WO2020143395A1 - 一种氟哌噻吨美利曲辛片剂及其制备方法 - Google Patents

一种氟哌噻吨美利曲辛片剂及其制备方法 Download PDF

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WO2020143395A1
WO2020143395A1 PCT/CN2019/125240 CN2019125240W WO2020143395A1 WO 2020143395 A1 WO2020143395 A1 WO 2020143395A1 CN 2019125240 W CN2019125240 W CN 2019125240W WO 2020143395 A1 WO2020143395 A1 WO 2020143395A1
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Prior art keywords
droperidol
hydrochloride
tablet
granules
melitrexine
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PCT/CN2019/125240
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English (en)
French (fr)
Inventor
卜水
陈运万
杨宇东
胡功允
王端统
郑伟国
许礼贵
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广东赛烽医药科技有限公司
海南辉能药业有限公司
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Priority to GB2111481.4A priority Critical patent/GB2595141B/en
Publication of WO2020143395A1 publication Critical patent/WO2020143395A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to a droperidol melitricine tablet and a preparation method thereof, which belong to the technical field of pharmaceutical preparations.
  • the stability of pharmaceutical preparations is a very important consideration during the design, production, and storage of pharmaceutical compositions. Drugs with poor stability may be degraded into certain degradation products to cause unnecessary side reactions or reduce the efficacy or bioavailability of the drug itself, making it difficult to achieve satisfactory results.
  • Haloperidol hydrochloride is the hydrochloride form of the atypical antipsychotic haloperidol. It is a thioxanthene derivative and has a strong dopamine receptor blocking effect. It has anxiolytic and antidepressant effects in small doses. Its chemical name is: 2-[4-[3(EZ)-(2-trifluoromethylthioanthracene-9-ylidene)propyl]piperazin-1-yl]ethanol dihydrochloride, structural formula as follows:
  • Melitrexine hydrochloride is a tricyclic biphasic antidepressant. It has exciting properties when used in low doses. Its chemical name is: 3-[10,10-dimethyl-9(10H)-anthracene]-N,N-dimethyl-1-propylamine hydrochloride, the structural formula is as follows:
  • Haloperidol was marketed in 1966, and its formulations include flupentixol tablets (specification: 0.5 mg and 5 mg) and droperidol injection (specification: 1 mL: 20 mg). Melicin was marketed in 1968, and its preparation is a capsule. Haloperidol and melitrexine compound formulations have antidepressant, anxiolytic and excitatory properties. Denmark's Lingbei Pharmaceutical Co., Ltd.
  • each tablet Contains 0.584mg of flupentixol dihydrochloride (0.5mg as flupenthixol) and 11.25mg of melitrexine hydrochloride (10mg as melitrexine), the product has mild to moderate depression and anxiety, neurasthenia Psychogenic depression, depressive neurosis have definite curative effect, fast onset, and small adverse reactions, and are one of the most used antidepressants in China.
  • the patent with publication number CN101912397A discloses a droperidol melitrisine tablet containing cyclodextrin, hydrogenated vegetable oil, lactose, starch, hydroxypropyl cellulose, microcrystalline cellulose and other auxiliary materials, in one of which
  • the premix of flupentixol is mixed with ⁇ -cyclodextrin, lactose monohydrate, corn starch, and hydroxypropylcellulose, and purified water is added to wet granulation, as the flupentixol granules, and then the United States Quxin, corn starch, lactose monohydrate, and hydroxypropylcellulose are mixed, and purified water is added for wet granulation.
  • the droperidol and meltriptan granules are combined with microcrystalline cellulose, Mix croscarmellose sodium, talc, hydroxypropyl cellulose, hydrogenated vegetable oil, and magnesium stearate, and tablet.
  • the process uses ⁇ -cyclodextrin as a stabilizer, the amount is large, and the tablet is easy to absorb moisture.
  • the patent with the publication number CN105663062A discloses a kind of droperidol xanthometricin tablet and its preparation method.
  • melitrixine is evenly divided into 2 to 5 batches and added to droperidol Mix evenly, add binder solution to granulate, dry, and adjust granules, mix evenly with disintegrant and lubricant, and tablet.
  • the process adopts the countercurrent gas flow method to add melitrexine to flupentixol.
  • the energy consumption of airflow crushing is large and the yield is unstable. It is difficult to ensure the controllability and reproducibility of the process. Litricin is highly irritating, the production process is dusty, and the operation is not feasible.
  • the patent with the publication number CN104288153A discloses a droperidol xanthometricin tablet and its preparation method, characterized by the use of fine particle size droperidol (particle size distribution D90 less than 150 ⁇ m), melitrixine, filling Agents, disintegrants, binders, lubricants are prepared by direct powder tableting process.
  • fine particle size droperidol particle size distribution D90 less than 150 ⁇ m
  • melitrixine filling Agents
  • disintegrants binders
  • lubricants are prepared by direct powder tableting process.
  • haloperidol is very sensitive to oxidation and light. Haloperidol is mainly degraded to Lu28-159 and trifluoromethyl thioxanthone, and melitrexine will also degrade under alkaline environment and oxidizing conditions The main degradation of melitrexin is 10,10-dimethylthioxanthone.
  • the main degradation pathways and degradation products of droperidol are as follows:
  • the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide a droperidol xanthimetrisine tablet and a preparation method thereof. Good reproducibility and stability, with excellent dissolution characteristics, stability, lower content of related substances, and more guarantee of product safety and effectiveness.
  • a droperidol xanthimetrisine tablet comprising the following components in mass percentage: droperidol hydrochloride 0.3% ⁇ 1.0%, melitrixine hydrochloride 5.78% to 19.26%, antioxidant 0.01% to 10%, filler 60% to 88%, disintegrant 0.5% to 6%, binder 2% to 6%, lubricant 0.2% to 3%.
  • the droperixant melitrixine tablet contains the following components in mass percentage: droperidol hydrochloride 0.4%-0.8%, hydrochloric acid Meltrixine 7.71% to 15.41%, antioxidant 0.02% to 5%, filler 72% to 85%, disintegrant 0.5% to 4%, binder 3% to 5%, lubricant 0.5% to 2%.
  • the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, sodium thiosulfate, L-cysteine, vitamin C or its sodium salt, vitamin C palm At least one of acid ester, vitamin E, and water-soluble organic weak acid;
  • the filler is at least one of microcrystalline cellulose, lactose, dibasic calcium phosphate, starch, mannitol, and calcium carbonate;
  • the disintegrant is croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium At least one of
  • the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, sodium carboxymethyl cellulose, methyl cellulose, and gum arabic;
  • the lubricant is at least one of silica, magnesium stearate, stearic acid, sodium stearyl fumarate, talc, and glyceryl behenate;
  • the flupentixol melitrexine tablet further includes a coating material, the mass of the coating material is 2% to 10% of the mass of the tablet core, and the coating material is Opadry II. At least one of Opadry 200 and Opadry amb.
  • the antioxidant is tert-butyl-p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, vitamin C, vitamin C At least one of palmitate and water-soluble organic weak acid.
