high-performance liquid chromatography (HPLC) (the fourth general rule 0512 of the Chinese Pharmacopoeia,. 2015 edition) under the following chromatographic conditions: packing material: phenylsilane-bonded silica gel (suitable for XBridge TM Phenyl 3.5 um, 4.6 mm x 100 mm chromatographic column); mobile phase: 0.02 molt ammonium acetate buffer-methanol (35:65); detection wavelength: 270 nm; flow rate: 1.0 mUmin; and column temperature: 40°C. The theoretical plate number calculated based on melitracen peak should be not less than 1 400, and the separation between melitracen peak and FPL peak should be greater than 2.0. in addition, an appropriate amount of each of FPL dihydrochloride and melitracen hydrochloride reference substances was accurately weighed and dissolved with methanol, and an appropriate amount of each of two resulting reference substance solutions was accurately measured and added into the same volumetric flask; and a resulting mixed solution was diluted with a dissolution medium and thoroughly shaken to obtain a reference substance solution with an FPL concentration of about 0.5 p.g/mL and a melitracen concentration of about 10 figimL (a conversion factor between melitracen and melitracen hydrochloride was 0.8887, and a conversion factor between FPL and FPL dihydrochloride was 0.8562). 10 ML of each of the test solutions and the reference substance solution was accurately measured and injected into a liquid chromatograph, chromatograms were recorded, and peak areas were calculated according to the external standard method to determine the dissolution quantities of FPL and melitracen in each tablet. A limit was 80% of a labeled amount and should meet the requirements. Test results were shown in Table 3,

00113 Table 3

Sample Dissolution rate/% FPL melitracen

Example 1 97% 100%

Example 2 98% 101%

Example 3 99% 98%

Example 4 97% 98%

Example 5 101% 102""

Example 6 100% 98%

Example 7 98% 101%

Example 8 98% 100%

Comparative example I 97% 98% Comparative Example 2 102% 100% 100114]It can be seen from Table 3 that the two active ingredients in the tablet prepared from the FPL-melitracen pharmaceutical composition of the present disclosure had high dissolution rates, which both met the requirements.

100115] Effect Example 2 100116] Stability test for Examples 1 to 8 and Comparative Examples Ito 2 of the present disclosure 1001171Products of Examples Ito 8 and Comparative Examples Ito 2 of the present disclosure were placed under accelerated test conditions (40°C/75% RH) for 6 months, and changes in the content, dissolution rate, and related substances were investigated. Test results were shown in Table 4.

[00118] Content determination: 20 tablets of a sample were accurately weighed and ground into powder. An appropriate amount of the powder (including 20 mg of mclitracen and 1 mg of FPL) was taken, accurately weighed, and added into a 50 ml volumetric flask; 40 ml of a mobile phase was added to the volumetric flask. The sample was completely dispersed and wetted by shaking the volumetric flask., The volumetric flask was then placed in an ultrasound for 20 min, and naturally cooled to room temperature. The mobile phase was further added to the volumetric flask to dilute, until the graduation mark was reached. The volumetric flask was thoroughly shaken, and the content of the volumetric flask was filtered. A primary filtrate was discarded, and a subsequent filtrate was collected to obtain a test solution. About 29 mg of an FPL dihydrochloride reference substance (a conversion factor between FPL and FPL dihydrochloride was 0.8562) was taken, accurately weighed and added into a 50 ml volumetric flask. The FPL dihydrochloride reference substance was dissolved and diluted with methanol until the graduation mark was reached, and thus a reference substance stock solution with an FPL content of 0.5 rriginil was obtained. About 22.6 mg of a melitracen hydrochloride reference substance (a conversion factor between melitracen and melitracen hydrochloride was 0.8887) was taken, accurately weighed, and added into a 50 ml volumetric flask, 2 ml of the FPL dihydrochloride reference substance stock solution was accurately pipetted into the volumetric flask, and a mobile phase was added until the graduation mark was reached. The volumetric flask was thoroughly shaken to obtain a reference substance solution with an FPL concentration of 0.02 mg/ml and a melitracen concentration of 0.4 mg/ml. HPLC (the fourth general rule 0512 of the Chinese Pharmacopoeia, 2015 edition) was conducted under the following chromatographic conditions: packing material: phenylsilane-bonded silica gel (XBridge TM Phenyl 3.5 pm. 4.6 mm x 100 mm); mobile phase: 0.02 mol/L ammonium acetate buffer-methanol (35:65); detection wavelength: 270 lam; flow rate: 1.0 mLimin; and column temperature: 40°C. The theoretical plate number calculated based on the melitracen peak should be not less than 3,000, and the separation between the melitracen peak and the FPL peak should be greater than 4.0. 10 FiL of each of the test solutions and the reference substance solution was accurately measured and injected into the high-performance liquid chromatograph, and peak areas were calculated according to the external standard method to determine the contents of FPL and melitracen in each tablet.

