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Flupentixol melitracen tablet and preparation method therefor
GB2595141A
United Kingdom
- Inventor
BU Shui Chen Yunwan Yang Yudong Hu Gongyun Wang Duantong Zheng Weiguo Xu Ligui - Current Assignee
- Guangdong Scient Finder Pharmaceutical Tech Co Ltd
- Hainan Huineng Pharmaceutical Co Ltd
Worldwide applications
Application GB2111481.4A events
2021-11-17
2023-06-14
Application granted
2023-06-14
Status
Active
2039-12-13
Anticipated expiration
Description
translated from
FLUPENTIXOL (FPL)-MELITRACEN TABLET AND PREPARATION METHOD
THEREOF
TECHNICAL FIELD
[0001] The present disclosure relates to a flupentixol (FPL)-melitracen tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations.
BACKGROUND
[0002] Generally, the stability of a pharmaceutical preparation is a very important factor considered during the design, production, and storage of a 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.
[0003] FPL dihydrochloridc is a hydrochloride form of the atypical antipsychotic dmg 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 dihydrochloride has a chemical name of 21443 (EZ)-(2-trifluoromethylthioxanthen-9-ylidene)propyl]piperazin-I -yl]ethanol dihydrochloride, and a structural formula as follows: H 2HCI [0004] -cF [0005] Melitracen hydrochloride is a tricyclic anti-bipolar disorder dmg, and exhibits an excitative effect when used at a low dosage. Melitracen hydrochloride has a chemical name of 3-110,10-dimethy1-9(10H)-anthracenylidene J-N,N-dimethyl-l-propylamine hydrochloride, and a structural formula as follows: H30 HC! j [0006] H3C CH3 [0007] FPL was marketed in 1966, and its preparations include FPL tablet (specification: 0.5 mg and 5 mg) and FPL injection (specification: 1 mL: 20 mg). Melitracen was marketed in 1968, and a its preparation is melitracen 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 Pharmaceutical 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). The Deanxit product shows definite curative effects on mild and moderate depression, anxiety, neurasthenia, psychogenic depression, and depressive psychoneurosis, with quick onset and small adverse reaction, which is one of the most-widely-used antidepressants in China.
[0008] An 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 microerystalline 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 monohydrate, 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, HPC, hydrogenated vegetable oil, and magnesium stearate, and a resulting mixture is tableted. This process uses 13-cyclodextrin as a stabilizer at a high dosage, so obtained tablets are easy to absorb moisture.
10010] 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 to subjected to granulation; resulting granules are dried, screened, and then thoroughly mixed with a disintegrant and a lubricant; and a resulting mixture is tableted. In this process, melitracen is added to FPL under opposed jet crushing, but the opposed jet crushing will result in large energy consumption and unstable yield, making it difficult to ensure the controllability and reproducibility of the process. Moreover, as FPL dihydrochloride and melitracen hydrochloride are highly irritant, dust nuisance during a production process will lead to low operation feasibility.
10011] Chinese Patent CNI04288153A 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 jun), melitmcen, a filler, a disintegrant, a binder, and a lubricant arc 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.
[0012] 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 10,10-dimethylthioxanthone. The main degradation pathway and degradation product of FPL are as follows: FPL dihydrochloride N. Trifluoromethyl thioxanthone [0013] [0014] Therefore, for the compound preparation of FPL arid melitracen, it is urgent to develop a preparation method of an FPL-melitracen tablet 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 tablet and a preparation method thereof The preparation method has prominent process reproducibility and stability. The FPL-melitracen tablet of the present disclosure has excellent dissolution characteristics and stability and low related substance contents, which can better ensure the safety and effectiveness of the product.
[0016] In order to achieve the above objective, the present disclosure adopts the following technical solutions: An FPL-melitracen tablet is provided, including the following components, in mass percentage: FPL dihydrochloride: 0.3% to 1.0%; melitracen hydrochloride: 5.78% to 19.26%; antioxidant: 0.01% to 10%; filler: 60% to 88%; disintegrant: 0.5% to 6%; binder: 2% to 6%; and lubricant: 0.2% to 3%.
[0017] As a preferred implementation of the FPL-melitracen tablet according to the present disclosure, the FPL-melitracen tablet may include the following components, in mass percentage: FPL dihydrochloride: 0.4% to 0.8%; melitracen hydrochloride: 7.71% to 15.41%; antioxidant: 0.02% to 5%; filler: 72% to 85%; disintegrant: 0.5% to 4%; binder: 3% to 5%; and lubricant: 0.5% to 2%. [0018] As a preferred implementation of the FPL-melitracen tablet according to the present disclosure, at least one of the following (a) to (f) may be defined: 100191 (a) the antioxidant may be 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; [0020] (b) the filler may be at least one from the group consisting of MCC, lactose, calcium hydrogen phosphate, starch, mannitol, and calcium carbonate, [0021] (c) the disintegrant may be at least one from the group consisting of cross-linked sodium CMC, crospovidone, low-substituted hydroxwropyl cellulose (L-HPC), sodium carboxymethyl starch (SCMS). CMC, and calcium CMC; [0022] (d) the binder may be at least one from the group consisting of HPC, hydroxypropyl methylcellulosc (HPMC), poyidonc, sodium CMC, methyl cellulose (MC), and gum arabic; [0023] (e) the lubricant may be at least one from the group consisting of silicon dioxide, magnesium stcarate, stcaric acid, sodium stearyl ftunarate, talcum powder, and glyccryl behenate, and [0024] (0 the FPL-melitracen tablet may further include a coating material, a mass of the coating material may be 2% to 10% of a mass of a core of the tablet, and the coating material may be at least one from the group consisting of Opadry TI, Opacity 200, and Opadry amb.