  • the antioxidant is at least one of t-butyl p-hydroxyanisole, dibutylhydroxytoluene, and propyl gallate.
  • the antioxidant is dibutylhydroxytoluene
  • the filler is at least one of microcrystalline cellulose, lactose, starch, and calcium hydrogen phosphate;
  • the disintegrant is at least one of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch;
  • the binder is at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and povidone;
  • the lubricant is at least one of silica, magnesium stearate, stearic acid, talc, and glyceryl behenate;
  • the mass of the coating material is 3% to 6% of the mass of the tablet core.
  • the present invention provides a wet granulation preparation method of the droperidol xanthimetrisine tablet, which includes the following steps:
  • the preferred preparation method of the droperisteine granules is to dissolve droperidol hydrochloride and an antioxidant in an organic solution Solvent/aqueous solution, after mixing part of the filler and part of the binder, add organic solvent/aqueous solution of droperidol hydrochloride and antioxidant, stirring granulation or fluidized spray granulation or extrusion granulation, drying, Obtained droperidol particles.
  • the granulation process is agitation granulation.
  • the coating material is dissolved or suspended in an appropriate amount of solvent, and the solvent is 20%-85% ethanol At least one of an aqueous solution and purified water.
  • the organic solvent is at least one of isopropyl alcohol, ethanol, and acetone.
  • the drying process uses fluidized bed drying, the temperature is controlled below 50°C, and the LOD% of the granules does not exceed 3%.
  • the present invention provides a dry granulation preparation method of the droperidol xanthimetrisine tablet, which includes the following steps:
  • the droperidol hydrochloride and the antioxidant are granulated after being micronized.
  • the bulk density of the droperixant granules and the melitoxine particles is 0.4-0.8 g/mL.
  • the coating material is dissolved or suspended in an appropriate amount of solvent, and the solvent is 20%-85% ethanol At least one of an aqueous solution and purified water.
  • the beneficial effects of the present invention are as follows: the droperixantomelitrixine tablet of the present invention, by adding an antioxidant, can effectively enhance the stability of droperidol ximelitricin tablet , Can effectively control the degradation of droperidol to produce Lu28-159, trifluoromethyl thioxanthone and other impurities, reduce the level of impurities, and ensure product safety and effectiveness; the droperidol melitresin tablets prepared according to the present invention The agent has similar in vitro dissolution behavior and bioequivalence to the original tablet Deanxit.
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.30%, 0.08%, 82.69%, 1.49%, 4.96%, 0.99%, the quality of each component is shown in Table 1.
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.19%, 0.82%, 81.68%, 1.96%, 4.41%, 1.47%, the quality of each component is shown in Table 1.
  • melitrexine hydrochloride anhydrous lactose, starch, and hydroxypropyl cellulose into a high-speed stirring granulator, add purified water, stir and shear granulation; fluidized bed drying, whole granulation, that is, melitrexine Particles
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.48 %, 9.20%, 0.65%, 81.81%, 1.96%, 4.42%, 1.47%, the quality of each component is shown in Table 1.
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.49 %, 9.38%, 8.38%, 73.40%, 3.00%, 4.50%, 0.83%, the quality of each component is shown in Table 1.
  • melitrexine hydrochloride lactose and microcrystalline cellulose into the fluidized granulator, add the aqueous solution of povidone K30, fluidize the granules, dry and adjust the granules to obtain the melitrexine granules;
  • a kind of droperidol melitrexine tablet wherein the mass percentages of droperidol hydrochloride, melitrexine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.47% , 9.12%, 0.61%, 81.05%, 2.92%, 4.86%, 0.97%, the quality of each component is shown in Table 1.
  • a kind of droperidol xanthimelide tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.53 %, 10.16%, 0.09%, 81.28%, 3.25%, 3.25%, 1.44%, the quality of each component is shown in Table 1.
  • melitrexine hydrochloride, anhydrous lactose, microcrystalline cellulose, and magnesium stearate uniformly, roll the tablets into a dry granulator, and then granulate to obtain melitrexine granules;
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 1.04, respectively %, 19.99%, 0.01%, 71.96%, 0.5%, 6.01%, 0.5%, the quality of each component is shown in Table 1.
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, antioxidant, filler, disintegrant, binder, lubricant are 0.26 %, 5%, 10%, 73.74%, 6%, 2%, 3%, the quality of each component is shown in Table 1.
  • melitrexine hydrochloride, anhydrous lactose, microcrystalline cellulose, and magnesium stearate uniformly, roll the tablets into a dry granulator, and then granulate to obtain melitrexine granules;
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, filler, disintegrant, binder, lubricant are 0.48% and 9.31%, respectively , 82.76%, 1.49%, 4.97%, 0.99%, the quality of each component is shown in Table 2.
  • the preparation method of the tablet of the comparative example is as follows:
  • a kind of droperidol xanthometricin tablet wherein the mass percentages of droperidol hydrochloride, melitroxine hydrochloride, filler, disintegrant, binder, lubricant are 0.53% and 10.17% respectively , 81.35%, 3.25%, 3.25%, 1.45%, the quality of each component is shown in Table 2.
  • the preparation method of the tablet of the comparative example is as follows:
  • melitrexine hydrochloride, lactose, and microcrystalline cellulose evenly, and roll-press the tablet with a dry granulator to form granules to obtain melitrexine granules;
  • dissolution determination method Choinese Pharmacopoeia 2015 edition four parts 0931 general rules second method
  • the dissolution of Examples 1 to 8 and Comparative Examples 1 to 2 were tested.
  • the rotation speed is 75 revolutions per minute, and samples are taken after 30 minutes, and the continuous filtrate is taken as the solution for the test product; according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) Determination.
  • phenylsilane-bonded silica gel as a filler (XBridge TM Phenyl 3.5 ⁇ m, 4.6 ⁇ 100mm chromatographic column is applicable), using 0.02mol/L ammonium acetate buffer-methanol (35:65) as the mobile phase, the detection wavelength is 270nm, Flow rate 1.0mL/min, column temperature 40°C.
  • the theoretical plate number should be no less than 1400 based on the melitrexine peak, and the resolution of the melitrexine peak and the droperidol peak should be greater than 2.0.
  • Examples 1 to 8 of the present invention and Comparative Examples 1 to 2 were placed under accelerated test conditions (40°C/75% RH) for 6 months, and the changes in content, dissolution and related substances were investigated.
  • the test results are shown in Table 4.
  • Determination of content take 20 tablets of this product, weigh accurately, grind them into powder, take appropriate amount of sample powder (equivalent to 20mg of melitrexine and 1mg of droperidol), weigh accurately, place in 50ml measuring bottle, add flow Phase 40ml, shake to completely disperse and wet the sample, sonicate for 20min, let cool to room temperature, dilute to the mark with mobile phase, shake and filter, discard the initial filtrate and collect the subsequent filtrate to obtain the test solution .
  • melitrexine hydrochloride reference substance (the conversion coefficient of melitrexine and melitrexine hydrochloride is 0.8887) about 22.6mg, accurately weigh it, put it in a 50ml measuring bottle, and accurately remove the droperidol hydrochloride reference substance reserve Dissolve 2ml into the same volumetric flask, dissolve with mobile phase and dilute to the mark, shake well to obtain a control solution containing haloperidol 0.02mg/ml and melitrexine 0.4mg/ml. According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) determination.