100119] Dissolution test: The dissolution test method in Effect Example 1 was adopted.

100120] Related substance test: An appropriate amount of the sample powder obtained in the content determination (including 20 mg of melitracen and 1 mg of FPL) was taken, accurately weighed, and added into a 50 ml volumetric flask, 40 ml of a mobile phase was added, and a resulting mixture was shaken to make the sample completely dispersed and wetted, then subjected to ultrasonic treatment for 20 min, and naturally cooled to room temperature; and a resulting solution was diluted with the mobile phase to a specified volume, thoroughly shaken, and filtered, and a subsequent filtrate was collected to obtain a test solution. An appropriate amount of each of Lu28-159 hydrochloride, 10,10-dimethylanthrone, trifluoromethyl thioxanthone hydrochloride, melitracen, and FPL reference substances was taken, accurately weighed, and added into a volumetric flask; and then a mobile phase was added, and a resulting mixture was thoroughly shaken to obtain a reference substance solution with 0.4 ug/m1 of Lu28-159, 1.6 jig/m1 of 10,10-dimethylanthrone, 0.8 pg/inl of melitracen, 0.24 kg/m1 of trifluoromethyl thioxanthone, and 0.20 ug/m1 of FPL. 20 jiL of each of the reference substance solution and the test solutions was injected into the high-performance liquid chromatograph, and HPLC was conducted under the same chromatographic conditions as in the content determination. Peak areas were calculated according to the external standard method. Relative to a labeled amount of FPL, an Lu28-159 content should not exceed 2.5% and a trifluoromethyl thioxanthone content should not exceed 2.0%; relative to a labeled amount of melitracen, a 10,10-dimethylanthrone content should not exceed 0.5%; and relative to a labeled amount of melitracen, a single unknown impurity content should not exceed 0.2%, and a total impurity content should not exceed 4.0%.

