WO2021129340A1 - 一种坦度螺酮药物组合物及其制备方法和用途 - Google Patents

一种坦度螺酮药物组合物及其制备方法和用途 Download PDF

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WO2021129340A1
WO2021129340A1 PCT/CN2020/133624 CN2020133624W WO2021129340A1 WO 2021129340 A1 WO2021129340 A1 WO 2021129340A1 CN 2020133624 W CN2020133624 W CN 2020133624W WO 2021129340 A1 WO2021129340 A1 WO 2021129340A1
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tandospirone
optionally
pharmaceutical composition
hpmc
cellulose
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English (en)
French (fr)
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刘康
石凯荣
孙样
宗太丽
谢鹏
陈功政
陈刚
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四川科瑞德制药股份有限公司
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Priority to KR1020227012970A priority Critical patent/KR20220066126A/ko
Priority to JP2022531069A priority patent/JP2023504409A/ja
Publication of WO2021129340A1 publication Critical patent/WO2021129340A1/zh

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    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/2022—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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Tandospirone is a new type of anti-anxiety drug developed by Japan's Sumitomo Pharmaceutical Co., Ltd., and it was approved for listing in Japan in 1996. It entered the Chinese market in 2004 and has become increasingly widely used in the domestic anti-anxiety field. Tandospirone can selectively act on 5-HT 1A receptors in the brain, focusing on the limbic system such as the hippocampus and amygdala of the emotional center and projecting to the raphe nucleus of 5-HTergic nerves, by activating the presynaptic The 5-HT 1A receptor inhibits neuronal firing and reduces the synthesis of 5-HT.
  • Tandospirone has specific anti-anxiety effects, fewer side effects, weak sedative and hypnotic effects, no muscle relaxation, no dependence and withdrawal symptoms, and no accumulation in the body after long-term use Such advantages have broad application prospects in the field of anti-anxiety.
  • tandospirone is sold as ordinary tablets and capsules in the form of its citrate, and the dosage is 10 mg three times a day.
  • the three-times-a-day dosing regimen such as large fluctuations in blood concentration and poor patient compliance with medications.
  • the medication compliance problem is particularly obvious.
  • a once-a-day sustained-release preparation can not only reduce the peak concentration of the drug in the blood, reduce or avoid dose-related side effects, and increase the efficacy of the drug by prolonging the effective concentration of the drug in the plasma.
  • the once-a-day administration improves the convenience of taking the medication, can effectively improve the patient's medication compliance, and reduce the patient's stigma.
  • Patent CN1899287A discloses a sustained-release pharmaceutical composition of tandospirone citrate, specifically a sustained-release tablet.
  • the matrix material used is hydroxypropyl methylcellulose K4M, which can make the number of administrations change from The three times a day is reduced to twice a day, the frequency of administration is reduced, and the medication is convenient.
  • the twice-daily administration method still cannot solve the problem of patient compliance with medication.
  • Patent application CN106619481A discloses a sustained-release preparation of tandospirone citrate and a preparation method thereof.
  • the preparation contains a certain proportion of tandospirone citrate, a hydrophilic gel material and a waxy material, and Add the right amount of fillers and lubricants.
  • the sustained-release preparation has the effect of maintaining the sustained release for 24 hours.
  • the inventor further studied its pharmacokinetics and found that the bioavailability of the sustained-release preparation is still not very satisfactory, which affects the therapeutic effect of the drug.
  • the present invention aims to provide a tandospirone pharmaceutical composition to solve the problems of frequent medications, poor medication compliance of patients, large fluctuations in blood drug concentration, large drug side effects, low bioavailability and the like.
  • the present invention provides a tandospirone pharmaceutical composition, which is characterized in that it comprises a pharmaceutical active ingredient, a matrix material, a filler, a bleaching aid, a lubricant, and an optional binder.
  • the ingredient is tandospirone, a pharmaceutically acceptable salt thereof, or a solvate of tandospirone or a pharmaceutically acceptable salt thereof;
  • the framework material includes one or a combination of several selected from polyethylene oxide WSR 303, polyethylene oxide WSR 1105, polyethylene oxide WSR 301, polyethylene oxide WSR 205, and polyethylene oxide N-80;
  • the bleaching aid is selected from one or a combination of sodium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, and calcium carbonate; optionally, the bleaching aid is selected from sodium carbonate and/or carbonic acid Sodium hydrogen.
  • the pharmaceutical active ingredient is tandospirone or a pharmaceutically acceptable salt thereof
  • the solvate of the tandospirone or a pharmaceutically acceptable salt thereof is in the form of a hydrate.
  • the content of the active pharmaceutical ingredient in the tandospirone pharmaceutical composition is 1-15%;
  • the content of the pharmaceutical active ingredient in the tandospirone pharmaceutical composition is 2.5-10%, the content of the framework material is 5-75%, and the content of the bleaching aid is 1-20%; optionally,
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the pharmaceutically acceptable salt is hydrochloride, sulfate, tartrate, oxalate, maleate, fumarate, citrate, methanesulfonate, p-toluenesulfonate Acid salt, nitrate; preferably hydrochloride or citrate; more preferably citrate.