[0025] As a preferred implementation of the FPL-melitracen tablet 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 a water-soluble organic weak acid.
10026] As a preferred implementation of the FPL-melitracen tablet according to the present disclosure, the antioxidant may be at least one from the group consisting of BHA, BHT, and PG. 10027] As a preferred implementation of the FPL-melitracen tablet according to the present disclosure, at least one of the following (a) to (0 may be defined: [0028] (a) the antioxidant may be BHT; 10029] (b) the filler may be at least one from the group consisting of MCC, lactose, starch, and calcium hydrogen phosphate; [0030] (c) the disintcgrant may be at least one from the group consisting of cross-linked sodium CMC, crospovidone, L-HPC, and SCIMS; 10031] (d) the binder may be at least one from the group consisting of HPC, HPMC, and povidone; 10032] (e) the lubricant may be at least one from the group consisting of silicon dioxide, magnesium stcarate, stcaric acid, talcum powder, and glyeeryl bchenate; and [0033] (0 the mass of the coating material may be 3% to 6% of the mass of the core of the tablet. 10034] The present disclosure further provides a wet granulation preparation method of the FPL-melitracen tablet, including the following steps: [0035] (1) mixing the FPL dihydrochloride with 5% to 30% of the filler in an equal incremental manner and then with 30% to 70% of the filler and 10% to 50% of the binder, adding an organic solvent/water solution of the antioxidant, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain FPL granules; or 100361 dissolving the FPL dihydrochloride and the antioxidant in an organic solvent/water solution, adding a mixture of 30% to 70% of the filler and 10% to 50% of the binder to the organic solvent/water solution with the FPL dihydrochloride and the antioxidant, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain FPL granules; [0037] (2) mixing the melitracen hydrochloride with 20% to 50% of the filler and 10% to 40% of the binder, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, centrifugal spray granulation, or extrusion granulation, and drying a resulting product to obtain melitracen granules; and 100381 (3) mixing the FPL granules with the melitracen granules, 5% to 30% of the filler, the disintegra.nt, 10% to 60% of the binder, and the lubricant, and tableting and coating a resulting mixture.
[0039] As a preferred implementation of the wet granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the preparation method of FPL granules may preferably include: dissolving the FPL dihydrochloride and the antioxidant in an organic solvent/water solution, adding a mixture of a part of the filler and a part of the binder to the organic solvent/water solution with the FPL dihydrochloride and the antioxidant, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain FPL granules.
[0040] As a preferred implementation of the wet granulation preparation method of the FPL-melitracen tablet according to the present disclosure, stirring granulation may be adopted.
10041] As a preferred implementation of the wet granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the coating material may be dissolved or suspended in an appropriate amount of a solvent, and the solvent may be at least one from the group consisting of a 20% to 85% ethanol aqueous solution and purified water.
10042] As a preferred implementation of the wet granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the organic solvent may be at least one from the group consisting of isopropanol, ethanol, and acetone.
[0043] As a preferred implementation of the wet granulation preparation method of the FPL-melitracen tablet according to the present disclosure, fluidized bed drying may be adopted, and the fluidized bed drying may be conducted at a temperature of lower than 50°C until LOD% of the granules is not more than 3%.
10044] The present disclosure further provides a dry granulation preparation method of the FPL-melitracen tablet, including the following steps: [0045] (I) thoroughly mixing the FPL dihydrochloride with the antioxidant, 10% to 70% of the filler, and 20% to 60% of the lubricant in an equal incremental manner, and subjecting a resulting mixture to dry rolling granulation to obtain FPL granules; [0046] (2) thoroughly mixing the melitracen with 10% to 50% of the filler and 20% to 50% of the lubricant, and subjecting a resulting mixture to dry rolling granulation to obtain melitracen granules; and [0047] (3) mixing the FPL granules with the melitracen granules, the disintegrant, the binder, and 20% to 40% of the lubricant, and tableting and coating a resulting mixture.
[0048] As a preferred implementation of the dry granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the FPL dihydrochloride and the antioxidant may be first micronized and then used for the granulation.
100491 As a preferred implementation of the dry granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the FPL granules and the melitracen gi-anules may have a bulk density of 0.4 g/mL to 0.8 g/mL.
[0050] As a preferred implementation of the dry granulation preparation method of the FPL-melitracen tablet according to the present disclosure, the coating material may be dissolved or suspended in an appropriate amount of a solvent, and the solvent may be at least one from the group consisting of a 20% to 85% ethanol aqueous solution mid purified water.