  • Phenylsilane-bonded silica gel as filler (XBridge TM Phenyl 3.5 ⁇ m, 4.6 ⁇ 100mm), with 0.02mol/L ammonium acetate buffer-methanol (35:65) as mobile phase, detection wavelength of 270nm, flow rate 1.0mL /min, column temperature 40°C.
  • the number of theoretical plates calculated according to the peak of Melitrexine should not be less than 3000, and the resolution of the peaks of Melitrexine and droperidol should be greater than 4.0. Precisely measure 10 ⁇ L each of the test solution and the reference solution, and inject it into a high-performance liquid chromatograph. Calculate the content of melitrexin and droperidol in each tablet according to the peak area according to the external standard method.
  • Dissolution test the same as the dissolution test method in Effect Example 1.
  • the chromatographic conditions were tested under the same content.
  • the control solution and the test solution were each 20 ⁇ L and injected into high performance liquid chromatography.
  • Relative to the marked amount of melitrexine a single unknown impurity shall not exceed 0.2%, and the total amount of impurities shall not exceed 4.0%.
  • Table 5 shows the AUC 0- ⁇ and C max of droperidol and melitrexine .
  • Table 6 compares the BE of the test formulation (T) and the reference formulation (R).
  • the inventors conducted a bioequivalence test on the tablets of the present invention with different ratios.
  • the test results show that the tablets prepared with the components and the ratio of the present invention are bioequivalent to Deanxit.
  • the test process and data are in This will not be repeated here.
  • the type of antioxidant of the present invention affects the stability of droperidol xanthimetrisine tablets.
  • the applicant prepared a test In the group, the dissolution rate and stability of the dropofixantomelitrixine tablets were tested according to the test methods of effect example 1 and effect example 2 according to the test methods of effect example 1 and effect example 2.
  • the types of antioxidants are different, and the rest are the same.
  • the types of antioxidants are shown in Table 7.
  • the mass of droperidol hydrochloride was 0.584 mg/tablet
  • the antioxidant mass was 0.4 mg/tablet
  • the filler was lactose and microcrystalline cellulose (1:2).
  • the mass is 58mg/tablet
  • the binder is hydroxypropylcellulose, and the mass is 1.8mg/tablet
  • the mass of melitrexine hydrochloride is 11.25mg/tablet
  • the filler is lactose and microcrystalline fibers Element (1:3)
  • the mass is 28mg/tablet
  • the binder is hydroxypropyl cellulose
  • the mass is 1.2mg/tablet
  • the disintegrant is croscarmellose sodium
  • the quality is 1.8mg Per tablet
  • the filler is microcrystalline cellulose with a mass of 14 mg per tablet
  • the binder is hydroxypropyl cellulose with a mass of 3 mg per tablet
  • the lubricant is stearic acid with a mass of 1.2 mg per tablet.
  • the type of antioxidant of the present invention affects the stability of droperidol melitricine tablets.
  • the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate , Vitamin C, vitamin C palmitate
  • the stability of droperidol melitrisine tablets is better; when the antioxidant is tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate
  • the stability of droperidol melitricine tablets is better; when the antioxidant is dibutylhydroxytoluene, the stability of droperidol melitricine tablets is the best.
  • the mass percentage of the antioxidant of the present invention affects the stability of droperidol melitricine tablets.
  • the test group and the control group of droperioxant melitrixine tablets were tested, and according to the test methods of effect example 1 and effect example 2, the effect group test group and control group of droperioxant melitrixine tablets were tested Dissolution and stability.
  • the mass percentages of antioxidants are different. Except for the mass percentage of fillers, the mass percentages of the other auxiliary materials are the same.
  • the mass percentages of droperidol hydrochloride, melitrexine hydrochloride, and antioxidants are shown in Table 8. Shown.
  • the antioxidant was dibutylhydroxytoluene
  • the filler was lactose and microcrystalline cellulose (1:2)
  • the mass was 58 mg/tablet
  • the binder was hydroxy Propylcellulose, mass: 1.8 mg/tablet
  • the mass is 28 mg/tablet
  • the binder is hydroxypropylcellulose
  • the mass is 1.2mg/tablet
  • the disintegrant is croscarmellose sodium
  • the quality is 1.8mg/tablet
  • the binder is hydroxypropyl cellulose
  • the quality is 3mg/tablet
  • the lubricant is stearic acid
  • the mass is 1.2mg/tablet
  • the rest are fillers
  • the filler is microcrystalline cellulose.
  • the mass percentage of the antioxidant of the present invention affects the stability of droperidol melitricine tablets.
  • the mass ratio of the antioxidant in the control group 1 is 0.006%
  • the stability of the related substances is slightly worse
  • the mass ratio of the antioxidant 2 in the control group is 12%
  • the stability is better, but it is not better than the mass ratio of 10%, so it is preferred that the mass percentage of the antioxidant is 0.01% to 10%.
  • the stability of thioxanthene and melitoxine tablets is better; when it is further preferred that the mass percentage of the antioxidant is 0.02% to 5%, the stability of flupentixol and melitoxine tablets is the best.
  • the mass percentage of flupentixol hydrochloride and melitrexine hydrochloride in the present invention affects the stability of flupentixol hydrochloride and melitrexine tablets.
  • the applicant prepared the test group and the control group of droperithione melitoxine tablets, and tested this effect according to the test methods of effect example 1 and effect example 2. Dissolution and stability of dropperidoxantimemeltrixine tablets in experimental group and control group.
  • the mass percentages of droperidol hydrochloride and melitrexine hydrochloride are different. Except for the mass percentage of fillers, the mass percentages of other auxiliary materials are the same. The mass percentage of octene and the mass of filler are shown in Table 9.
  • the antioxidant was dibutylhydroxytoluene with a mass percentage of 0.08%, and the binder was hydroxypropylcellulose with a mass percentage of 1.49%; melitroxine granules Medium, the mass of melitrexine hydrochloride is 11.25mg/tablet, the binder is hydroxypropyl cellulose, the mass percentage is 0.99%; in the auxiliary materials, the disintegrant is croscarmellose sodium, the mass percentage is 1.49 %, the binder is hydroxypropyl cellulose, the mass percentage is 2.48%, the lubricant is magnesium stearate, the mass percentage is 0.99%, and the rest are fillers.
  • the mass percentage of droperidol hydrochloride and melitrexine hydrochloride of the present invention affects the stability of droperidol xenolide melitrexine tablets.
  • the mass percentage of droperisen hydrochloride is 0.3% to 1.0 %
  • the mass percentage of melitrexine hydrochloride is 5.78% to 19.26%
  • the stability of droperidol melitrexine tablets is better
  • the mass percentage of droperisen hydrochloride is 0.4% to 0.8%
  • the mass percentage of melitrexine hydrochloride is 7.71% to 15.41%
  • the stability of flupentixol mexterine tablets is the best.