  • the framework material also optionally includes selected from hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC) ), ethyl cellulose (EC), cellulose acetate (CA), cross-linked polyvinylpyrrolidone, croscarmellose sodium, or a combination of several;
  • HPC hydroxypropyl cellulose
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • MC methyl cellulose
  • EC ethyl cellulose
  • CA cellulose acetate
  • cross-linked polyvinylpyrrolidone croscarmellose sodium, or a combination of several
  • the hydroxypropyl methylcellulose is selected from one or a combination of HPMC E4M, HPMC E10M, HPMC K4M, HPMC K15M, HPMC K100M;
  • the hydroxypropyl methylcellulose is selected from one or a combination of HPMC K4M, HPMC K15M, HPMC K100M;
  • the framework material is selected from polyethylene oxide WSR 303, polyethylene oxide WSR 1105, polyethylene oxide WSR 301, polyethylene oxide WSR 205, polyethylene oxide N-80, HPMC K4M, HPMC K15M, hydroxyethyl One or a combination of cellulose, hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone;
  • the binder is selected from one or a combination of polyvinylpyrrolidone, gelatin, xanthan gum, dextrin, polyvinyl alcohol, and carboxymethyl cellulose;
  • the adhesive is selected from polyvinylpyrrolidone and/or polyvinyl alcohol.
  • the filler is selected from lactose, sucrose, microcrystalline cellulose, pregelatinized starch, mannitol, sorbitol, xylitol, glucose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium chloride, One or a combination of aluminum chloride, sodium chloride, calcium oxide, zinc oxide, and magnesium oxide; microcrystalline cellulose can be selected.
  • the lubricant is selected from talc, micronized silica gel, magnesium stearate, calcium stearate, zinc stearate, sodium fumarate stearate, magnesium lauryl sulfate, dodecane
  • talc micronized silica gel
  • magnesium stearate calcium stearate
  • zinc stearate sodium fumarate stearate
  • magnesium lauryl sulfate sodium fumarate stearate
  • dodecane One or a combination of sodium sulfate and hydrogenated vegetable oil may be magnesium stearate.
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the tandospirone pharmaceutical composition includes the following components in weight percentage:
  • the dosage form of the tandospirone pharmaceutical composition is selected from a tablet, a pill, or a capsule, and can be a tablet.
  • the mixed powder prepared in step b is compressed into tablets to obtain tablets.
  • the compression method is direct compression of powder. Or, use the following preparation steps:
  • step b Sieve the bleaching aid and lubricant separately, and mix them with the particles in step a to obtain;
  • the granules obtained in step b are compressed to obtain tablets.
  • preparation method of the above-mentioned tandospirone pharmaceutical composition adopts the following preparation steps:
  • a 16.4mm ⁇ 7.9mm punch is used to compress the mixed powder prepared in step b to obtain a tablet.
  • the compression method is direct compression of powder.
  • step b Pass the bleaching aid and lubricant through a 20-60 mesh sieve, and mix them with the dry granules obtained in step a for 3-10 minutes, to obtain;
  • a 16.4mm ⁇ 7.9mm punch is used to compress the granules obtained in step b to obtain tablets.
  • the central nervous system disease includes anxiety, depression, insomnia, schizophrenia, age-related memory disorders, neurasthenia, and Alzheimer's;
  • the ocular diseases include diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration, and retinal edema.
  • the tandospirone pharmaceutical composition of the present invention can quickly float in a simulated gastric juice environment, and the float-off time is not more than 5 seconds, preferably not more than 3 seconds, more preferably not more than 2 seconds; and the bleaching time is greater than 24 hours.
  • the tandospirone pharmaceutical composition of the present invention prolongs the residence time of the drug in the stomach, so that the drug can be fully released and absorbed, can last for more than 12 hours of sustained release, and has high bioavailability.
  • the uniformity of drug release is good, there is no risk of sudden release, the blood concentration fluctuation after medication is small, the side effects are small, and the safety is high.
  • the tandospirone pharmaceutical composition of the present invention has a small initial volume, making the product easy to swallow, and can quickly expand to a diameter of about 14 mm or more in simulated gastric juice, making it difficult to be excreted by gastric contents. Not affected by eating. After the drug is released, it can gradually become smaller and discharged from the pylorus, avoiding the drug from staying in the stomach and reducing the burden on the stomach.
  • the tandospirone pharmaceutical composition of the present invention can be taken only once a day, which improves the convenience of taking medication and greatly increases the medication compliance of patients.
  • the tandospirone pharmaceutical composition of the invention has stable quality and is suitable for long-term storage and transportation; the preparation process is simple, no special equipment requirements are required, the process controllability is strong, and it is suitable for industrial production.
  • the tandospirone pharmaceutical composition was prepared according to the components and proportions shown in Table 1-3.
  • step b Use a 16.4mm ⁇ 7.9mm punch to directly compress the mixed powder prepared in step b to obtain tablets.
  • step b Pass the bleaching aid through a 20-mesh sieve and mix with the dry granules prepared in step a for 5 minutes; then add magnesium stearate (pass through a 60-mesh sieve) and mix for 3 minutes to obtain mixed granules;
  • step b Use a 16.4mm ⁇ 7.9mm punch to compress the mixed granules prepared in step b to obtain tablets.
  • Test 1 Floating performance test of Tandospirone pharmaceutical composition
  • Example 1 2 3 4 5 6 7 8 9 10 Drift time 4s ⁇ 2s 2s ⁇ 2s ⁇ 2s ⁇ 2s ⁇ 2s ⁇ 2s 4s Drifting time* 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h
  • Example 11 12 13 14 15 16 17 18 19 20 Comparative example 1 Drift time ⁇ 2s ⁇ 2s 4s 3s 3s ⁇ 2s ⁇ 2s 5s 4s 5s Unable to float Drifting time* 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h /
  • the tandospirone pharmaceutical composition of the present invention has a short bleaching time, which does not exceed 5s, preferably does not exceed 3s, and even more preferably does not exceed 2s.