[0051] Compared with the prior art, the present disclosure has the following beneficial effects: in the FPL-melitracen tablet according to the present disclosure, the antioxidant is added, such that the stability of the FPL-melitracen tablet can be effectively enhanced, and the production of Lu28-159, trifluoromethyl thioxanthone, and other impurities from the degradation of FPL can be effectively controlled to reduce an impurity level, thereby ensuring the safety and effectiveness of the product. An FPL-melitracen tablet prepared according to the present disclosure has similar in vitro dissolution behaviors and bioequiavailability to the original tablet Deanxit.
DETAILED DESCRIPTION
100521 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.
[0053] Example 1
100541 An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.48%, 9.30%, 0.08%, 82.69%, 1.49%, 4.96%, and 0.99%, respectively, and masses of the components were shown in Table I. [0055] A preparation method of the tablet in this exampleincluded: [0056] (I) Preparation of FPL granules [0057] 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.
[0058] (2) Preparation of melitracen granules [0059] Melitracen 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.
[0060] (3) The FPL granules, the mclitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
0061 Table 1
Component Example Example Example Example Example Example Example Exampl e8 1 3 3 4 5 6 7 FPL FPL mass 0.584 0.584 0.584 0.584 0.584 0.584 0.584 0.584 granules dilwdroc (mg/tabl !donde et) a ntioxid substenic BHT PG BHA BHT and vitamin C BHT and PG BHT vitamin vitamin ant c C C pahnitat
C
MaSs 0.1 1.0 0.8 0_05 and 0.05 and 0.1 0.006 22.5 (mgitabl 10 0.7 et) filler substanc anhydr ou anhydrou calcium hydrogen phosph at lactose lactose anhydrou lactose anhydr ous lactose and MCC e s lactose s lactose e and and MCC and s lactose and and MCC and MCC starch and MCC MCC starch mass 30 and 30 and 28 25 and 33 15 and 33 30 and 28 20 and 40 8.1 and 25 and (mg/tabl 28 16.2 75 et) binder substanc HPC HPC HPMC povidonc K30 HPC HPC e mass 1.8 1.8 1.8 3 1.8 1.35 --(mg/tabl Cl) lubricant substanc magnesiu magnes e III ium stcarate stcaratc mass 0.48 2.
(mg/tabl et) Melitrac melitrac mass 11.25 11.25 11.25 11.25 11.25 11.25 11.25 11.25 en en (mg/tabl granules hvdrochl ct) oride filler substanc anhydrou anhydrou calcium lactose lactose lactose lactose anhvdr e s lactose s lactose hydrogen and MCC and and MCC and ous and MCC and phosphat starch MCC lactose starch e and and
MCC MCC
mass 7 and 21 7 aml 21 7 and 21 7 and 21 7 and 21 10 and 20 5 and 16.48 Ong/tab! II.2 and et) 49.44 binder substanc 11PC 11PC 11PMC povidone K30 11PC 11PC c mass 1.2 1.2 1.2 2.4 1.2 1.01 (mg/tabl el) lubricant SOMME magncsiu magncs C III ium stearate stearate mass 0.32 2.03 (mg/lab] et) Addition al disintcgr ant substanc cross-fill cross-link cross-link crospovid 011C. L-HPC cross-link cross-lip CMC adjuvant c ked ed ed ed Iced SOCIal111 SOdillIll SOdillIll sodium sodium
CMC CMC CMC CMC CMC
mass 1.8 2.4 2.4 3.6 3.6 3.6 0.28 13.5 (mg/tabl Cl) filler substanc MCC MCC MCC MCC MCC c mass 14 A 14 17 14 (ngitabl et) binder substanc HPC HPC HPMC HPC HPC HPC HPC
C
mass 3 2.4 2.4 3 3.6 1.02 4.5 (mg/tabl ct) lubricant substanc magncsiu stcaric glyccryl magnesia magncsiu magncsiu magncsi magncs c m acid hchcnatc m m m um ium stcaratc stcaratc stcaratc stcaratc stcaratc stcaratc mass 1.2 1.8 1.8 1.0 1.2 0.8 0.28 2.02 (mg/tabl et) Coating Opadrv mass 4.8 4.8 4.8 4.8 4.9 4.4 2.13 9.0 material - (mg/tabl IT et)
[0062] Example 2
10063] An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitraecn hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.48%, 9.19%, 0.82%, 81.68%, 1.96%, 4.41%, and 1.47%, respectively, and masses of the components were shown in Table I. [0064] A preparation method of the tablet in this example included: [0065] (1) Preparation of FPL granules [0066] FPL dihvdrothloride and PG were added to a 75% ethmol-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.
[0067] (2) Preparation of melitracen granules [0068] Mclitracen 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.
[0069] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitraccn pharmaceutical tablet.
[0070] Example 3
[0071] An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.48%, 9.20%, 0.65%, 81.81%, 1.96%, 4.42%, and 1.47%, respectively, and masses of the components were shown in Table 1.
[0072] A preparation method of the tablet in this example included: [0073] (1) Preparation of FPL granules [0074] 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.
[0075] (2) Preparation of melitracen granules [0076] Melitracen 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.