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Abstract

一种氟哌噻吨美利曲辛片剂及其制备方法，属于药物制剂技术领域。氟哌噻吨美利曲辛片剂包含如下质量百分比的组分：盐酸氟哌噻吨0.3％～1.0％、盐酸美利曲辛5.78％～19.26％、抗氧剂0.01％～10％、填充剂60％～88％、崩解剂0.5％～6％、粘合剂2％～6％、润滑剂0.2％～3％。通过加入抗氧剂，能够有效增强氟哌噻吨美利曲辛片剂的稳定性，能够有效控制氟哌噻吨降解产生Lu28-159、三氟甲基噻吨酮等杂质，降低杂质水平，保证产品安全性和有效性；与原研片剂Deanxit具有相似的体外溶出行为和生物等效性。

Description

一种氟哌噻吨美利曲辛片剂及其制备方法 技术领域
本发明涉及一种氟哌噻吨美利曲辛片剂及其制备方法，属于药物制剂技术领域。
背景技术
通常情况下，在药物组合物设计、生产、存储期间，药物制剂的稳定性是非常重要的考虑因素。稳定性不佳的药物可能降解成某些降解产物引起一些不必要副反应或减低药物本身具备的疗效或生物利用度，从而很难达到令人满意的效果。
盐酸氟哌噻吨是非典型抗精神病药物氟哌噻吨的盐酸盐形式，为硫杂蒽类衍生物，具有强大的阻断多巴胺受体作用，小剂量具有抗焦虑和抗抑郁作用。其化学名为：2-[4-[3(EZ)-(2-三氟甲基硫杂蒽-9-基亚基)丙基]哌嗪-1-基]乙醇二盐酸盐，结构式如下：
Figure PCTCN2019125240-appb-000001
盐酸美利曲辛是一种三环类双相抗抑郁药，低剂量应用时，具有兴奋特性。其化学名为：3-[10，10-二甲基-9(10H)-蒽亚基]-N，N-二甲基-1-丙胺盐酸盐，结构式如下：
Figure PCTCN2019125240-appb-000002
氟哌噻吨于1966年上市，其制剂有氟哌噻吨片(规格：0.5mg及5mg)及氟哌噻吨注射液(规格：1mL:20mg)。美利曲辛于1968年上市，其制剂为胶囊剂。氟哌噻吨和美利曲辛两种成分的复方制剂具有抗抑郁、抗焦虑和兴奋特性，丹麦灵北制药有限公司开发上市的氟哌噻吨美利曲辛片，商品名为Deanxit，每片含二盐酸氟哌噻吨0.584mg(以氟哌噻吨计0.5mg)和盐酸美利曲辛11.25mg(以美利曲辛计10mg)，该产品对轻、中度抑郁和焦虑、神经衰弱、心 因性抑郁、抑郁性神经官能症疗效确切、起效快、不良反应小，是国内使用最多的抗抑郁药之一。
目前已有多篇文献公开了氟哌噻吨美利曲辛复方制剂及其制备方法。
公开号为CN101912397A的专利公开了一种含环糊精、氢化植物油、乳糖、淀粉、羟丙基纤维素、微晶纤维素等辅料的氟哌噻吨美利曲辛片剂，在其中一个实施例中，将氟哌噻吨预混物与与β环糊精、一水乳糖、玉米淀粉、羟丙纤维素混合，加入纯化水进行湿法制粒，作为氟哌噻吨颗粒，再将美利曲辛、玉米淀粉、一水乳糖、羟丙纤维素混合，加入纯化水进行湿法制粒，作为美利曲辛颗粒，将氟哌噻吨颗粒和美利曲辛颗粒合并，与微晶纤维素、交联羧甲基纤维素钠、滑石粉、羟丙纤维素、氢化植物油、硬脂酸镁混合，压片。该工艺采用β环糊精作为稳定剂，用量较大，片剂易吸潮。
公开号为CN105663062A的专利公开了一种氟哌噻吨美利曲辛片及其制备方法，对冲气流粉碎下，将美利曲辛均匀地分2～5批次加入到氟哌噻吨中进行混合均匀，加入粘合剂溶液制粒、干燥、整粒，与崩解剂和润滑剂混合均匀，压片。该工艺采用对冲气流法将美利曲辛加入氟哌噻吨中，气流粉碎能耗较大且收率不稳定，难以保证工艺可控性和重现性，且盐酸氟哌噻吨和盐酸美利曲辛刺激性强，生产过程粉尘飞扬，操作可行性不佳。
公开号为CN104288153A的专利公开了一种氟哌噻吨美利曲辛片及其制备方法，特征在于采用细粒径的氟哌噻吨(粒径分布D90小于150μm)、美利曲辛、填充剂、崩解剂、粘合剂、润滑剂，采用全粉末直接压片工艺制备。该发明中虽生产工艺简单，但由于不含有稳定剂，不能保证产品在制备及贮藏过程中的稳定性。
上述现有技术均未根据氟哌噻吨和美利曲辛的稳定性特点，而进行处方成分选择。根据强制降解试验，氟哌噻吨对氧化和光照非常敏感，氟哌噻吨主要降解为Lu28-159和三氟甲基噻吨酮，美利曲辛也会在碱性环境和氧化条件下降解，美利曲辛主要降解为10,10-二甲基噻吨酮。氟哌噻吨的主要降解途径和降解产物如下：
Figure PCTCN2019125240-appb-000003
因此，针对氟哌噻吨美利曲辛复方制剂，亟待寻求一种能够保证产品质量稳定、制备工艺简便可行的氟哌噻吨美利曲辛片剂的制备方法。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种氟哌噻吨美利曲辛片剂及其制备方法，本发明制得的氟哌噻吨美利曲辛片剂，工艺重现性及稳定性好，具有优异的溶出特性、稳定性、更低的有关物质含量、更能保证产品的安全性和有效性。
为实现上述目的，本发明采取的技术方案为：一种氟哌噻吨美利曲辛片剂，包含如下质量百分比的组分：盐酸氟哌噻吨0.3％～1.0％、盐酸美利曲辛5.78％～19.26％、抗氧剂0.01％～10％、填充剂60％～88％、崩解剂0.5％～6％、粘合剂2％～6％、润滑剂0.2％～3％。
作为本发明所述氟哌噻吨美利曲辛片剂的优选实施方式，氟哌噻吨美利曲辛片剂包含如下质量百分比的组分：盐酸氟哌噻吨0.4％～0.8％、盐酸美利曲辛7.71％～15.41％、抗氧剂0.02％～5％、填充剂72％～85％、崩解剂0.5％～4％、粘合剂3％～5％、润滑剂0.5％～2％。
作为本发明所述氟哌噻吨美利曲辛片剂的优选实施方式，如下(a)～(f)中的至少一项：
(a)所述抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、硫代硫酸钠、L-半胱氨酸、维生素C或其钠盐、维生素C棕榈酸酯、维生素E、水溶性有机弱酸中的至少一种；
(b)所述填充剂为微晶纤维素、乳糖、磷酸氢钙、淀粉、甘露醇、碳酸钙中的至少一种；
(c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀 粉钠、羧甲基纤维素、羧甲基纤维素钙中的至少一种；
(d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、***胶中的至少一种；
(e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、硬脂酰富马酸钠、滑石粉、山嵛酸甘油酯中的至少一种；
(f)所述氟哌噻吨美利曲辛片剂还包括包衣材料，所述包衣材料的质量为片剂片芯质量的2％～10％，所述包衣材料为欧巴代II、欧巴代200、欧巴代amb中的至少一种。
作为本发明所述氟哌噻吨美利曲辛片剂的优选实施方式，所述抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、维生素C、维生素C棕榈酸酯、水溶性有机弱酸中的至少一种。
作为本发明所述氟哌噻吨美利曲辛片剂的优选实施方式，所述抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯中的至少一种。
作为本发明所述氟哌噻吨美利曲辛片剂的优选实施方式，如下(a)～(f)中的至少一项：
(a)所述抗氧剂为二丁基羟基甲苯；
(b)所述填充剂为微晶纤维素、乳糖、淀粉、磷酸氢钙中的至少一种；
(c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀粉钠中的至少一种；
(d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮中的至少一种；
(e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、滑石粉、山嵛酸甘油酯中的至少一种；
(f)所述包衣材料的质量为片剂片芯质量的3％～6％。
