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WO2019237446A1 - 一种曲美他嗪缓释片及其制备方法 - Google Patents

一种曲美他嗪缓释片及其制备方法 Download PDF

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Publication number
WO2019237446A1
WO2019237446A1 PCT/CN2018/095425 CN2018095425W WO2019237446A1 WO 2019237446 A1 WO2019237446 A1 WO 2019237446A1 CN 2018095425 W CN2018095425 W CN 2018095425W WO 2019237446 A1 WO2019237446 A1 WO 2019237446A1
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Prior art keywords
coating
release
sustained
pellet
pellets
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PCT/CN2018/095425
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English (en)
French (fr)
Inventor
戴金柱
张伟明
陶安进
袁建成
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深圳翰宇药业股份有限公司
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Publication of WO2019237446A1 publication Critical patent/WO2019237446A1/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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of pharmaceutical preparations and relates to a preparation process of trimetazidine sustained-release tablets.
  • Angina pectoris is a common cardiovascular disease. It is caused by insufficient coronary blood supply due to coronary atherosclerosis and stenosis, temporary myocardial ischemia and hypoxia, and a combination of precardiac pain as the main clinical manifestations. Symptoms are one of the highest rates of coronary heart disease, which seriously threatens human health and life. It is mainly divided into stable angina and unstable angina. Angina pectoris can occur at any time within 24 hours, but it is mostly from early morning to morning. Variant angina pectoris occurs regularly at night. Therefore, it is required that the therapeutic drug can maintain an effective therapeutic concentration within 24 hours to ensure the effectiveness, safety and stability of the treatment. Trimetazidine hydrochloride belongs to other classes of anti-angina pectoris cardiovascular drugs. It is the first drug that acts on cardiomyocyte metabolism and exerts direct cytoprotective effects by rationalizing cardiac energy metabolism.
  • Trimetazidine has high bioavailability, up to 88.7%, protein binding rate is about 16%, plasma distribution volume is 318.6L, clearance half-life is 6h, 80% of the drug is excreted from the kidney (of which 62% is the original form), and the total clearance The rate is 37.45L / h. Trimetazidine does not affect the hemodynamics of the heart. Animal experiments in dogs have shown that intravenous injections of trimetazidine have no significant effect on heart rate, blood pressure, cardiac output, and left ventricular pressure.
  • Patent CN00138060.5 provides a matrix tablet capable of long-term release of trimetazidine after oral administration, which is characterized in that the matrix tablet does not contain a hydrophobic component and the long-term release is through a combination of 25-50% of the total tablet weight.
  • Hypromellose Cellulose (HPMC) was mixed for control.
  • Trimetazidine dihydrochloride in the tablet accounts for 15-30% of the total tablet weight
  • binder PVP accounts for 3-12% of the total tablet weight
  • the diluent CaHPO 4 ⁇ 2H 2 O accounts for 25- 75%
  • the rest is lubricant magnesium stearate and flow agent anhydrous colloidal SiO 2 , wet granulation.
  • Patent CN95103558.4 discloses an orally delayed-release trimetazidine drug combination that ensures controlled release of trimetazidine through a depot system selected from the water-insoluble polymers of EC and polymethacrylic polymers and The mixture of plasticizer acetyl tributyl citrate forms a film that encloses small particles of tablets or pills.
  • Patent ZL200610166205.2 discloses trimetazidine sustained-release pellets and a preparation method thereof, and provides a weight ratio of a film coating layer containing a drug pill core to control drug release of 20: 1-5: 1. The content is 10-60%.
  • the pellet core is mainly prepared by the extrusion spheronization method, and the fluidized bed is used for slow-release coating.
  • Patent 20111005676.5 discloses a trimetazidine hydrochloride sustained-release tablet and a preparation method thereof.
  • a mixture of polyvinyl acetate, povidone and ethylcellulose is used as a sustained-release skeleton material, and is characterized in that it is based on a weight percentage.
  • Each component accounts for the total weight of the tablet as follows: 15-25% trimetazidine hydrochloride, 45-55% KollidonSR and ethyl cellulose mixture, 25-35% filler, 0-2% lubricant and 0-1 % Other auxiliary materials, wet granulation.
  • Patent CN00138060.5 uses a higher proportion of HPMC as a sustained-release material, CaHPO 4 ⁇ 2H 2 O as a filler, and the patent uses a large amount of calcium hydrogen phosphate dihydrate as a diluent, and an excessively high amount of calcium hydrogen phosphate At lower pH, the drug release rate will be significantly accelerated, so after the drug enters the stomach, it may be affected by gastric acid to accelerate the drug release.
  • Patent CN95103558.4 provides an orally delayed-release trimetazidine pharmaceutical composition, which is a tablet or granule coated with a controlled release film.
  • the inventor's purpose is to take it as a single daily dose. Therefore, the cumulative release of the composition for 16 hours is only 80%, the release is incomplete, and it does not meet the requirements of the Pharmacopoeia ( ⁇ 85%).