[0077] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
[0078] Example 4
[0079] An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.49%, 9.38%, 8.38%, 73.40%, 3.00%, 4.50%, and 0.83%, respectively, and masses of the components were shown in Table 1.
[0080] A preparation method of the tablet in this exampleincluded: [0081] (I) Preparation of FPL granules [0082] FPL dihydrochloride, BHT, vitamin C, and povidone 1(30 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.
100831 (2) Preparation of melitracen granules 100841 Melitracen hydrochloride, lactose, and MCC were added to a fluidized granulator, then a povidone 1(30 aqueous solution was added, and fluidized granulation was conducted; and a resulting product was dricd and screened to obtain melitracen granules.
[0085] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
100861 Example 5
[0087] An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydroehloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.47%, 9.12%, 0.61%, 81.05%, 2.92%, 4.86%, and 0.97%, respectively, and masses of the components were shown in Table 1.
10088] A preparation method of the tablet in this example included: [0089] ( I) Preparation of FPL granules [0090] 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.
[0091] (2) Preparation of melitracen granules 100921 Melitraccn 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 diving and screening to obtain FPL granules.
100931 (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
[0094] Example 6
100951 An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.53%, 10.16%, 0.09%, 81.28%, 3.25%, 3.25%, and 1.44%, respectively, and masses of the components were shown in Table I. [0096] A preparation method of the tablet in this example lauded: 100971 ( I) Preparation of FPL granules 100981 FPL dihydrochloride and BHT were thoroughly mixed with anhydrous lactose in an equal incremental manner, and then thoroughly mixed with anhydrous 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.
[0099] (2) Preparation of melitracen granules 1001001Melitracen 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.
1001011(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
1001021 Example 7
1001031An FPL-melitracen tablet was provided. In the FPL-mclitraccn tablet, FPL dihydrochloridc, melitracen hydrochloride, an antioxidant, a filler, a disintegra.nt, a binder, and a lubricant had mass percentages of 1.04%, 19.99%, 0.01%, 71.96%, 0.5%, 6.01%, and 0.5%, respectively, and masses of the components were shown in Table 1.
1001041A preparation method of the tablet in this exampleincluded: 1001051(1) Preparation of FPL granules 1001061FPL dihydrochloride and vitamin C palmitate were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; lactose, MCC, and LIPC 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.
1001071(2) Preparation of mclitracen granules 1001081Melitracen 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. 1001091(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
1001101Example 8
[00111[An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, an antioxidant, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.26%, 5%, 10%, 73.74%, 6%, 2%, and 3%, respectively, and masses of the components were shown in Table I. [001121A preparation method of the tablet in this example included: 1001131(1) Preparation of FPL granules 1001141FPL 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, arid a resulting mixture was subjected to rolling granulation with a dry granulator; and a resulting product was screened to obtain FPL granules.
100115] (2) Preparation of melitracen granules [001161Melitracen 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.
100117] (3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
1001181 Comparative Example 1 1001191An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloridc, melitracen hydrochloride, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.48%, 9.31%. 82.76%, 1.49%, 4.97%, and 0.99%, respectively, and masses of the components were shown in Table 2.
1001201A preparation method of the tablet in this comparative example included: 1001211(1) Preparation of FPL granules 1001221 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. 100123] (2) Preparation of melitracen granules 1001241TYIelitracen 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.
1001251(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
[00126] Comparative Example 2 1001271 An FPL-melitracen tablet was provided. In the FPL-melitracen tablet, FPL dihydrochloride, melitracen hydrochloride, a filler, a disintegrant, a binder, and a lubricant had mass percentages of 0.53%, 10.17%, 81.35%, 3.25%, 3.25%, and 1.45%, respectively, and masses of the components were shown in Table 2.
1001281A preparation method of the tablet in this comparative example included: [001291( I) Preparation of FPL granules 1001301FPL 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.
[00131] (2) Preparation of melitraeen granules 1001321Melitracen 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.
1001331(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen pharmaceutical tablet.