1001211 It can be seen from Table 4 that, after the samples of the examples provided by the present disclosure were placed at 40°C/75%RH for 6 months, the contents, related substances, and dissolution rates did not significantly change compared with that on day 0, indicating that the samples were stable in the contents, related substances, and dissolution rates. However, for the comparative example, the content, related substances, and dissolution rate of FPL were significantly reduced, exceeding the limit requirements; and degradation impurities Lu28-159 and trifluoromethyl thioxanthone related to FPL increased significantly, indicating that the quality stability of a product could hardly be guaranteed without the protection of an antioxidant. Therefore, the FPL-melitracen pharmaceutical composition provided by the present disclosure can effectively improve the stability of a product to obtain an FPL-melitracen tablet with excellent efficacy and stable and reliable quality. 00122 Table 4 Time Content% Dissolution rate/ % Triflnoro methyl Illioxanth onc/% 10,10-Di Max imn Total Lu28-159 methvlant in impurity/ (l4i Wile% unknown impurily/ 4% % FPL Melitrac en FPL Melihue en Exarnpl 0 98 100 97 100 0.12 0.01 0.02 0.03 0.26 month 97 99 96 97 0.15 0.08 0.02 0.07 0.33 Exampl 0 99 102 9/3 101 0.2 0.05 0.03 0.02 0.32 e 2 month 98 100 97 99 0.25 0.07 0.05 0.03 0.42 Exampl 0 99 98 98 98 0.15 0.04 0.03 0.04 0.28 e 3 month 97 98 96 98 0_2 0_05 0_05 0_04 0_36 Exampl 0 101 102 99 101 0.05 0.01 0.02 0.03 0.13 month 99 101 98 100 0.08 0.04 0.04 0.05 0.23 Exarnpl 0 98 99 97 98 0.08 0.05 0.02 0.02 0.19 month 97 99 97 98 0.1 0.06 0.04 0.05 0.27 Exampl c6 0 101 99 100 98 0.15 0.02 0.01 0.02 0.22 month 98 99 96 96 0.12 0.05 0.02 0.05 0.26 Exarnpl 0 98 98 98 97 0.09 0.04 0.02 0.03 0.20 month 97 97 96 97 0.15 0.08 0.05 0.05 0.35 Exampl e /3 0 101 100 98 100 0.15 0.05 0.04 0.04 0.30 month 98 98 97 98 0.2 0.1 0.06 0.08 0.46 Compar 0 99 100 97 98 0.20 0.05 0.02 0.05 0.35 alive E.xampl e 1 month 82 97 80 95 3.10 1.01 0.81 0.18 6.57 Compar 0 103 102 102 100 0.12 0.02 0.02 0.02 0.20 alive Exampl e2 month 84 9/3 83 96 2.51 0135 0.40 0.12 4.80 100123 Effect Example 3 1001241 In order to investigate whether the composition of the present disclosure is bioequivalent to Deanxit, a randomized, open, single-dose, two-cycle, and cross-over human bioequivalence test was conducted by orally administering the FPL-melitracen tablet to healthy subjects on an empty stomach. 24 subjects were recruited. The subjects received random single-dose oral administration of the FPL-melitracen tablet (home-made preparation) in Example 1 of the composition of the present disclosure or Deanxit (reference preparation) on day 1. After a cleaning period of 14 d, the subjects were administered with another drug (home-made preparation or reference preparation), and blood samples were collected until 120 h after the administration. The FPL and melitracen concentrations in plasma were determined, and the 90% confidence interval of a geometric mean ratio of the main phanuaeokinetic parameters (AUCo-. and Gm) was calculated to evaluate the bioequivalence. Table 5 shows the AUG-, and Cinaw of FPL and melitracen