  • the effective absorption time of the drug in the gastrointestinal tract is only 9-12 hours, and it is not necessary to design continuous release for more than 16 hours.
  • Patent ZL200610166205.2 provides a method for preparing trimetazidine sustained-release pellets containing active pharmaceutical ingredients, which is characterized by consisting of a drug-containing pill core and a film coating layer that controls drug release.
  • the core is coated with a fluidized bed.
  • the pellets preferably have a diameter of 0.6mm-1.5mm.
  • the diameter of the pellet core is large, and the particle size of the excipient is greatly different. It can only be used for capsule filling. Release tablets, if used for pellet compression, may have uneven mixing.
  • the patent uses extrusion and spheronization to prepare drug-loaded pellet cores.
  • the prepared pellet cores have a wide range of particle size distribution and reproducibility of scale-up production. More stringent measures are needed.
  • Patent 20111005676.5 which uses a mixture of polyvinyl acetate and povidone mixture with ethyl cellulose as a sustained release matrix material.
  • the composition has a long release time, but the drug is released about 75% in 16 hours, and the release is incomplete.
  • Pharmacopoeia does not meet the requirements ( ⁇ 85%).
  • trimetazidine sustained-release tablets rarely use multi-unit microparticles or pellet systems to weaken the reproducibility (different batches) and consistency (same batch) of drug release laws.
  • Tarazine is very soluble in water and has a problem of burst release.
  • Trimetazidine hydrochloride is very easy to dissolve in water, and its solubility is greater than 1000 mg / ml, so controlling the burst release of highly soluble drugs is the key to the present invention.
  • the so-called burst release refers to the phenomenon of large-dose release of the drug in the initial release of the slow-release and controlled-release preparation.
  • Trimetazidine hydrochloride sustained-release tablets have been marketed twice daily in foreign countries and are under development at home and abroad. Trimetazidine is very water-soluble. It is difficult to control the release rate of the drug with a simple matrix sustained-release preparation. A large amount of matrix materials and blockers are added, and the long-term release of trimetazidine matrix tablets described in patent CN00138060.5 controls drug release for 3-4 hours.
  • the invention provides a trimetazidine sustained-release tablet, which is composed of a blank pill core, trimetazidine, and a drug-containing pellet coating binder, and the drug-containing pellets are composed of the drug-containing pellets and the sustained-release microparticles.
  • Coating materials for pill coating, porogens, plasticizers and anti-sticking agents form sustained-release pellets, which are composed of slow-release pellets, coating materials for protecting pellet coatings, and plasticizers for protecting pellet coatings.
  • Protective pellets are formed, cores are formed from pellets, fillers, disintegrants and lubricants, and final trimetazidine sustained-release tablets are formed from the cores and the coating material for tablet film coating.
  • the quality of the limited components of the tablet is controllable, and the drug release behavior in various media can achieve the expected effect, and the similar factors to the reference preparation are greater than 70.
  • the drug-loaded pellets are prepared by laminating an aqueous solution containing a drug-loaded pellet coating binder and trimetazidine in a fluidized bed on a blank pellet core in a fluidized bed.
  • the slow-release pellets are a fluidized bed that a solution containing a porogen, a coating material for coating the slow-release pellets, a plasticizer, and an anti-sticking agent is laminated in a liquid phase. Prepared on drug-loaded pellets.
  • the protective pellet is a fluidized bed in which a solution containing a coating material for protective pellet coating and a plasticizer solution for protective pellet coating is layered on the sustained-release pellets through a liquid phase. Made on.
  • the tablet core is prepared by mixing protective pellets, fillers, disintegrants and lubricants, and then tabletting.
  • the trimetazidine sustained-release tablet is prepared by liquid-phase deposition method of a solution of a coating material for tablet film coating on the surface of a tablet core by liquid-phase deposition.
  • the proportion of each component is 10 to 20 parts of trimetazidine, 10 to 15 parts of blank pills, and 3 to 5 parts of a binder for drug-loaded pellets. 8 to 14 parts of coating material for slow-release pellet coating, 1 to 5 parts of porogen, 0.5 to 5 parts of plasticizer, 0.5 to 2 parts of anti-adhesive agent, 10 coating materials for protecting pellet coating -17 parts, plasticizer for protective pellet coating 1-5 parts, filler 25-35 parts, disintegrant 3-4 parts, lubricant 0.1-1 part, tablet film coating material 2 ⁇ 5 servings.
  • the sustained-release tablet is composed of the following components in the following weight percentages:
  • Another aspect of the present invention provides a method for preparing trimetazidine sustained-release pellets, which includes the following steps:
  • the protective pellet coating material and the protective pellet coating plasticizer are added to the purified water in order, and the protective pellet coating liquid is obtained after being stirred uniformly.