001341 Table 2
Component Comparative example 1 Comparative Example 2 FPL granules FPL mass 0.584 0.584 dilwdrochloride (mg/tablet) filler substance anhydrous lactose and MCC lactose and MCC mass 30 and 28 20 and 40
(mg/tablet)
binder substance HPC Mass 1.8
(mng/tablet)
lubricant substa nce magnesium stea rate Mass 0.48
(mg/tablet)
Melitracen granules mel i trace ml mass 11.25 11.25 hydrochloride (mu/tablet) filler substance anhydrous lactose and MCC lactose and MCC mass 7 and 21 10 and 20
(mg/tablet)
binder substance HPC mass 1.2
(mg/tablet)
lubricant substance magnesium stearate mass -- 0.32
(rng/tablet)
Additional adjuvant disintegrant substance cross-linked sodium CMC cross-linked sodium CMC mass 1.8 3.6
(mg/tablet)
filler substance MCC mass 14
(mng/tablet)
binder substance HPC HPC mass 3 3.6
(mg/tablet)
lubricant substance magnesium stearate magnesium stearate mass 1.2 0.8
(mg/tablet)
Coating material °pally 11 mass 4.8 4.4
(nig/tablet)
1001351Effect Example 1 [00136[Dissolution test for Examples 1 to 8 and Comparative Examples 1 to 2 of the present
disclosure
1001371 According to the dissolution rate determination method (the second method in the fourth general mle 0931 of the Chinese Pharmacopoeia, 2015 edition), dissolution rates of Examples 1 to 8 and Comparative Examples I to 2 were determined. 900 mL of a 0.1 mon hydrochloric acid solution was used as a dissolution medium to dissolve a sample, a 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 (}-PLC) (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 -11" Phenyl 3.5 am, 4.6 mm x 100 mm chromatographic column); mobile phase: 0.02 mol/L ammonium acetate buffer-metlnnol (35:65); detection wavelength: 270 run; flow rate: 1.0 mUmin; and column temperature: 40°C. The number of theoretical plates calculated based on melitracen peak should be not less than 1,400, and the resolution 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 ji.g/mL and a melitracen concentration of about 10 jig/mL (a conversion factor between melitracen and melitracen hydrochloride was 0.8887, and a conversion factor between FPL and FPL dihydrochloride was 0.8562). 10 aL 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.
1001381 Table 3
Sample Dissoluti n 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 1 97% 98% Comparative Example 2 107% 100% 1001391 It can be seen from Table 3 that the two active ingredients in the FPL-melitracen tablets of the present disclosure had high dissolution rates, which both met the requirements.
1001401Effect Example 2 1001411 Stability test for Examples Ito 8 and Comparative Examples Ito 2 of the present disclosure 1001421Products of Examples 1 to Sand Comparative Examples 1 to 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.
1001431Contcnt determination: 20 tablets of a sample were taken, accurately weighed, and ground into a powder, and an appropriate amount of the sample powder (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 to the volumetric flask, 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; a resulting solution was diluted with the mobile phase to a specified volume, thoroughly shaken, and filtered; and 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; and then the FPL dihydrochloride reference substance was dissolved with methanol and diluted to a specified volume to obtain a reference substance stock solution with an FPL content of 0.5 mg/ml. 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 and added into the volumetric flask, and a mobile phase was added to dilute to a specified volume; and a resulting mixture 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 uti, 4.6 mm x 100 mm); mobile phase: 0.02 mol/L ammonium acetate buffer-methanol (35:65); detection wavelength: 270 am; flow rate: 1.0 ml/min; and column temperature: 40°C. The number of theoretical plates calculated based on melitracen peak should be not less than 3,000, and the resolution between melitracen peak and FPL peak should be greater than 4.0. 10 0_, of each of the test solutions and the reference substance solution was accurately measured and injected into a 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.
1001441Dissolution test: The dissolution test method in Effect Example I was adopted.
1001451Related 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 nil volumetric flask, 40 nil 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 pg/m1 of Lu28-159, 1.6 pg/ml of 10,10-dimethylanthrone, 0.8 pg/ml of rnelitracen, 0.24 pg/ml of trifluoromethyl thioxanthone, and 0.20 gg/m1 of FPL. 20 tff of each of the reference substance solution and the test solutions was injected into a 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%.
1001461 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°442H 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 tablet provided by the present disclosure can effectively improve the stability of a product and had excellent efficacy and stable and reliable quality.
00147 Table 4
Time Content% Dissolution rate.% Lu28-159 Trifluoro methyl throxant-h onel% 10,10-Di Maximu Total % methylant, m impurity/ monel% unknown impurity/ % % FPL melitrace FPL m elitrace n
II
Exampl 0 98 100 97 100 0.12 0.01 0.02 0.03 0.26 e 1 month 97 99 96 97 0.15 0.08 0.02 0.07 0.33 Emilio' 0 99 102 98 101 0.2 0.05 0.03 0.02 0.32 e 2 month 98 100 97 99 0.75 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 C 4 month 99 101 98 100 0.08 0.04 0.04 0.05 0.23 Exampl 0 98 99 97 98 0.08 0.05 0.02 0.02 0.19 e 5 month 97 99 97 98 0.1 0.06 0.04 0.05 0.27 Exampl 0 101 99 100 98 0.15 0.02 0.01 0.02 0.22 c 6 month 9/3 99 96 96 0.12 0.05 0.02 0.05 0.26 Exampl 0 98 98 98 97 0.09 0.04 007 0 03 0 20 e7 month 97 97 96 97 0.15 0.08 0.05 0.05 0.35 Exampl 0 101 100 98 100 0.15 0.05 0.04 0.04 0.30 c8 month 9/3 98 97 98 0.2 0.1 0.06 0.0% 0.46 Compar 0 99 100 97 98 0.20 0.05 0.02 0.05 0.35 alive Exampl e 1 month 82 97 80 95 3.10 1.01 0.81 0.18 6.57 Coruna' 0 103 102 102 100 0.12 0.02 0.02 0.02 0.20 ative Exampl e2 month 84 98 83 96 2.51 0.85 0.40 0.12 4.80 100148 Effect Example 3 [00149[1n order to investigate whether the tablet 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 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 phannacokinetic parameters (AUCo-, and Comix) was calculated to evaluate the bioequivalence.