第二方面，本发明提供了所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法，包括如下步骤：
(1)将盐酸氟哌噻吨与5％～30％填充剂进行等量递加混合，再与30％～70％填充剂、10％～50％粘合剂混合，加入抗氧剂的有机溶剂/水溶液，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得氟哌噻吨颗粒；
或将盐酸氟哌噻吨与抗氧剂溶于有机溶剂/水溶液，将30％～70％填充剂、10％～50％粘合剂混合后，加入盐酸氟哌噻吨与抗氧剂的有机溶剂/水溶液，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得氟哌噻吨颗粒；
(2)将盐酸美利曲辛与20％～50％填充剂、10％～40％粘合剂混合，进行搅拌制粒或流化 喷雾制粒或离心喷雾制粒或挤压制粒，干燥，得美利曲辛颗粒；
(3)将氟哌噻吨颗粒与美利曲辛颗粒、5％～30％填充剂、崩解剂、10％～60％粘合剂、润滑剂混合，压片，包衣。
作为本发明所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法的优选实施方式，氟哌噻吨颗粒的优选制备方法为：将盐酸氟哌噻吨与抗氧剂溶于有机溶剂/水溶液，将部分填充剂、部分粘合剂混合后，加入盐酸氟哌噻吨与抗氧剂的有机溶剂/水溶液，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得氟哌噻吨颗粒。
作为本发明所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法的优选实施方式，制粒工艺为搅拌制粒。
作为本发明所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法的优选实施方式，所述包衣材料溶解或混悬在适量溶剂中，所述溶剂为20％～85％乙醇水溶液、纯化水中的至少一种。
作为本发明所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法的优选实施方式，所述有机溶剂为异丙醇、乙醇、丙酮中的至少一种。
作为本发明所述氟哌噻吨美利曲辛片剂的湿法制粒制备方法的优选实施方式，所述干燥过程采用流化床干燥，温度控制在50℃以下，干燥至颗粒LOD％不超过3％。
第三方面，本发明提供了所述氟哌噻吨美利曲辛片剂的干法制粒制备方法，包括如下步骤：
(1)将盐酸氟哌噻吨与抗氧剂、10％～70％填充剂、20％～60％润滑剂进行等量递加混合均匀，通过辊压法进行干法制粒，得氟哌噻吨颗粒；
(2)将美利曲辛与10％～50％填充剂、20％～50％润滑剂混合混合均匀，通过辊压法进行干法制粒，得美利曲辛颗粒；
(3)将氟哌噻吨颗粒与美利曲辛颗粒、崩解剂、粘合剂、20％～40％润滑剂混合，压片，包衣。
作为本发明所述氟哌噻吨美利曲辛片剂的干法制粒制备方法的优选实施方式，所述盐酸氟哌噻吨、抗氧剂经过微粉化处理后进行制粒。
作为本发明所述氟哌噻吨美利曲辛片剂的干法制粒制备方法的优选实施方式，所述氟哌噻吨颗粒与美利曲辛颗粒的松密度为0.4～0.8g/mL。
作为本发明所述氟哌噻吨美利曲辛片剂的干法制粒制备方法的优选实施方式，所述包衣材料溶解或混悬在适量溶剂中，所述溶剂为20％～85％乙醇水溶液、纯化水中的至少一种。
与现有技术相比，本发明的有益效果为：本发明的氟哌噻吨美利曲辛片剂，通过加入抗氧剂，能够有效增强氟哌噻吨美利曲辛片剂的稳定性，能够有效控制氟哌噻吨降解产生Lu28-159、三氟甲基噻吨酮等杂质，降低杂质水平，保证产品安全性和有效性；按照本发明制备的氟哌噻吨美利曲辛片剂与原研片剂Deanxit具有相似的体外溶出行为和生物等效性。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
实施例1
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.48％、9.30％、0.08％、82.69％、1.49％、4.96％、0.99％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、二丁基羟基甲苯溶于80％乙醇-水溶液中，搅拌至澄清；将无水乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与二丁基羟基甲苯的80％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、无水乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物片剂。
表1
Figure PCTCN2019125240-appb-000004
Figure PCTCN2019125240-appb-000005
Figure PCTCN2019125240-appb-000006
实施例2
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.48％、9.19％、0.82％、81.68％、1.96％、4.41％、1.47％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、没食子酸丙酯溶于75％乙醇-水溶液中，搅拌至澄清；将无水乳糖、淀粉、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与没食子酸丙酯的75％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、无水乳糖、淀粉、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例3
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.48％、9.20％、0.65％、81.81％、1.96％、4.42％、1.47％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、叔丁基对羟基茴香醚溶于75％乙醇-水溶液中，搅拌至澄清；将磷酸氢钙、微晶纤维素、羟丙甲纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与叔丁基对羟基茴香醚的75％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、磷酸氢钙、微晶纤维素、羟丙甲纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例4
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.49％、9.38％、8.38％、73.40％、3.00％、4.50％、0.83％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、二丁基羟基甲苯、维生素C、聚维酮K30溶于75％乙醇-水溶液中，搅拌至澄清；将乳糖、微晶纤维素放入流化制粒机中，加入盐酸氟哌噻吨与二丁基羟基甲苯、维生素C、聚维酮K30的75％乙醇-水溶液，流化制粒，干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素放入流化制粒机中，加入聚维酮K30水溶液，流化制粒，干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例5