  • the tandospirone pharmaceutical composition of the invention can achieve 24 hours of bleaching.
  • the excellent floating performance allows the tandospirone pharmaceutical composition product of the present invention to stay in the stomach for a long time, effectively prolong the release of the drug in the stomach, and enhance the absorption effect of the drug at the absorption site, thereby improving the bioavailability of the drug. To achieve better drug treatment effect.
  • the product size of the tandospirone pharmaceutical composition of the present invention swells rapidly in a simulated gastric juice environment, and the smallest diameter can swell to more than 14 mm, which is 13 mm larger than the diameter of the human gastric pylorus. After being placed for 16 hours, the minimum diameter of the product can still be maintained above 13mm.
  • the swelling property of the product of the present invention can prolong the residence time of the tandospirone pharmaceutical composition in the stomach, increase the release and absorption of the drug, and achieve the purpose of a lasting, flat and slow-release drug.
  • the pharmaceutical composition of the present invention dissolves to a size smaller than the diameter of the gastric pylorus after 24 hours, ensuring the smooth discharge of the drug carrier.
  • the first method (basket method) of the dissolution and release determination method in the four appendices of the Chinese Pharmacopoeia 2015 edition was used to investigate the in vitro dissolution conditions of Examples 1-20.
  • Table 7-8 The specific results are shown in Table 7-8.
  • the investigation conditions are strong light irradiation (4500 ⁇ 500lx), high temperature (60°C), and high humidity (relative humidity 92.5%, 25°C).
  • the preparations prepared in Example 6 of the present invention were placed under the above-mentioned different investigation conditions for 10 days respectively, and samples were taken for determination on the 5th and 10th days respectively, and compared with the data of the same batch of samples on day 0. The results are shown in Table 9.
  • test results in Table 9 show that the tandospirone pharmaceutical composition of the present invention has no significant changes in product content and total impurities under strong light irradiation, high temperature and high humidity conditions, indicating that the product of the present invention has good stability .
  • Example 6 of the present invention The preparation prepared in Example 6 of the present invention was sealed and packaged in a polyethylene film plastic bag, and placed in a constant temperature and humidity incubator at 40°C ⁇ 2°C and a relative humidity of 75 ⁇ 5% for six months. Sampling and testing at the end of 2, 3, and 6 months, and compared with the results of 0 months. The results are shown in Table 10.
  • test results in Table 10 show that the tandospirone pharmaceutical composition of the present invention has no significant decrease in content and no significant increase in the total amount of impurities under the accelerated test conditions within six months, which meets the quality standard. It can be seen that the tandospirone pharmaceutical composition provided by the present invention has stable quality and is suitable for long-term storage.
  • Tandospirone citrate tablets (commercial preparation, manufacturer: Suzhou Sumitomo Pharmaceutical Co., Ltd., specification: 10mg)
  • the LC-MS/MS method was used to determine the concentration of tandospirone in the plasma of Beagle dogs and calculate the relevant pharmacokinetic parameters.
  • the AUC 0- ⁇ of the sustained-release preparation was bioequivalence with the 3 times AUC of the normal-release preparation. Inspection, the results are shown in Table 11.
  • Tandospirone citrate tablets (commercial preparation, manufacturer: Suzhou Sumitomo Pharmaceutical Co., Ltd., specification: 10mg)
  • a randomized, open, three-agent, two-period, sequential, and double-crossover experimental design was adopted, and the cleaning period between the weeks was 4 days.
  • the commercial tandospirone citrate tablets are taken three times on the first day of each cycle, with an interval of 5 hours, 10 mg each time; 30 mg of the preparation of the present invention is taken on the second day of each cycle.