Table 5

FPL Mclitraccn home-made reference preparation home-made reference preparalion preparation preparation Cm. (lighttL) 0.141 0.151 10.5 11.0 AUCn-(h*nglmL) 8.67 9.11 178 284 [00126]Table 6 shows the BE comparison between the test preparation (T) and the reference preparation (R). ;1001271 Table 6 ;FPL Melitracen GMR (%) 90% CI GMR (%) 90% CI LoCntax(ng/mL) 93.84 85.12iO3.46 96.80 90.11-103.98 LnAUC0-(10ng/mL) 102.85 88.82419.11 99.85 92.07-108.29 1001281 It can be seen from Tables 5 and 6 that the geometric mean ratio and 90% CT obtained from logarithmic transfatmation of AUG, and Cilta, were both in the range of 80.00% to 125.00%, which reached the bioequivalent standard, indicating that the tablet prepared from the FPL-melitracen composition of the present disclosure was bioequivalent to Deanxit. ;1001291 In addition, a biocquivalence test was conducted for the compositions with different ratios of the present disclosure, and test results showed that tablets prepared from the compositions with different components and ratios of the present disclosure were all bioequivalent to Deanxit. Test processes and related data will not be repeated here. ;1001301 Effect Example 4 [00131]The antioxidants of the present disclosure affect the stability of the FPL-melitracen pharmaceutical composition. In order to investigate the influence of different antioxidants on the stability of the FPL-melitracen pharmaceutical composition, tablets were prepared from FPL-melitracen pharmaceutical compositions in experimental groups, and the dissolution rate and stability of the FPL-melitracen tablets in the experimental groups of this effect example were tested according to the test methods in Effect Examples I and 2. ;1001321 In this effect example, experimental groups were the same except that different antioxidants were adopted. The different antioxidants were shown in Table 7. in the experimental group, in FPL granules, FPL dihydrochloride had a mass of 0.584 mg/tablet, an antioxidant had a mass of 0.4 mg/tablet, a filler was a mixture of lactose and MCC (1:2) and had a mass of 58 mg/tablet, and a binder was HPC and had a mass of 1.8 mg/tablet; in melitracen granules, melitracen hydrochloride had a mass of 11.25 mg/tablet, a filler was a mixture of lactose and MCC (1:3) and had a mass of 28 mg/tablet, and a binder was HPC and had a mass of 1.2 mg/tablet; and among additional adjuvants, a disintegrant was cross-linked sodium CMC and had a mass of 1.8 mg/tablet, a filler was MCC and had a mass of 14 mg/tablet, a binder was HPC and had a mass of 3 mg/tablet, and a lubricant was stearic acid and had a mass of I.2 mg/tablet. ;1001331A preparation method of the FPL-melitracen tablet in this effect example included: [00134] (1) Preparation of FPL granules 100135IFPL dihydrochloride and an antioxidant were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; lactose, MCC, and HPC were added to a high-speed stirring granulator, then the 75% ethanol-water solution with the FPL dihydrochloridc and the antioxidant was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules. ;[00136] (2) Preparation of melitracen granules [00137IIVIelitracen hydrochloride, lactose, MCC, and FIPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules. 1001381(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen tablet. ;[00139]In this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 7. ;001401 Table 7 ;Expe rime n tali group 1 Expe rime n tal group 2 Experi me n tali group 3 Experi men hit group 4 Experi men tal group 5 Expe rime n tal group 6 Experi men tal group 7 Experi men tal group 8 Antioxidant BHA B11T PC soclUm L-cvsteine. vital rin C. . thiosullate vitamin C palmitate vitamin E mo mo mo mo mo mo mo mo Time 0 lith 0 nut 0 nth 0 nth 0 nth 0 nth 0 nth 0 nth 6 6 6 6 6 6 6 6 FPL 99 97 101 100 98 97 98 94 98 95 100 96 99 96 101 96 Content I% melitrac 101 99 100 100 99 98 98 97 99 98 101 98 101 98 100 97 en Dissolut FPL 98 97 100 99 97 97 95 90 96 94 99 95 99 95 100 95 ion ratet'it melitow 100 98 100 100 97 98 96 96 98 96 100 96 99 98 99 96 en 0.1 0.0 0.0 0.1 0.2 0,4 0,8 0,3 0,7 0.1 0.3 0.0 0,2 0,3 0,8 Lu28 159% 9 5 R 5 1 5 5 2 8 5 5 5 5 5 Trifluoromethyl 0.0 0,0 0.0 0.0 0.0 0.0 0,0 0.1 0,0 0.1 0.0 0,1 0.0 01 0,0 0,0 thioxanthone/% 4 8 2 2 3 6 8 5 5 2 4 1 8 * 5 9 10,10-D1111011y lanai 0.0 0,0 0.0 0.0 0.0 0.0 0,0 0,0 0,0 0,0 0.0 0.0 0.0 0,0 0,0 0,0 roue/it 3 4 3 4 5 5 1- 6 2 4 5 8 5 7 4 8 Maximum unknown 0.0 0,0 0.0 0.0 0.0 0.0 0,0 0,0 0,0 0,0 0.0 0.0 0.0 0,0 0,0 0,0 impurityN 3 5 3 5 3 4 7 9 5 7 2 5 5 5 4 6 0.2 0.3 0.1 0.2 0.2 0.3 0.6 1.1 0.4 1.0 0.2 0.6 0.2 0.4 0.5 1.1 Total impurith% 4 9 5 1 8 8 6 7 6 0 8 1 5 9 3 0 1001411 It can be seen from Table 7 that the antioxidants of the present disclosure affected the stability of the FPL-melitracen pharmaceutical composition; when the antioxidant was vitamin C or vitamin C palmitate, a tablet prepared from the FPL-melitracen pharmaceutical composition exhibited high stability; when the antioxidant was BHA or PG, a tablet prepared from the FPL-melitracen pharmaceutical composition exhibited higher stability; and when the antioxidant was BHT a tablet prepared from the FPL-melitracen pharmaceutical composition exhibited the highest stability.