一种氟哌噻吨美利曲辛片剂，其中盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.47％、9.12％、0.61％、81.05％、2.92％、4.86％、 0.97％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将二丁基羟基甲苯、没食子酸丙酯溶于80％乙醇-水溶液中，搅拌至澄清；将盐酸氟哌噻吨与乳糖等量递加混合均匀，再与淀粉、羟丙纤维素混合，放入高速搅拌制粒机中，加入二丁基羟基甲苯、没食子酸丙酯的80％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、淀粉、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例6
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.53％、10.16％、0.09％、81.28％、3.25％、3.25％、1.44％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、二丁基羟基甲苯与无水乳糖等量递加混合均匀，再与无水乳糖、微晶纤维素、硬脂酸镁混合均匀，干法制粒机辊压制片，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、无水乳糖、微晶纤维素、硬脂酸镁混合均匀，干法制粒机辊压制片，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例7
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩 解剂、粘合剂、润滑剂的质量百分比分别为1.04％、19.99％、0.01％、71.96％、0.5％、6.01％、0.5％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、维生素C棕榈酸酯溶于75％乙醇-水溶液中，搅拌至澄清；将乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与维生素C棕榈酸酯的75％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
实施例8
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.26％、5％、10％、73.74％、6％、2％、3％，各组分的质量如表1所示。
本实施例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨与无水乳糖等量递加混合均匀，再与无水乳糖、维生素C、微晶纤维素、硬脂酸镁混合均匀，干法制粒机辊压制片，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、无水乳糖、微晶纤维素、硬脂酸镁混合均匀，干法制粒机辊压制片，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
对比例1
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、填充剂、崩解剂、粘 合剂、润滑剂的质量百分比分别为0.48％、9.31％、82.76％、1.49％、4.97％、0.99％，各组分的质量如表2所示。
本对比例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨溶于80％乙醇-水溶液中，搅拌至澄清；将无水乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入药物溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、无水乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与外加辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
对比例2
一种氟哌噻吨美利曲辛片剂，其中，盐酸氟哌噻吨、盐酸美利曲辛、填充剂、崩解剂、粘合剂、润滑剂的质量百分比分别为0.53％、10.17％、81.35％、3.25％、3.25％、1.45％，各组分的质量如表2所示。
本对比例所述片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨与乳糖等量递加混合均匀、再与乳糖、微晶纤维素、硬脂酸镁混合均匀，干法制粒机辊压制片，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素混合均匀，干法制粒机辊压制片，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与外加辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛药物组合物。
表2
Figure PCTCN2019125240-appb-000007
Figure PCTCN2019125240-appb-000008
效果例1
本发明实施例1～8和对比例1～2的溶出度试验
照溶出度测定法(中国药典2015年版四部0931通则第二法)，检测实施例1～8和对比例1～2的溶出度。以0.1mol/L盐酸溶液900mL为溶出介质，转速为每分钟75转，经30分钟时，取样，取续滤液作为供试品溶液；照高效液相色谱法(中国药典2015年版四部通则0512)测定。以苯基硅烷键合硅胶为填充剂(XBridge  TM Phenyl 3.5μm，4.6×100mm色谱柱适用)，以0.02mol/L醋酸铵缓冲液-甲醇(35:65)为流动相，检测波长为270nm，流速1.0mL/min，柱温40℃。理论板数按美利曲辛峰计算应不低于1400，美利曲辛峰与氟哌噻吨峰的分离度应大于2.0。另精密称取盐酸氟哌噻吨对照品、盐酸美利曲辛对照品适量，加甲醇溶解，精密量取两对照品溶液适量，置同一量瓶中，加溶出介质稀释，制成每1mL约含氟哌噻吨0.5μg及美利曲辛10μg的溶液，摇匀，作为对照品溶液(美利曲辛与盐酸美利曲辛的换算因子为0.8887，氟哌噻吨与盐酸氟哌噻吨的换算因子为0.8562)。精密量取供试品溶液和对照品溶液各10μL，分别注入液相色谱仪，记录色谱图，按外标法以峰面积计算，分别测定每片中氟哌噻吨和美利曲辛的溶出量。限度均为标示量的80％，应符合规定。试验结果如表3所示。
表3
Figure PCTCN2019125240-appb-000009
由表3可知，本发明氟哌噻吨美利曲辛片剂的两个活性成分的溶出度高，均符合要求。
效果例2
本发明实施例1～8和对比例1～2的稳定性试验
取本发明实施例1～8和对比例1～2放置于加速试验条件(40℃/75％RH)下6个月，考察含量、溶出度和有关物质的变化情况。试验结果如表4所示。
含量测定：取本品20片，精密称定，研磨成粉，取适量样品粉末(相当于含美利曲辛20mg，氟哌噻吨1mg)，精密称定，置50ml量瓶中，加流动相40ml，振摇使样品完全分散与被润湿，超声处理20min，放冷至室温，用流动相稀释至刻度，摇匀，过滤，弃去初滤液后收集续滤液，即得供试品溶液。取盐酸氟哌噻吨对照品(氟哌噻吨与盐酸氟哌噻吨的换算系数为0.8562)约29mg，精密称定，置50ml量瓶中，加甲醇溶解并稀释至刻度，即可得含氟哌噻吨0.5mg/ml对照品储备液。取盐酸美利曲辛对照品(美利曲辛与盐酸美利曲辛的换算系数为0.8887)约22.6mg，精密称定，置50ml量瓶中，精密移取盐酸氟哌噻吨对照品储备液2ml至同一量瓶中，用流动相溶解并稀释至刻度，摇匀，即得含氟哌噻吨0.02mg/ml，美利曲辛0.4mg/ml的对照溶液。照高效液相色谱法(中国药典2015年版四部通则0512)测定。以苯基硅烷键合硅胶为填 充剂(XBridge  TM Phenyl 3.5μm，4.6×100mm)，以0.02mol/L醋酸铵缓冲液-甲醇(35:65)为流动相，检测波长为270nm，流速1.0mL/min，柱温40℃。理论板数按美利曲辛峰计算应不低于3000，美利曲辛峰与氟哌噻吨峰的分离度应大于4.0。精密量取供试品溶液和对照品溶液各10μL，注入高效液相色谱仪，按外标法以峰面积分别计算每片中美利曲辛和氟哌噻吨的含量。