Abstract

坦度螺酮药物组合物及其制备方法和用途。所述坦度螺酮药物组合物包含药物活性成分、骨架材料、填充剂、助漂剂、润滑剂以及任选的粘合剂，所述药物活性成分为坦度螺酮、其药学上可接受的盐或者坦度螺酮或其药学上可接受的盐的溶剂合物，所述骨架材料包括选自聚氧化乙烯WSR 303、聚氧化乙烯WSR 1105、聚氧化乙烯WSR 301、聚氧化乙烯WSR 205、聚氧化乙烯N-80中的一种或几种的组合；所述助漂剂选自碳酸钠、碳酸氢钠、碳酸氢钾、碳酸镁、碳酸钙中的一种或几种的组合。所述坦度螺酮药物组合物延长了药物在胃中的滞留时间，使得药物可以被充分释放和吸收，其生物利用度大大提高。

Description

一种坦度螺酮药物组合物及其制备方法和用途 背景技术
坦度螺酮是由日本住友制药株式会社开发的一种新型抗焦虑药，并于1996年在日本获准上市，2004年开始进入中国市场，在国内抗焦虑领域的应用日益广泛。坦度螺酮能够选择性作用于脑内5-HT 1A受体，作用部位集中在情感中枢的海马、杏仁核等大脑边缘***并投射至5-HT能神经的中缝核，通过激活突触前5-HT 1A受体，抑制神经元放电，减少5-HT的合成，同时对突触后的5-HT 1A受体具有部分激动作用，从而达到综合调节突触的5-HT功能，发挥抗焦虑作用。长期使用同时还可以发挥抗抑郁作用。与传统镇静催眠药相比，坦度螺酮具有抗焦虑作用专一、副作用较少、镇静催眠作用弱、无肌肉松弛作用、无依赖性和停药戒断症状、长期应用后在体内无蓄积等优势，在抗焦虑领域应用前景广阔。
目前，临床上坦度螺酮以其枸橼酸盐的形式，作为普通片剂和胶囊剂销售，剂量是一日三次，每次10mg。每日三次的给药方案存在较多问题，如血药浓度波动大，患者服药顺应性差等。尤其对于年长患者和同时服用多种药物的患者而言，服药顺应性问题尤其明显。另外，在精神疾病患者中普遍存在“病耻感”的共性问题，它给患者带来诸多不良影响，其中最为明显的是服药顺应性差，从而导致药物治疗效果不理想。开发每日一次给药的缓释制剂不仅可以降低药物在血液中的药峰浓度，减轻或避免与剂量相关的副作用，并通过延长药物在血浆中的有效浓度而增加药物疗效。同时，每日一次给药提高了服药的便利性，可以有效改善患者的服药顺应性，降低患者病耻感。
由于受胃排空和肠道转运的影响，普通缓释制剂在人体上消化道(胃、十二指肠)内的停留时间较短，部分药物尚未完全释放或吸收就 已被转运至下消化道，错失最佳的吸收部位，从而导致部分药物被浪费，影响到药物的治疗效果。
专利CN1899287A中公开了一种枸橼酸坦度螺酮的缓释药物组合物，具体为一种缓释片，采用的基质材料为羟丙甲基纤维素K4M，其作用可以使给药次数从一天三次减少到一天两次，给药次数减少，服药方便。然而，每日两次的给药方式仍不能很好的解决患者服药顺应性问题。
专利申请CN106619481A中公开了一种枸橼酸坦度螺酮的缓释制剂及其制备方法，该制剂包含一定比例的枸橼酸坦度螺酮、亲水性凝胶材料和蜡质材料，并加入适量的填充剂和润滑剂。该缓释制剂具有维持24小时缓释的作用。然而，本发明人进一步研究其药代动力学发现，该缓释制剂的生物利用度仍不十分理想，影响药物的治疗效果。
发明内容
本发明旨在提供一种坦度螺酮药物组合物，以解决用药次数多，患者用药顺应性差，血药浓度波动大，药物副作用大，生物利用度低等问题。
鉴于此，本发明提供一种坦度螺酮药物组合物，其特征在于，包含药物活性成分、骨架材料、填充剂、助漂剂、润滑剂，以及任选的粘合剂，所述药物活性成分为坦度螺酮、其药学上可接受的盐，或者坦度螺酮或其药学上可接受的盐的溶剂合物；
所述骨架材料包括选自聚氧化乙烯WSR 303、聚氧化乙烯WSR 1105、聚氧化乙烯WSR 301、聚氧化乙烯WSR 205、聚氧化乙烯N-80中的一种或几种的组合；
所述助漂剂选自碳酸钠、碳酸氢钠、碳酸氢钾、碳酸镁、碳酸钙中的一种或几种的组合；可选地，所述助漂剂选自碳酸钠和/或碳酸氢钠。
可选地，所述药物活性成分为坦度螺酮或其药学上可接受的盐；
可选地，所述坦度螺酮或其药学上可接受的盐的溶剂合物为其水合物的形式。
可选地，所述坦度螺酮药物组合物中药物活性成分的含量为1-15％；
可选地，所述坦度螺酮药物组合物中药物活性成分的含量为2.5-10％，骨架材料的含量为5-75％，助漂剂的含量为1-20％；可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000001
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000002
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000003
可选地，所述药学上可接受的盐为盐酸盐、硫酸盐、酒石酸盐、草酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、硝酸盐；优选为盐酸盐或枸橼酸盐；更优选为枸橼酸盐。
可选地，所述骨架材料还任选的包括选自羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、甲基纤维素(MC)、乙基纤维素(EC)、乙酸纤维素(CA)、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠中的一种或几种的组合；
可选地，所述羟丙基甲基纤维素选自HPMC E4M、HPMC E10M、HPMC K4M、HPMC K15M、HPMC K100M中的一种或几种的组合；
可选地，所述羟丙基甲基纤维素选自HPMC K4M、HPMC K15M、HPMC K100M中的一种或几种的组合；
可选地，所述骨架材料选自聚氧化乙烯WSR 303、聚氧化乙烯WSR 1105、聚氧化乙烯WSR 301、聚氧化乙烯WSR 205、聚氧化乙烯N-80、HPMC K4M、HPMC K15M、羟乙基纤维素、羟丙基纤维素、交联聚乙烯吡咯烷酮中的一种或几种的组合；