1001421Effect Example 5 100143] The mass percentage of the antioxidant of the present disclosure affects the stability of the FPL-melitracen pharmaceutical composition. In order to investigate the influence of antioxidant mass percentages on the stability of the FPL-melitracen pharmaceutical composition, tablets were prepared from FPL-melitracen pharmaceutical compositions in experimental groups and control groups, and the dissolution rate and stability of the FPL-melitracen tablets in the experimental groups and control groups of this effect example were tested according to the test methods in Effect Examples 1 and 2.

10014411n this effect example, the antioxidant mass percentages were different, and the adjuvant mass percentages were all the same except for the filler mass percentages. The mass percentages of FPL dihydrochloride, melitracen hydrochloride, and antioxidant were shown in Table 8. In the experimental group and control group, in FPL granules, an antioxidant was BHT, a filler was a mixture of lactose and MCC (1:2) and had a mass of 58 mg/tablet, and a binder was HPC and had a mass of 1.8 mg/tablet; in melitracen granules, a filler was a mixture of lactose and MCC (1:3) and had a mass of 28 mg/tablet, and a binder was HPC and had a mass of 1.2 mg/tablet; and among additional adjuvants, a disintegrant was cross-linked sodium CMC and had a mass of 1.8 mg/tablet, a binder was HPC and had a mass of 3 mg/tablet, a lubricant was stearic acid and had a mass of 1.2 mg/tablet, and a filler was MCC and had a mass of the balance.

100145] A preparation method of the FPL-melitracen tablet in this effect example included: 1001461( I) Preparation of FPL granules 100147] FPL dihydrochloride and BHT were added to an 80% ethanol-water solution, and a resulting mixture was stirred until clear; lactose, MCC, and HPC were added to a high-speed stirring granulator, then the 80% ethanol-water solution with the FPL dihydrochloride and BHT was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

1001481(2) Preparation of melitracen granules 100149]Melitracen hydrochloride, lactose, MCC, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules. 1001501(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen tablet.

[001511In this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 8.

100152]Table 8

Experiment I Experiment I Experiment Experiment Experiment Control I Control I al group 1 al group 2 al group 3 al group 4 al group 5 group 1 group 2 FPL mass/rug 0.584 0.584 0.584 0.584 0.584 0.584 0.584 dilly &rich Lori& miss 0.49 0.49 0.49 0.49 0.49 0.49 0.49 pereentagel% melilmee MaSSling 11.25 11.25 11.25 11.25 11.25 11.25 11.25 Ii hydroeldo ride mass 9.37 9.37 9.37 9.37 9.37 9.37 9.37 percentagel% Antioxida mass/lug 0.012 0.024 3.60 6.00 12.00 0.006 14.41 in mass 0.01 0.02 3 5 10 0.005 12 pereentagei% Time 0 HMI 0 11101I 0 11101I 0 MOD 0i6 0 111011 0 111011 0 ITIOTI th 6 th 6 th 6 (h6 th 6 (h6 Content/ FPL 100 97 99 99 101 100 100 100 99 99 98 95 100 100 % melitracen 99 97 98 97 100 99 101 101 99 99 98 96 99 99 Dissol uti on ratc/% FPL 98 96 98 98 100 99 99 100 98 99 98 94 100 99 melitracen 99 96 98 97 99 99 101 100 98 98 97 95 98 98 Lu28-159% 0.2 0.42 0.15 0.26 0 0.1 0 0.08 0 0.09 0.35 0.84 0 0.07 Dalt orometlwl 0.04 0.08 0.02 0.05 0.04 0.08 0.02 0.04 0.02 0.05 0.08 0.49 0.03 0.05 thioxintlione/% 10.10-Dimethydruithrone/% 0.05 0.07 0.03 0.05 0.01 0.03 0.02 0.03 0.03 0.03 0.03 0.3 0.02 0.03 Maximum unknown 0.04 0.04 0.02 0.03 0.03 0.04 0.03 0.03 0.03 0.03 0.03 0.05 0.02 0.04 impurity/% Total npurity/% 0.34 0.6 0.21 0.37 0.12 0.28 0.08 0.2 0.1 0.22 0.51 1.45 0.09 0.22 10015311t can be seen from Table 8 that the mass percentage of the antioxidant of the present disclosure affected the stability of the FPL-melitracen composition; when an antioxidant mass percentage was 0.005% in the control group 1, the stability of the composition was slightly poor; and when an antioxidant mass percentage was 12% in the control group 2, the stability was prominent, but not better than that at a mass percentage of 10%. Therefore, preferably, when an antioxidant mass percentage was 0.01% to 10%, the tablet prepared from the FPL-melitracen composition had excellent stability; and further preferably, when an antioxidant mass percentage was 0.02% to 5%, the tablet prepared from the FPL-melitracen composition had the optimal stability.