溶出度检查：同效果例1中溶出度试验方法。
有关物质检查：取含量测定项下适量本品粉末(相当于含美利曲辛20mg和氟哌噻吨1mg)，精密称定，置50ml量瓶中，加流动相40ml，振摇使样品完全分散与被润湿，超声处理20min，放冷至室温，用流动相稀释至刻度，摇匀即得，过滤，取续滤液即得；称取Lu28-159盐酸盐、10,10-二甲基蒽酮、盐酸三氟甲基噻吨酮、美利曲辛、氟哌噻吨对照品适量，精密称定，置量瓶中，用流动相稀释，摇匀，配制含有Lu28-159 0.4μg/ml、10,10-二甲基蒽酮1.6μg/ml、美利曲辛0.8μg/ml、三氟甲基噻吨酮0.24μg/ml和氟哌噻吨0.20μg/ml的对照溶液。色谱条件同含量项下试验，取对照品溶液、供试品溶液各20μL，分别注入高效液相色谱。按外标法以峰面积计算，相对于氟哌噻吨的标示量，含Lu28-159不得过2.5％；三氟甲基噻吨酮不得过2.0％；相对于美利曲辛的标示量，含10,10-二甲基蒽酮不得过0.5％。相对于美利曲辛的标示量，含单个未知杂质不得过0.2％，杂质总量不得过4.0％。
由表4可知，本发明提供的实施例样品在40℃/75％RH条件下放置6个月，含量、有关物质、溶出度均较稳定性，与0天比无明显变化。而对比例的氟哌噻吨含量、有关物质和溶出度有显著下降，超出限度要求，其中与氟哌噻吨相关的降解杂质Lu28-159和三氟甲基噻吨酮显著升高，表明在没有抗氧剂保护下，本品难以保证产品的质量稳定性。因此，本发明提供的氟哌噻吨美利曲辛片剂，能够有效的提高产品的稳定性，疗效好，质量稳定可靠。
表4
Figure PCTCN2019125240-appb-000010
Figure PCTCN2019125240-appb-000011
效果例3
为了研究本发明片剂与Deanxit是否生物等效，进行健康受试者空腹口服氟哌噻吨美利曲辛片随机、开放、单剂量、两周期、交叉人体生物等效性试验。24位受试者入选。受试者于第一天接受随机单剂量口服给药本发明片剂实施例1中的氟哌噻吨美利曲辛片(自制制剂)或Deanxit(参比制剂)给药。间隔14天清洗期后，受试者接受另一种药物(自制制剂或参比制剂)给药，采集血样直至给药后120小时，测定血浆中氟哌噻吨和美利曲辛浓度，通过计算主要药代参数(AUC 0-∞和C max)的几何平均值比率的90％置信区间，评价生物等效性。
表5显示了氟哌噻吨和美利曲辛的AUC 0-∞和C max。
表5
Figure PCTCN2019125240-appb-000012
表6为受试制剂(T)与参比制剂(R)BE比较。
表6
Figure PCTCN2019125240-appb-000013
由表5和表6可知，AUC 0-∞和C max经对数转换后的几何平均值比率及90％CI均在80.00～125.00％范围，达到生物等效标准，表明本发明的氟哌噻吨美利曲辛片和Deanxit是生物等效的。
此外，发明人对不同配比的本发明片剂进行了生物等效性试验，试验结果显示采用本发明组分和配比制备的片剂均与Deanxit是生物等效的，试验过程与数据在此不再赘述。
效果例4
本发明抗氧剂的种类影响氟哌噻吨美利曲辛片剂的稳定性，为考察抗氧剂的种类对氟哌噻吨美利曲辛片剂稳定性的影响，申请人制备了试验组氟哌噻吨美利曲辛片剂，并按照效果例1和效果例2的测试方法，测试了本效果例试验组氟哌噻吨美利曲辛片剂的溶出度和稳定性。
本效果例中，抗氧剂的种类不同，其余均相同，抗氧剂的种类如表7所示。试验组中，氟哌噻吨颗粒中，盐酸氟哌噻吨的质量为0.584mg/片，抗氧剂的质量为0.4mg/片，填充剂为乳糖和微晶纤维素(1:2)，质量为58mg/片，粘合剂为羟丙纤维素，质量为1.8mg/片；美利曲辛颗粒中，盐酸美利曲辛的质量为11.25mg/片，填充剂为乳糖和微晶纤维素(1:3)，质量为28mg/片，粘合剂为羟丙纤维素，质量为1.2mg/片；外加辅料中，崩解剂为交联羧甲基纤维素钠，质量为1.8mg/片，填充剂为微晶纤维素，质量为14mg/片，粘合剂为羟丙纤维素，质量为3mg/片，润滑剂为硬脂酸，质量为1.2mg/片。
本效果例所述氟哌噻吨美利曲辛片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、抗氧剂溶于75％乙醇-水溶液中，搅拌至澄清；将乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与抗氧剂的75％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛片。
本效果例中，试验组氟哌噻吨美利曲辛片剂的性能测试结果如表7所示。
表7
Figure PCTCN2019125240-appb-000014
由表7可知，本发明抗氧剂的种类影响氟哌噻吨美利曲辛片剂的稳定性，当抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、维生素C、维生素C棕榈酸酯时，氟哌噻吨美利曲辛片剂的稳定性较好；当抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯时，氟哌噻吨美利曲辛片剂的稳定性更好；当抗氧剂为二丁基羟基甲苯时，氟哌噻吨美利曲辛片剂的稳定性最佳。
效果例5
本发明抗氧剂的质量百分比影响氟哌噻吨美利曲辛片剂的稳定性，为考察抗氧剂的质量百 分比对氟哌噻吨美利曲辛片剂稳定性的影响，申请人制备了试验组和对照组氟哌噻吨美利曲辛片剂，并按照效果例1和效果例2的测试方法，测试了本效果例试验组和对照组氟哌噻吨美利曲辛片剂的溶出度和稳定性。
本效果例中，抗氧剂的质量百分比不同，除填充剂的质量百分比外，其余辅料的质量百分比均相同，盐酸氟哌噻吨、盐酸美利曲辛、抗氧剂的质量百分比如表8所示。试验组和对照组中，氟哌噻吨颗粒中，抗氧剂为二丁基羟基甲苯，填充剂为乳糖和微晶纤维素(1:2)，质量为58mg/片，粘合剂为羟丙纤维素，质量为1.8mg/片；美利曲辛颗粒中，填充剂为乳糖和微晶纤维素(1:3)，质量为28mg/片，粘合剂为羟丙纤维素，质量为1.2mg/片；外加辅料中，崩解剂为交联羧甲基纤维素钠，质量为1.8mg/片，粘合剂为羟丙纤维素，质量为3mg/片，润滑剂为硬脂酸，质量为1.2mg/片，剩余均为填充剂，填充剂为微晶纤维素。
本效果例所述氟哌噻吨美利曲辛片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、二丁基羟基甲苯溶于80％乙醇-水溶液中，搅拌至澄清；将乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与二丁基羟基甲苯的80％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛片。
本效果例中，试验组氟哌噻吨美利曲辛片剂的性能测试结果如表8所示。
表8
Figure PCTCN2019125240-appb-000015
Figure PCTCN2019125240-appb-000016
由表8可知，本发明抗氧剂的质量百分比影响氟哌噻吨美利曲辛片剂的稳定性，当对照组1抗氧剂的质量比为0.006％时，有关物质的稳定性略差，当对照组2抗氧剂的质量比为12％时，稳定性较好，但并未比质量比10％更优，故优选抗氧剂的质量百分比为0.01％～10％时，氟哌噻吨美利曲辛片剂的稳定性较好；当进一步优选抗氧剂的质量百分比为0.02％～5％时，氟哌噻吨美利曲辛片剂的稳定性最佳。
效果例6