1001501Table 5 shows the AUCIF:c arid Cala:, of FPL and melitracen.
[00151] Table 5
FPL mclitraccn home-made reference preparation home-made reference preparation preparation preparation Cain (ngimL) 0.141 0.151 10.5 11.0 AUC0-,. (It * nginaL) 8.67 9.11 278 284 1001521Table 6 shows the BE comparison between the test preparation (T) and the reference preparation (R).
1001531 Table 6
FPL melitracen GNTR (%) 90% CT 0\412(%) 90% Cl LnC.D.Olg/mL) 93.84 85.12-103.46 96.80 90.11-103.98 LnAUC0-(Iltng/mL) 102.85 88.82-119.11 99.85 92.07-108.29 1001541 It can be seen from Tables 5 and 6 that the geometric mean ratio and 90% CI obtained from logarithmic transformation of AUCo-g, and Curax were both in the range of 80.00% to 125.00% and reached the bioequivalent standard, indicating that the FPL-melitracen tablet of the present disclosure was bioequivalent to Deanxit.
1001551In addition, a bioequivalence test was conducted for the tablets with different ratios of the present disclosure, and test results showed that the tablets with different components and ratios of thc present disclosure were all bioequivalent to Deanxit. Test processes and related data will not be repeated here.
[00156] Effect Example 4 1001571 The antioxidants of the present disclosure affect the stability of the FPL-melitracen tablet. In order to investigate the influence of different antioxidants on the stability of the FPL-melitracen tablet, FPL-melitracen tablets in experimental groups were prepared, and the dissolution rate and stability of the FPL-melitracen tablet in the experimental group of this effect example were tested according to the test methods in Effect Examples 1 and 2.
1001581111 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 ing/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 stcaric acid and had a mass of 1.2 mg/tablet.
1001591 A preparation method of the FPL-rnelitracen tablet in this effect example included: 100160] (1) Preparation of FPL granules [00161] FPL dihydrochloride and an antioxidant were added to a 75% ethanol-water solution, and a resulting mixture was stirred until clear; lactose, MCC, and FIPC were added to a high-speed stirring granulator, then the 75% ethanol-water solution with the FPL dihydrochloride 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.
[00162] (2) Preparation of melitracen granules 1001631Melitracen 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. 1001641(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen tablet.
10016511n this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 7.
1001661 Table 7
Experimen Lai group 1 Experimen tal group 2 Expel-hum MI group 3 Experimen (al vroup 4 Experimen tal group 5 Expo-Sun tal group 6 Experimen (al group? Experimen tal group 8 Antioxidant BRA BHT PG illiOS sodium L-ey leme," vitamin C. . .r, il fate Vlial11111 L palmiple VIth111111 L mo mei mo mo mei mo mo mo Time 0 nth 0 nth 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 melitrac en 101 99 100 100 99 98 98 97 99 98 101 98 101 98 100 97 Dissolut ion FPL 98 97 100 99 97 97 95 90 96 94 99 95 99 95 100 95 mel itrac mile% en 100 98 100 100 97 98 96 96 98 96 100 96 99 98 99 96 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 01 0.8 Lu28 15 9% 0.1.
1 5 8 5 1 5 5 2 5 5 5 5 5 /3 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 0 1 0.0 0.0 thioxanthonel% 4 8 2 2 3 6 8 5 5 2 4 1 8 5 9 10,10-Dimetlsylanth 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 rone/% 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 impurity/% 3 5 3 5 3 4 7 9 5 7 2 5 5 5 4 6 0.2 0.3 OA 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 impurity/% 4 9 5 1 8 8 6 7 6 0 8 1 5 9 3 0 10016711t can be seen from Table 7 that the antioxidants of the present disclosure affected the stability of the FPL-melitracen tablet; when the antioxidant was vitamin C or vitamin C palmitate, an FPL-melitracen tablet exhibited high stability; when the antioxidant was BHA or PG, an FPL-melitracen tablet exhibited higher stability; and when the antioxidant was BHT, an FPL-melitracen tablet exhibited the highest stability.
1001681Effect Example 5 1001691The mass percentage of the antioxidant of the present disclosure affects the stability of the FPL-melitracen tablet. In order to investigate the influence of antioxidant mass percentages on the stability of the FPL-melitracen tablet, FPL-melitracen tablets in experimental groups and control groups were prepared, 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.
1001701In 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 dihvdrochloride, 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.
1001711A preparation method of the FPL-melitracen tablet in this effect example included: [00172] (1) Preparation of FPL granules 1001731FPL 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.
1001741(2) Preparation of melitracen granules 1001751Melitracen 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. 1001761(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen tablet.
10017711n this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 8.