可选地，所述粘合剂选自聚乙烯吡咯烷酮、明胶、黄原胶、糊精、聚乙烯醇、羧甲基纤维素中的一种或几种的组合；
可选地，所述粘合剂选自聚乙烯吡咯烷酮和/或聚乙烯醇。
可选地，所述填充剂选自乳糖、蔗糖、微晶纤维素、预胶化淀粉、 甘露醇、山梨醇、木糖醇、葡萄糖、硫酸钙、磷酸氢钙、磷酸钙、氯化钙、氯化铝、氯化钠、氧化钙、氧化锌、氧化镁中的一种或几种的组合；可选为微晶纤维素。
可选地，所述的润滑剂选自滑石粉、微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸富马酸钠、十二烷基硫酸镁、十二烷基硫酸钠、氢化植物油中的一种或几种的组合，可选为硬脂酸镁。
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000004
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000005
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000006
Figure PCTCN2020133624-appb-000007
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000008
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000009
可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
Figure PCTCN2020133624-appb-000010
可选地，所述坦度螺酮药物组合物的剂型选自片剂、丸剂或胶囊，可选为片剂。
另一方面，提供一种上述坦度螺酮药物组合物的制备方法，采用以下制备步骤：
a、将各组分分别过筛，取药物活性成分、骨架材料、粘合剂和填充剂，混合均匀；
b、再加入助漂剂、润滑剂混合均匀，制成混合粉末，即得；
可选地，将步骤b中制得的混合粉末压片，制得片剂。
可选地，所述压片的方式为粉末直接压片。或者，采用以下制备步骤：
a、将药物活性成分、骨架材料、粘合剂和填充剂分别过筛，混合均匀，加入水制备软材，湿颗粒干燥，整粒过筛，制得干燥颗粒；
b、将助漂剂和润滑剂分别过筛，与步骤a中颗粒混合均匀，即得；
可选地，将步骤b中制得的颗粒进行压片，制得片剂。
进一步地，上述坦度螺酮药物组合物的制备方法，采用以下制备步骤：
a、将各组分分别过20～60目筛，取药物活性成分、骨架材料、粘合剂和填充剂，混合10～30分钟；
b、再依次加入助漂剂、润滑剂混合3～10分钟，制成混合粉末，即得；
可选地，使用16.4mm×7.9mm的冲头将步骤b中制得的混合粉末压片，制得片剂。
可选地，所述压片的方式为粉末直接压片。
或者，采用以下制备步骤：
a、将药物活性成分、骨架材料、粘合剂和填充剂分别过20～60 目筛，混合5～30分钟，加入水制备软材，湿颗粒在35～70℃、20～50cfm条件下干燥5～30分钟，整粒过10～30目筛，制得干燥颗粒；
b、将助漂剂和润滑剂分别过20～60目筛，与步骤a中制得的干燥颗粒混合3～10分钟，即得；
可选地，使用16.4mm×7.9mm的冲头将步骤b中制得的颗粒进行压片，制得片剂。
另一方面，提供上述坦度螺酮药物组合物在制备治疗中枢神经***疾病和眼部疾病的药物中的用途。
可选地，所述中枢神经***疾病包括焦虑症、抑郁症、失眠症、精神***、增龄性记忆障碍、神经衰弱、老年痴呆；
可选地，所述眼部疾病包括青光眼、糖尿病性视网膜病、年龄相关性黄斑变性、视网膜水肿等疾病。
有益技术效果
本发明坦度螺酮药物组合物在模拟胃液环境中，能迅速起漂，起漂时间不超过5秒，优选不超过3秒，更优选不超过2秒；持漂时间大于24小时。
本发明坦度螺酮药物组合物延长了药物在胃中的滞留时间，使得药物可以被充分释放和吸收，可以持续12小时以上的缓释作用，生物利用度高。释药均匀性好，无突释风险，用药后血药浓度波动小，副作用小，安全性高。
此外，本发明坦度螺酮药物组合物具有较小的初始体积，使得产品易吞服，在模拟胃液中能够迅速膨胀至直径约14mm或更大，使得其不易被胃内容物排走，达到不受进食的影响。药物释放完后能够逐渐溶蚀变小并从幽门排出，避免了药物一直在胃中停留，减轻胃部负担。
本发明坦度螺酮药物组合物每日可只需服药一次，提高了服药便利性，大大增加了患者的用药顺应性。
本发明坦度螺酮药物组合物质量稳定，适合长期储存和运输；制备工艺简单，无特殊设备要求，工艺可操控性强，适合工业化生产。
具体实施方式
以下通过具体实施方式对本发明作进一步的详细描述。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
实施例1-20
按照表1-3所示的组分和配比来制备坦度螺酮药物组合物。
表1.坦度螺酮药物组合物—实施例1-8
Figure PCTCN2020133624-appb-000011
表2.坦度螺酮药物组合物—实施例9-14
Figure PCTCN2020133624-appb-000012
表3.坦度螺酮药物组合物—实施例15-20
Figure PCTCN2020133624-appb-000013
Figure PCTCN2020133624-appb-000014
对于实施例1-7，9-12以及15-18，其制备工艺如下：
a、将硬脂酸镁过60目筛，除硬脂酸镁以外的各组分分别过20目筛，取枸橼酸坦度螺酮、骨架材料、粘合剂和填充剂，混合15分钟；
b、加入助漂剂，混合10分钟；再加入硬脂酸镁，混合3分钟，制得混合粉末；
c、使用16.4mm×7.9mm的冲头将步骤b中制得的混合粉末直接压片，制得片剂。
对于实施例8，13-14以及19-20，其制备工艺如下：