1001541Effect Example 6 1001551The mass percentages of the FPL dihydrochloride and melitracen hydrochloride of the present disclosure affect the stability of the FPL-melitracen composition. In order to investigate the influence of FPL dihydrochloride and melitracen hydrochloride mass percentages on the stability of the FPL-melitracen composition, tablets were prepared from FPL-melitracen compositions in experimental groups and control groups, and the dissolution rate and stability of the FPL-melitracen tablets in the experimental groups and control groups of this effect example were tested according to the test methods in Effect Examples 1 and 2.

1001561In this effect example, the mass percentages of FPL dihydrochloride and melitracen hydrochloride were different, and the adjuvant mass percentages were all the same except for the filler mass percentages. The mass percentages of FPL dihydrochloride and melitracen hydrochloride and the mass of filler were shown in Table 9. in the experimental group and control group, in FPL granules, an antioxidant was BHT and had a mass percentage of 0.08%, and a binder was HPC: and had a mass percentage of 1.49%; in melitracen granules, melitracen hydrochloride had a mass of 11.25 mg/tablet, and a binder was HPC and had a mass percentage of 0.99%; and among additional adjuvants, a disintegrant was cross-linked sodium CMC and had a mass percentage of 1.49%, a binder was FIPC and had a mass percentage of 2.48%, a lubricant was magnesium stearate and had a mass percentage of 0.99%, and a filler had a mass of the balance.

[00157] A preparation method of the FPL-melitracen tablet in this effect example included: 1001581(1) Preparation of FPL granules [00159] FPL dihydrochloride and BUT were added to an 80% ethanol-water solution, and a resulting mixture was stirred until clear; lactose, MCC, and HPC were added to a high-speed stirring granulator, then the 80% ethanol-water solution with the FPL dihydrochloride and BUT was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain FPL granules.

[00160] (2) Preparation of melitracen granules 100161]Melitracen hydrochloride, lactose, MCC, and HPC were added to a high-speed stirring granulator, then purified water was added, and shear granulation was conducted under stirring; and a resulting product was subjected to fluidized bed drying and screening to obtain melitracen granules. 1001621(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was pressed into a tablet, and the tablet was film-coated to obtain an FPL-melitracen tablet.

1001631In this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 9.

001641 Table 9

Experiment al vroup 1 Experiment al group 2 Experiment al group 3 Experiment al group 4 Experiment al group 5 Control group 1 Control group 2 FPL mass/mg 0.584 0.584 0.584 0.584 0,584 0,584 0.584 dihydroch bride mass 0.3 0.4 0.6 0.8 1.0 0.2 1.1 pereentagel% FPL filler lactose mid lactose mid lactose mid lactose and lactose mid lactose mid lactose mid granules MCC MCC MCC MCC MCC MCC MCC massang 33.64 and 24.64 and 15.59 and 11.04 and 8.31 and 51.98 and 7.32 and 63.91 46.81 29.62 20.97 15.79 98.76 13.90 Mclitrace mass/mg 11.25 11.25 11.25 H.25 11.25 11.25 11.25