001781 Table 8
EXperiMeill al group 1 EXperithelll al group 2 EXperithelll at group 3 EXperillIelit at group 4 Experiment at group 5 Control Control group 1 group 2 FPL IllaSSIIng 0.584 0.584 0.584 0.584 0.584 0.584 0.584 dihydroch bon& mass 0.49 0.49 0.49 0.49 0.49 0.49 0.49 percentage:1% ineliluice IllaSSIIng 11.25 11.25 11.25 11.25 11.25 11.25 11.25 n hydrochlo ride mass 9.37 9.37 9.37 9.37 9.37 9.37 9.37 percentage/3'4 Anlioxida MaSS/Ing 0.0 1 2 0.024 3.60 6.00 12.00 0.006 14.41 nt mass 0.01 0.02 5 10 0.005 17 percentage/ % Time 0 111011 th 6 0 111.011 0 111011 th 6 0 111011 th 6 0 111011 th 6 0 111011 th 6 0 111011 th 6 th 6 Content; FPL 100 97 99 99 101 100 100 100 99 99 98 95 100 100 mailmen 99 97 98 97 100 99 101 101 99 99 98 96 99 99 Dissoluti FPL 98 96 98 98 100 99 99 100 98 99 98 94 100 99 on rater% 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 Trifluoromelhyl 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 thioxanthonei% 10,10-Dimellwlanthronel% 0.05 0.07 0.03 0.05 0.01 0.03 0.02 0.03 0.03 0.03 (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 impurily/% Total impurity/% 0.34 0.6 0.21 0.37 0.12 0.28 0.08 0.2 0.1 0.22 0.51 L45 0.09 0.22 100179111 can be seen from Table 8 that the mass percentage of dm antioxidant of the present disclosure affected the stability of the FPL-melitracen tablet; when an antioxidant mass percentage was 0.006% in the control group I, the stability of the tablet 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 FPL-melitracen tablet had excellent stability; and further preferably, when an antioxidant mass percentage was 0.02% to 5%, the FPL-melitracen tablet had the optimal stability.
1001801Effect Example 6 [00181 [The mass percentages of the FPL dihydrochloride and melitracen hydrochloride of the present disclosure affect the stability of the FPL-melitracen tablet. In order to investigate the influence of FPL dihydrochloride and melitracen hydrochloride mass percentages on the stability of the FPL-melitracen tablet, FPL-melitracen tablets in the experimental groups and control groups were prepared, and the dissolution ratc and stability of the FPL-melitracen tablets in the experimental groups and a control groups of this effect example were tested according to the test methods in Effect Examples 1 and 2.
10018211n 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 TIPC 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.
1001831A preparation method of the FPL-melitracen tablet in this effect example included: [001841(1) Preparation of FPL granules 1001851 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 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.
1001861(2) Preparation of melitracen granules [001871Melitracen 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.
1001881(3) The FPL granules, the melitracen granules, and additional adjuvants were thoroughly mixed, a resulting mixture was tableted, and a resulting product was film-coated to obtain an FPL-melitracen tablet.
1001891111 this effect example, performance test results of the FPL-melitracen tablets in the experimental groups were shown in Table 9.
1001901Table 9
Experiment al group 1 Experiment al group 2 Experiment al group 3 Experiment al group 4 Experiment al group 5 Control Control group 1 group 2 FPL mast/log 0.584 0.584 0.584 0.584 0.584 0.584 0.584 dihydroch loride Mass 0.3 0.4 0.6 0.8 1.0 0.2 1.1 percentage% FPL filler lactose and lactose and lactose and lactose and lactose and lactose and lactose and granules MCC MCC MCC MCC MCC MCC MCC Ind ss/Ing 33.64, 24.64. 15.59, 11.04, 8.31, 15.79 51.98, 7.32, 13.90 63.91 46.81 29.62 20.97 98.76 melitrace mass/mg 11.25 11.25 11.25 11.25 11.25 11.25 11.25 n hydrochlo ride mass 5.7% 11.56 15.41 19.26 3.85 21.19 percentage/% Mclitracc filler laclose and lactose and laclose and lactose and lactose and lactose and laclose and It MCC MCC MCC MCC MCC MCC MCC granules m a ssling 11.77, 8.62, 25.87 5.46, 16.37 3.86, 11.59 2.91, 8. 73 18.19, 2.56, 7.68 35.32 54.58 Additiona 1 adjuvant filler MCC MCC MCC MCC MCC MCC MCC 1 ssling 23 55 1725 10 91 7.73 5.87 36 38 5.12 Time 0 mon 0 mon th 6 0 mon lb 6 0 mon I ho 0 mon th 6 0 mon lb 6 0 mon th 6 Content.' 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 9/3 D i ssoluti FPL 100 98 98 99 98 99 99 98 99 99 98 94 99 96 on rate% 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 Trilluoromethvi 0.04 0.08 0.02 0.04 0.03 0.03 0.03 0.04 0.08 0.12 0.05 0.09 0.03 0.05 thiox'mthone% 10,10-Dimethylanthrone% 0.05 0.07 0.02 0.03 0.02 0.03 0.02 0.04 0.03 0.1 0.03 0.23 0.05 0.13 Maximum unknown 0.04 0.04 0.03 0.04 0.03 0.03 0.03 0.05 0.03 0.03 0.03 0.05 0.02 0.04 impurity/% Total impurity/% 0.2 0.72 0.07 0.47 0.1 0.31 0.08 0.39 0.16 0.67 0.23 1.23 0.32 0.91 1001911It 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.