a、将枸橼酸坦度螺酮、骨架材料、粘合剂和填充剂分别过20目筛，混合10分钟；加入水制备软材，湿颗粒于50℃和35cfm条件下干燥15分钟，整粒过20目筛，制得干燥颗粒；
b、将助漂剂过20目筛，与步骤a中制得的干燥颗粒混合5分钟；再加入硬脂酸镁(过60目筛)混合3分钟，制得混合颗粒；
c、使用16.4mm×7.9mm的冲头将步骤b中制得的混合颗粒压片， 制得片剂。
对比例1(参照专利申请CN106619481A中实施例1)
原料处方：
Figure PCTCN2020133624-appb-000015
共制成1000片；
制备方法：
将蜡质材料加热熔融，加入枸橼酸坦度螺酮，搅拌混合均匀，冷却成固态，将含药固体研磨粉碎，过筛，加入亲水性凝胶材料、填充剂、75％乙醇进行制粒，干燥，过筛整粒，加入润滑剂后混合均匀，压片即得。
将蜡质材料加热熔融，加入枸橼酸坦度螺酮，搅拌混合均匀，冷却成固态，将含药固体研磨粉碎，过筛，加入亲水性凝胶材料、填充剂、75％乙醇进行制粒，干燥，过筛整粒，加入润滑剂后混合均匀，压片即得。
试验一坦度螺酮药物组合物漂浮性能试验
试验方法：
将实施例1-20以及对比例1制得的片剂置于(37±0.5)℃，900mL 0.1mol/L的盐酸溶液中，搅拌速度为50r/min，观察起漂时间及持漂 时间。具体结果见表4-5。
表4坦度螺酮药物组合物漂浮性能—实施例1-10
实施例 1 2 3 4 5 6 7 8 9 10
起漂时间 4s <2s 2s <2s <2s <2s <2s <2s <2s 4s
持漂时间* 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h
*注：持漂时间只记录到24h。
表5坦度螺酮药物组合物漂浮性能—实施例11-20
实施例 11 12 13 14 15 16 17 18 19 20 对比例1
起漂时间 <2s <2s 4s 3s 3s <2s <2s 5s 4s 5s 无法起漂
持漂时间* 24h 24h 24h 24h 24h 24h 24h 24h 24h 24h /
*注：持漂时间只记录到24h。
表4-5结果可知，本发明坦度螺酮药物组合物起漂时间短，起漂时间不超过5s，较优的不超过3s，更优的不超过2s。本发明坦度螺酮药物组合物能达到24小时持漂。优良的漂浮性能使得本发明坦度螺酮药物组合物产品在胃中可以滞留较长时间，有效延长药物在胃部的释放，增强药物在吸收部位的吸收效果，从而提高药物的生物利用度，达到更好的药物治疗效果。
试验二坦度螺酮药物组合物溶胀性能测定试验
试验方法：
将实施例2、6、12中制得的制剂分别置于(37±0.5)℃，900mL 0.1mol/L的盐酸溶液中，测量其在第5min、30min、2h、6h、12h、16h、18h、20h和24h的尺寸，结果见表6。
表6坦度螺酮药物组合物溶胀性能试验结果
Figure PCTCN2020133624-appb-000016
Figure PCTCN2020133624-appb-000017
由表6可知，本发明的坦度螺酮药物组合物在模拟胃液环境下，产品尺寸迅速溶胀，最小直径可溶胀至14mm以上，大于人体胃幽门直径13mm。在放置16小时后，产品最小直径仍能维持在13mm以上。本发明产品的溶胀性能可延长坦度螺酮药物组合物在胃中的滞留时间，增加药物的释放和吸收，达到持久平缓释药的目的。此外，本发明药物组合物在24小时后，产品溶蚀至尺寸小于胃幽门直径，保证了药物载体的顺利排出。
试验三坦度螺酮药物组合物体外溶出度试验
采用中国药典2015版四部附录溶出度与释放度测定法第一法(篮法)，考察实施例1-20的体外溶出情况。以900mL 0.1mol/L的盐酸溶液为溶出介质，设置转速为50r/min，温度为37±0.5℃；依法操作，在15min、30min、1h、2h、4h、6h、8h、10h、12h、14h、16h、20h分别取溶液5mL进行测定，并计算出累计溶出度。具体结果见表7-8。
表7实施例1-10的体外溶出结果
Figure PCTCN2020133624-appb-000018
表8实施例11-20的体外溶出结果
Figure PCTCN2020133624-appb-000019
Figure PCTCN2020133624-appb-000020
表7-8体外溶出结果表明，实施例1～18的坦度螺酮药物组合物16h溶出度达80％以上，达到持久缓慢释药的目的，且释药平稳，无突释效应，避免了血药浓度大幅度波动。
试验四坦度螺酮药物组合物稳定性试验
(1)影响因素试验
考察条件为强光照射(4500±500lx)、高温(60℃)、高湿(相对湿度92.5％，25℃)。将本发明实施例6制备得到的制剂在上述不同考察条件下分别放置10天，于第5和第10天分别取样测定，与0天同批样品数据进行比较，结果见表9。
表9影响因素试验结果
Figure PCTCN2020133624-appb-000021
Figure PCTCN2020133624-appb-000022
由表9中的试验结果表明，本发明的坦度螺酮药物组合物，在强光照射、高温及高湿条件下，产品含量和杂质总量均无明显变化，说明本发明产品稳定性良好。
(2)加速试验
将本发明实施例6制备得到的制剂用聚乙烯薄膜塑料袋密封包装，置于40℃±2℃，相对湿度75±5％的恒温恒湿培养箱中，放置六个月，分别于1，2，3，6个月末取样检测，并与0月的结果进行对照。结果见表10。
表10加速试验结果
Figure PCTCN2020133624-appb-000023
Figure PCTCN2020133624-appb-000024
由表10中的试验结果表明，本发明坦度螺酮药物组合物，在六个月内的加速试验条件下，含量无明显降低，杂质总量未见明显增加，符合质量标准。由此可见，本发明提供的坦度螺酮药物组合物质量稳定，适宜长期保存。