II

hydrochlo ride IMISS 5.78 7.71 11.56 15.41 19.26 3.85 21.19 percentage/9'i, Melilrace filler lactose and lactose and lactose and lactose and lactose and lactose and lactose and n MCC MCC MCC MCC MCC MCC MCC granules mass/mg 11.77 and 8.62 and 5.46 and 3.86 and 2.91 and 18.19 and 2.56 and 35.32 25.87 16.37 11.59 8.73 54.58 7.68 Addiliona I adjuvant filler MCC MCC MCC MCC MCC MCC MCC mass/mg 23 55 17 25 10 91 7.73 5.82 36 38 5.12 Time 0 mon th 6 0 mon th 6 0 mon th 6 0 mont b 6 0 mon th 6 0 mon th 6 0 mon th 6 Content/ I FPL 100 99 99 99 99 99 100 99 100 100 98 95 100 97 melitracen 100 100 100 99 100 99 99 99 99 99 98 96 99 98 Dissoluli OH rater% FPL 100 98 98 99 98 99 99 98 99 99 98 94 99 96 melitracen 99 97 100 98 99 99 99 98 99 98 97 95 98 98 Lu28-159% 0.05 0.51 0 0.36 0 0.2 0 0.24 0 0.4 0.1 0.84 0.2 0.67 Trilluorometlwl 0.04 0.08 0.02 0.04 0.03 0.03 0.03 0.04 0 0. 0.12 0.05 0.09 0.03 0.05 thioxanthoneN, 8 0.05 0.07 10,10-Dimethylanthrond % 0.03 0.02 0.03 0.02 0.04 0.0 0.1 0.03 0.23 0.05 0.13 0.02 3 Maximum unknown 0.04 0.04 0.03 0.04 0.03 0.03 0.03 0.05 0.0 0.03 0.03 0.05 0.02 0.04 irnpurily/% , Total impurity/% 0.2 0.72 0.07 0.47 0.1 0 1 0.08 0.39 0.1 0.67 0.23 1.23 0.32 0.91 - 6 1001651 It can be seen from Table 9 that the mass percentages of FPL dihydrochloride and melitracen hydrochloride of the present disclosure affected the stability of an FPL-melitracen tablet; when a mass percentage of FPL dihydrochloride was 0.3% to 1.0% and a mass percentage of melitracen hydrochloride was 5.78% to 19.26%, the FPL-melitracen tablet had prominent stability, and when a mass percentage of FPL dihydrochloride was 0.4% to 0.8% and a mass percentage of melitracen hydrochloride was 7.71% to 15.41%, the FPL-melitracen tablet had the optimal stability.

1001661Finally, it should be noted that the above examples are provided merely to describe the technical solutions of the present disclosure, rather than to limit the protection scope of the present disclosure. Although the present disclosure is described in detail with reference to preferred examples, a person of ordinary skill in the art should understand that modifications or equivalent replacements may be made to the technical solutions of the present disclosure without departing from the spirit and scope of the technical solutions of the present disclosure.

Claims (10)

1. CLAIMS: 1. A flupentixol (FPL)-melitracen pharmaceutical composition, comprising FPL dihydrochloride, melitracen hydrochloride, and an antioxidant.
2. 2. The pharmaceutical composition according to claim 1, wherein in the pharmaceutical composition, the FPL dihydrochloride has a mass percentage of 0.3% to 1.0%, the melitracen hydrochloride has a mass percentage of 5.78% to 19.26%, and the antioxidant has a mass percentage of 0.01% to 10%.
3. 3. Thc pharmaceutical composition according to claim 2, wherein the FPL dihydrochloride has a mass percentage of 0.4% to 0.8%, the melitracen hydrochloride has a mass percentage of 7.71% to 15,41%. and the antioxidant has a mass percentage of 0.02% to 5%.
4. 4. The pharmaceutical composition according to claim 1, wherein the antioxidant is at least one from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium thiosulfate. L-cysteine, vitamin C or a sodium salt thereof, vitamin C palmitate, vitamin E, and a water-soluble organic weak acid.
5. 5. The pharmaceutical composition according to claim 4, wherein the antioxidant is at least one from the group consisting of BHA, BHT, PG, vitamin C, vitamin C palmitate, and the water-soluble organic weak acid.
6. 6. The pharmaceutical composition according to claim 5, wherein the antioxidant is at least one from the group consisting of BHA. BHT, and PG.
7. 7. The pharmaceutical composition according to claim 6 wherein the antioxidant is BHT.
8. 8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a phaimaceutically acceptable adjuvant, and the pharmaceutically acceptable adjuvant is at least one from the group consisting of a filler, a disintegrant, a binder, and a lubricant.
9. 9. A pharmaceutical preparation, wherein raw materials for preparing the pharmaceutical preparation comprise the pharmaceutical composition according to any one of claims 1 to 8.
10. 10. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is in a dosage form of a tablet, granules, a capsule, or an injection.