[001921Finally, 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)
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- CLAIMS: I. A flupentixol (FPL)-melitracen tablet, comprising the following components, in mass percentage: FPL dihydrochloride: 0.3% to 1.0%; melitracen hydrochloride: 5.78% to 1926%; antioxidant: 0.01% to 10%; filler: 60% to 88%; disintegrant: 0.5% to 6%; binder: 2% to 6%; and lubricant: 0.2% to 3%.
- 2. The FPL-melitracen tablet according to claim 1, wherein the FPL-melitracen tablet comprises the following components, in mass percentage: FPL dihydrochloride: 0.4% to 0.8%; melitracen hydrochloride: 7.71% to 15.41%; antioxidant: 0.02% to 5%; filler: 72% to 85%; disintegrant: 0.5% to 4%; binder: 3% to 5%; and lubricant: 0.5% to 2%.
- 3, The FPL-melitracen tablet according to claim 1 or 2, wherein (a) the antioxidant is at least one from the group consisting of butvlated hydroxyanisolc (BHA), butvlated hvdroxytoluene (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; (b) the filler is at least one from the group consisting of microcry:stalline cellulose (MCC), lactose, calcium hydrogen phosphate, starch, mannitol, and calcium carbonate; (c) the disintegrant is at least one from the group consisting of cross-linked sodium carboxymethyl cellulose (CIVIC), crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (SIEVES), CMC, and calcium CMC; (d) the binder is at least one from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPIVIC), povidone, sodium CMC, methyl cellulose (MC), and gum arable; (c) the lubricant is at least one from the group consisting of silicon dioxide, magnesium stcarate, stearic acid, sodium stearyl fumarate, talcum powder, and glyceryl behenate; and (f) the FPL-melitracen tablet further comprises a coating material, a mass of the coating material is 2% to 10% of a mass of a core of the tablet, and the coating material is at least one from the group consisting of Opadry II, Opadry 200, and Opadry amb.
- 4. The FPL-melitracen tablet according to claim 3, wherein (a) the antioxidant is BHT; (b) the filler is at least one from the group consisting of MCC, lactose, starch, and calcium hydrogen phosphate, (c) the disintegrant is at least one from the group consisting of cross-linked sodium CIVIC, crospovidone, L-HPC, and SCMS; (d) the binder is at least one from the group consisting of HPC, HPTVIC, and povidone; (e) the lubricant is at least one from the group consisting of silicon dioxide, magnesium stearate, stearic acid, talcum powder, and glycelylbehenate; and (f) the mass of the coating material is 3% to 6% of the mass of the core of the tablet.
- 5. A preparation method of the FPL-melitracen tablet according to any one of claims 1 to 4, comprising the following stcps: (1) mixing the FPL dihydrochloridc with 5% to 30% of the filler in an equal incremental manner and then with 30% to 70% of the filler and 10% to 50% of the binder, adding an organic solvent/water solution of the antioxidant, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain FPL granules; or dissolving the FPL dihydrochloride and the antioxidant in an organic solvent/water solution, adding a mixture of 30% to 70% of the filler and 10% to 50% of the bindcr to the organic solvent/water solution with the FPL dihydrochloride and the antioxidant, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain FPL granules; (2) mixing the melitracen hydrochloride with 20% to 50% of the filler and 10% to 40% of the binder, subjecting a resulting mixture to stirring granulation, fluidized bed spray granulation, or extrusion granulation, and drying a resulting product to obtain melitracen granules; mid (3) mixing the FPL granules with the melitracen granules, 5% to 30% of the filler, the disintegrant; 10% to 60% of the binder, and the lubricant, and tableting and coating a resulting mixture.
- 6. The preparation method of the FPL-melitracen tablet according to claim 5, wherein the organic solvent is at least one from the group consisting of isopropanol, ethanol, and acetone.
- 7. The preparation method of the FPL-melitracen tablet according to claim 5, wherein fluidized bed drying is adopted, and the fluidized bed drying is conducted at a temperature of lower than 50°C until LOD% of the granules is not more than 3%.
- 8. A preparation method of the FPL-melitracen tablet according to any one of claims 1 to 4, comprising the following steps: ( I) thoroughly mixing the FPL dihydrochloride with the antioxidant, 10% to 70% of the filler, and 20% to 60% of the lubricant in an equal incremental manner, and subjecting a resulting mixture to dry rolling granulation to obtain FPL granules; (2) thoroughly mixing the melitracen hydrochloride with 10% to 50% of the filler and 20% to 50% of the lubricant, and subjecting a resulting mixture to dry rolling granulation to obtain melitracen granules; and (3) mixing the FPL granules with the melitracen granules, the disintegrant the binder, and 20% to 40% of the lubricant, and tableting and coating a resulting mixture.
- 9. The preparation method of the FPL-melitracen tablet according to claim 8, wherein the FPL dihydrochloride, and the antioxidant are first micronized mid then used for the granulation.
- 10. The preparation method of the FPL-melitracen tablet according to claim 8, wherein the FPL granules and the melitracen granules have a bulk density of 0.4 g/mL to 0.8 gimL.