试验五坦度螺酮药物组合物的药代动力学试验
(一)动物药代动力学试验
试验样品：
(1)枸橼酸坦度螺酮片(市售制剂，生产商：苏州住友制药有限公司，规格：10mg)
(2)枸橼酸坦度螺酮缓释片(对比例1)
(3)本发明制剂(实施例7)
试验方法及试验结果：
6只雄性Beagle犬，按体重随机分为3个组，采用3周期、3交叉(3×3拉丁方)设计，每个周期分别经口给予市售枸橼酸坦度螺酮片10mg、对比例1枸橼酸坦度螺酮缓释片30mg、本发明实施例7制剂30mg，给药前禁食12h。给予对比例1枸橼酸坦度螺酮缓释片和本发明实施例7制剂的Beagle犬于每次给药前及给药后0.5min、1h、2h、3h、4h、5h、6h、8h、10h、12h、14h、16h、20h、24h、30h采集血样，给予市售枸橼酸坦度螺酮片的Beagle犬于每次给药前及给药后5min、10min、20min、30min、40min、1h、1.5h、2h、2.5h、 3h、4h、6h、8h、10h、12h采集血样。
以LC-MS/MS法测定Beagle犬血浆中坦度螺酮的浓度并计算相关的药代动力学参数，对缓释制剂的AUC 0-∞与常释制剂的3倍AUC进行生物等效性检验，结果见表11。
表11 Beagle犬药代动力学试验结果
Figure PCTCN2020133624-appb-000025
表11结果表明，相较于市售枸橼酸坦度螺酮片，本发明坦度螺酮药物组合物有效延迟了药物的达峰时间(T max)，降低了峰浓度(C max)，达到了使枸橼酸坦度螺酮持久平缓释放的目的，且用药安全性得到了保障。与对比例1枸橼酸坦度螺酮缓释片相比，本发明坦度螺酮药物组合物的生物利用度(AUC 0-∞)明显增高，有效提高了生物利用度。
(二)人体药代动力学试验
试验样品：
(1)枸橼酸坦度螺酮片(市售制剂，生产商：苏州住友制药有限公司，规格：10mg)
(2)本发明制剂(实施例6)
(3)本发明制剂(实施例7)
试验方法及试验结果：
采用随机、开放、三制剂、两周期、序贯、双交叉试验设计，周期间的清洗期为4天。每周期第1天三次服用市售枸橼酸坦度螺酮片，给药间隔5h，每次10mg；每周期第2天服用本发明制剂30mg。每周期第1天受试者于首次给药前(0h)及给药后0.25h、0.5h、1h、1.5h、2h、5h、5.25h、5.5h、6h、6.5h、7h、8h、10h、10.25h、10.5h、11h、11.5h、12h、13h、16h分别采集静脉血3mL，共21个采血点。
每周期第2天受试者于给药前(0h)及给药后0.5h、1h、1.5h、2h、2.5h、3h、3.5h、4h、4.5h、5h、5.5h、6h、8h、10h、12h、14h、16h、24h分别采集静脉血3mL，共19个采血点。计算相关的药代动力学参数，结果见表12。
表12人体药代动力学试验结果
Figure PCTCN2020133624-appb-000026
表12结果表明，与市售枸橼酸坦度螺酮片相比，本发明坦度螺酮药物组合物有效延迟了药物的达峰时间(T max)，提高了生物利用度(AUC 0-24)，达到了药物持久平缓释放的目的。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。

Claims (10)

  1. 一种坦度螺酮药物组合物，其特征在于，包含药物活性成分、骨架材料、填充剂、助漂剂、润滑剂以及任选的粘合剂，所述药物活性成分为坦度螺酮、其药学上可接受的盐、或者坦度螺酮或其药学上可接受的盐的溶剂合物；
    所述骨架材料包括选自聚氧化乙烯WSR 303、聚氧化乙烯WSR 1105、聚氧化乙烯WSR 301、聚氧化乙烯WSR 205、聚氧化乙烯N-80中的一种或几种的组合；
    所述助漂剂选自碳酸钠、碳酸氢钠、碳酸氢钾、碳酸镁、碳酸钙中的一种或几种的组合；可选地，所述助漂剂选自碳酸钠和/或碳酸氢钠。
  2. 根据权利要求1所述的坦度螺酮药物组合物，其特征在于，所述坦度螺酮或其药学上可接受的盐的溶剂合物为其水合物的形式。
  3. 根据权利要求1所述的坦度螺酮药物组合物，其特征在于，所述坦度螺酮药物组合物中药物活性成分的含量为1-15％；
    可选地，所述坦度螺酮药物组合物中药物活性成分的含量为2.5-10％，骨架材料的含量为5-75％，助漂剂的含量为1-20％；
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100001
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100002
    Figure PCTCN2020133624-appb-100003
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100004
  4. 根据权利要求1-3任一项所述的坦度螺酮药物组合物，其特征在于，所述药学上可接受的盐为盐酸盐、硫酸盐、酒石酸盐、草酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、硝酸盐；优选为盐酸盐或枸橼酸盐；更优选为枸橼酸盐。
  5. 根据权利要求1-4任一项所述的坦度螺酮药物组合物，其特征在于，所述骨架材料还任选的包括羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、乙酸纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠中的一种或几种的组合；
    可选地，所述羟丙基甲基纤维素选自HPMC E4M、HPMC E10M、HPMC K4M、HPMC K15M、HPMC K100M中的一种或几种的组合；
    可选地，所述羟丙基甲基纤维素选自HPMC K4M、HPMC K15M、HPMC K100M中的一种或几种的组合；