本发明盐酸氟哌噻吨和盐酸美利曲辛的质量百分比影响氟哌噻吨美利曲辛片剂的稳定性，为考察盐酸氟哌噻吨和盐酸美利曲辛的质量百分比对氟哌噻吨美利曲辛片剂稳定性的影响，申请人制备了试验组和对照组氟哌噻吨美利曲辛片剂，并按照效果例1和效果例2的测试方法，测试了本效果例试验组和对照组氟哌噻吨美利曲辛片剂的溶出度和稳定性。
本效果例中，盐酸氟哌噻吨和盐酸美利曲辛的质量百分比不同，除填充剂的质量百分比外，其余辅料的质量百分比均相同，盐酸氟哌噻吨的质量百分比、盐酸美利曲辛的质量百分比、填充剂的质量如表9所示。试验组和对照组中，氟哌噻吨颗粒中，抗氧剂为二丁基羟基甲苯，质量百分比为0.08％，粘合剂为羟丙纤维素，质量百分比为1.49％；美利曲辛颗粒中，盐酸美利曲辛质量为11.25mg/片，粘合剂为羟丙纤维素，质量百分比为0.99％；外加辅料中，崩解剂为交联羧甲基纤维素钠，质量百分比为1.49％，粘合剂为羟丙纤维素，质量百分比为2.48％，润滑剂为硬脂酸镁，质量百分比为0.99％，剩余均为填充剂。
本效果例所述氟哌噻吨美利曲辛片剂的制备方法为：
(1)氟哌噻吨颗粒的制备
将盐酸氟哌噻吨、二丁基羟基甲苯溶于80％乙醇-水溶液中，搅拌至澄清；将乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入盐酸氟哌噻吨与二丁基羟基甲苯的80％乙醇-水溶液，搅拌剪切制粒；流化床干燥，整粒，即得氟哌噻吨颗粒；
(2)美利曲辛颗粒的制备
将盐酸美利曲辛、乳糖、微晶纤维素、羟丙纤维素放入高速搅拌制粒机中，加入纯化水，搅拌剪切制粒；流化床干燥，整粒，即得美利曲辛颗粒；
(3)将氟哌噻吨颗粒、美利曲辛颗粒与剩余辅料混合均匀，压片，薄膜包衣后得到氟哌噻吨美利曲辛片。
本效果例中，试验组氟哌噻吨美利曲辛片剂的性能测试结果如表9所示。
表9
Figure PCTCN2019125240-appb-000017
由表9可知，本发明盐酸氟哌噻吨和盐酸美利曲辛的质量百分比影响氟哌噻吨美利曲辛片剂的稳定性，当盐酸氟哌噻吨的质量百分比为0.3％～1.0％，盐酸美利曲辛的质量百分比为5.78％～19.26％时，氟哌噻吨美利曲辛片剂的稳定性较好；当盐酸氟哌噻吨的质量百分比为0.4％～0.8％，盐酸美利曲辛的质量百分比为7.71％～15.41％时，氟哌噻吨美利曲辛片剂的稳定性最佳。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (10)

  1. 一种氟哌噻吨美利曲辛片剂，其特征在于，包含如下质量百分比的组分：盐酸氟哌噻吨0.3％～1.0％、盐酸美利曲辛5.78％～19.26％、抗氧剂0.01％～10％、填充剂60％～88％、崩解剂0.5％～6％、粘合剂2％～6％、润滑剂0.2％～3％。
  2. 如权利要求1所述的氟哌噻吨美利曲辛片剂，其特征在于，包含如下质量百分比的组分：盐酸氟哌噻吨0.4％～0.8％、盐酸美利曲辛7.71％～15.41％、抗氧剂0.02％～5％、填充剂72％～85％、崩解剂0.5％～4％、粘合剂3％～5％、润滑剂0.5％～2％。
  3. 如权利要求1或2所述的氟哌噻吨美利曲辛片剂，其特征在于：
    (a)所述抗氧剂为叔丁基对羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、硫代硫酸钠、L-半胱氨酸、维生素C或其钠盐、维生素C棕榈酸酯、维生素E、水溶性有机弱酸中的至少一种；
    (b)所述填充剂为微晶纤维素、乳糖、磷酸氢钙、淀粉、甘露醇、碳酸钙中的至少一种；
    (c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀粉钠、羧甲基纤维素、羧甲基纤维素钙中的至少一种；
    (d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮、羧甲基纤维素钠、甲基纤维素、***胶中的至少一种；
    (e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、硬脂酰富马酸钠、滑石粉、山嵛酸甘油酯中的至少一种；
    (f)所述氟哌噻吨美利曲辛片剂还包括包衣材料，所述包衣材料的质量为片剂片芯质量的2％～10％，所述包衣材料为欧巴代II、欧巴代200、欧巴代amb中的至少一种。
  4. 如权利要求3所述的氟哌噻吨美利曲辛片剂，其特征在于：
    (a)所述抗氧剂为二丁基羟基甲苯；
    (b)所述填充剂为微晶纤维素、乳糖、淀粉、磷酸氢钙中的至少一种；
    (c)所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羧甲基淀粉钠中的至少一种；
    (d)所述粘合剂为羟丙基纤维素、羟丙甲基纤维素、聚维酮中的至少一种；
    (e)所述润滑剂为二氧化硅、硬脂酸镁、硬脂酸、滑石粉、山嵛酸甘油酯中的至少一种；
    (f)所述包衣材料的质量为片剂片芯质量的3％～6％。
  5. 如权利要求1～4任一项所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，包括 如下步骤：
    (1)将盐酸氟哌噻吨与5％～30％填充剂进行等量递加混合，再与30％～70％填充剂、10％～50％粘合剂混合，加入抗氧剂的有机溶剂/水溶液，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得氟哌噻吨颗粒；
    或将盐酸氟哌噻吨与抗氧剂溶于有机溶剂/水溶液，将30％～70％填充剂、10％～50％粘合剂混合后，加入盐酸氟哌噻吨与抗氧剂的有机溶剂/水溶液，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得氟哌噻吨颗粒；
    (2)将盐酸美利曲辛与20％～50％填充剂、10％～40％粘合剂混合，进行搅拌制粒或流化喷雾制粒或挤压制粒，干燥，得美利曲辛颗粒；
    (3)将氟哌噻吨颗粒与美利曲辛颗粒、5％～30％填充剂、崩解剂、10％～60％粘合剂、润滑剂混合，压片，包衣。
  6. 如权利要求5所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，所述有机溶剂为异丙醇、乙醇、丙酮中的至少一种。
  7. 如权利要求5所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，所述干燥过程采用流化床干燥，温度控制在50℃以下，干燥至颗粒LOD％不超过3％。
  8. 如权利要求1～4任一项所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，包括如下步骤：
    (1)将盐酸氟哌噻吨与抗氧剂、10％～70％填充剂、20％～60％润滑剂进行等量递加混合均匀，通过辊压法进行干法制粒，得氟哌噻吨颗粒；
    (2)将美利曲辛与10％～50％填充剂、20％～50％润滑剂混合混合均匀，通过辊压法进行干法制粒，得美利曲辛颗粒；
    (3)将氟哌噻吨颗粒与美利曲辛颗粒、崩解剂、粘合剂、20％～40％润滑剂混合，压片，包衣。
  9. 如权利要求8所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，所述盐酸氟哌噻吨、抗氧剂经过微粉化处理后进行制粒。
  10. 如权利要求8所述的氟哌噻吨美利曲辛片剂的制备方法，其特征在于，所述氟哌噻吨颗粒与美利曲辛颗粒的松密度为0.4～0.8g/mL。
PCT/CN2019/125240 2019-01-10 2019-12-13 一种氟哌噻吨美利曲辛片剂及其制备方法 WO2020143395A1 (zh)

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