    可选地，所述骨架材料选自聚氧化乙烯WSR 303、聚氧化乙烯 WSR 1105、聚氧化乙烯WSR 301、聚氧化乙烯WSR 205、聚氧化乙烯N-80、HPMC K4M、HPMC K15M、羟乙基纤维素、羟丙基纤维素、交联聚乙烯吡咯烷酮中的一种或几种的组合；
    可选地，所述粘合剂选自聚乙烯吡咯烷酮、明胶、黄原胶、糊精、聚乙烯醇、羧甲基纤维素中的一种或几种的组合；
    可选地，所述粘合剂选自聚乙烯吡咯烷酮和/或聚乙烯醇；
    可选地，所述填充剂选自乳糖、蔗糖、微晶纤维素、预胶化淀粉、甘露醇、山梨醇、木糖醇、葡萄糖、硫酸钙、磷酸氢钙、磷酸钙、氯化钙、氯化铝、氯化钠、氧化钙、氧化锌、氧化镁中的一种或几种的组合；
    可选地，所述填充剂选自微晶纤维素；
    可选地，所述的润滑剂选自滑石粉、微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸富马酸钠、十二烷基硫酸镁、十二烷基硫酸钠、氢化植物油中的一种或几种的组合；
    可选地，所述润滑剂选自硬脂酸镁。
  6. 根据权利要求1-5任一项所述的坦度螺酮药物组合物，其特征在于，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100005
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100006
    Figure PCTCN2020133624-appb-100007
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100008
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100009
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100010
    Figure PCTCN2020133624-appb-100011
    可选地，所述坦度螺酮药物组合物包括如下重量百分比的组分：
    Figure PCTCN2020133624-appb-100012
  7. 根据权利要求1-6任一项所述的坦度螺酮药物组合物，其特征在于，所述坦度螺酮药物组合物的剂型选自片剂、丸剂或胶囊；可选为片剂。
  8. 权利要求1-7任一项所述的坦度螺酮药物组合物的制备方法，其特征在于，采用以下制备步骤：
    a、将各组分分别过筛，取药物活性成分、骨架材料、粘合剂和填充剂，混合均匀；
    b、加入助漂剂、润滑剂混合均匀，制成混合粉末，即得；
    可选地，将步骤b制得的混合粉末压片，制得片剂；可选地，所述压片的方式为粉末直接压片；
    或者，采用以下制备步骤：
    a、将药物活性成分、骨架材料、粘合剂和填充剂分别过筛，混合均匀，加入水制备软材，湿颗粒干燥，整粒过筛，制得干燥颗粒；
    b、将助漂剂和润滑剂分别过筛，与步骤a中颗粒混合均匀，即得；
    可选地，将步骤b中制得的颗粒进行压片，制得片剂。
  9. 根据权利要求8所述的坦度螺酮药物组合物的制备方法，其特征在于，采用以下制备步骤：
    a、将各组分分别过20～60目筛，取药物活性成分、骨架材料、粘合剂和填充剂，混合10～30分钟；
    b、再依次加入助漂剂、润滑剂混合3～10分钟，制成混合粉末，即得；
    可选地，使用16.4mm×7.9mm的冲头将步骤b中制得的混合粉末压片，制得片剂；可选地，所述压片的方式为粉末直接压片；
    或者，采用以下制备步骤：
    a、将药物活性成分、骨架材料、粘合剂和填充剂分别过20～60目筛，混合5～30分钟，加入水制备软材，湿颗粒在35～70℃、20～50cfm条件下干燥5～30分钟，整粒过20～60目筛，制得干燥颗粒；
    b、将助漂剂和润滑剂分别过20～60目筛，与步骤a中制得的干燥颗粒混合3～10分钟，即得；
    可选地，使用16.4mm×7.9mm的冲头将步骤b中制得的颗粒进行压片，制得片剂。
  10. 权利要求1-7任一项所述的坦度螺酮药物组合物在制备治疗中枢神经***疾病和/或眼部疾病的药物中的用途；
    可选地，所述中枢神经***疾病包括焦虑症、抑郁症、失眠症、精神***、增龄性记忆障碍、神经衰弱、老年痴呆；
    可选地，所述眼部疾病包括青光眼、糖尿病性视网膜病、年龄相关性黄斑变性、视网膜水肿。
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TANG LEI, ZHANG WEN-BIN, TANG SHI-WEI, LIAO YAN, TU LI, HE QIN: "Investigation on the Preparation and the Factors Influencing the Drug Release Rate in Vitro of Osmotic Pump Tablet of Tandospirone Citrate", HUAXI YAOXUE ZAZHI - WEST CHINA JOURNAL OF PHARMACEUTICALSCIENCES, ZHONGGUO YAOXUEHUI, SICHUAN FENHUI, CHENGDU, CN, vol. 24, no. 3, 1 January 2009 (2009-01-01), CN, pages 232 - 234, XP055824288, ISSN: 1006-0103, DOI: 10.13375/j.cnki.wcjps.2009.03.039 *

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