  • the protective pellet coating solution is coated on the surface of the sustained-release pellet to obtain a protective pellet;
  • the blank pellet core used in the present invention is a starch pellet core or a microcrystalline cellulose pellet core, and the microcrystalline cellulose pellet core is preferred because the microcrystalline cellulose pellet core is insoluble in most organic solvents and water and is suitable for solution lamination.
  • the method of applying medicine, and the surface of the microcrystalline cellulose pellet core is smooth and high in hardness. It is the best choice for pellet coating and tabletting.
  • the particle size is preferably 50 to 1000 ⁇ m, and more preferably 50 to 500 ⁇ m. Crystalline cellulose pellet cores, because smaller particle size and narrower particle size distribution are beneficial for pellet coating and tabletting.
  • the binder for coating drug-loaded pellets used in the present invention is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl cellulose (HPMC), and hydroxypropyl methyl cellulose is preferred because hydroxypropyl cellulose Methylcellulose has better dispersing ability and is more suitable for spray coating.
  • the coating material for slow-release pellet coating used in the present invention is cellulose acetate (CA) or ethyl cellulose (EC), and ethyl cellulose is preferred because ethyl cellulose is a slow-release, high-density Materials, coatings coated with organic solvents have better pressure resistance and are more suitable for pellet compression. Low viscosity ethyl cellulose is more preferred because low viscosity ethyl cellulose often requires more sustained release. Polymer coating, so that a sustained-release coating film with a certain thickness can be obtained, which is more conducive to tabletting.
  • CA cellulose acetate
  • EC ethyl cellulose
  • the porogen used in the present invention is polyethylene glycol (PEG), povidone (PVP), sucrose or hydroxypropyl methyl cellulose (HPMC), and hydroxypropyl methyl cellulose is preferred because hydroxypropyl Methylcellulose has suitable water solubility, and it can be used as a porogen to cooperate with highly dense and water-insoluble ethylcellulose to ensure reasonable drug release.
  • PEG polyethylene glycol
  • PVP povidone
  • HPMC hydroxypropyl methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • the plasticizer used in the present invention is dimethyl phthalate, dibutyl sebacate or triethyl citrate, preferably triethyl citrate, because the clothing made by using ethyl cellulose alone
  • the film has poor physical properties, limited elongation coefficient and compression resistance, and the film release process is often accompanied by the rupture of the coating film to change the drug release behavior.
  • triethyl citrate as a plasticizer can effectively solve the problem of tabletting The film ruptures during the process.
  • the anti-sticking agent used in the present invention is silicon dioxide, titanium dioxide or talc, and talc is preferred, because when ethyl cellulose is used as a slow-release material for coating, the pellets are liable to stick.
  • the blocking phenomenon can be overcome, and the particle size is preferably 500-2000 mesh, more preferably 500-1500 mesh, because if the particle size of the talc is too large, it will easily settle during the coating process and cause the spray gun to block; , Talcum powder with smaller particle size can make the coating film more dense and complete.
  • the coating material for protecting the pellets used in the present invention is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl cellulose (HPMC), and hydroxypropyl methyl cellulose is preferred.
  • Methylcellulose has better dispersing ability and is more suitable for spray coating.
  • the plasticizer for protecting the pellets used in the present invention is polyethylene glycol (PEG), povidone (PVP) or hydroxypropylmethyl cellulose (HPMC), and polyethylene glycol is preferred because Ethylene glycol has a very strong elastic deformation ability, and has a better protective effect on the sustained-release coating film during the tabletting process. Polyethylene glycol with excellent elastic deformation ability and commonly available are more preferred.
  • the filler used in the present invention is starch, dextrin, lactose or microcrystalline cellulose (MCC).
  • MMC microcrystalline cellulose
  • Microcrystalline cellulose is preferred because microcrystalline cellulose is an ideal filler for pellet compression, and it acts as a buffer when compressed. The effect can avoid direct contact between the pellets, and a larger hardness can be obtained under a smaller pressure, thereby avoiding damage to the clothing film by the pressure.
  • the disintegrant used in the present invention is sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC) or croscarmellose sodium (CCMC-Na). Because of the fiber properties of croscarmellose sodium, croscarmellose sodium has a strong capillary action, so it has good water absorption capacity. At the same time, the cross-linking chemical structure of croscarmellose sodium can Forms a hydrophilic, super absorbent substance that is insoluble in water and has good rapid expansion characteristics. Compared with other disintegrants, this dual function makes croscarmellose sodium have super disintegrating function when used.
  • the lubricant used in the present invention is talc, micropowder silica gel or magnesium stearate, and preferably magnesium stearate, because magnesium stearate is easy to mix with the drug particles to be compressed, and can reduce the friction between the particles and the die. Force, one-sided smooth and beautiful after pressing.
  • the coating material for tablet film coating used in the present invention is a gastric-soluble Opadry film coating premix, because when the pellets are compressed, the polymer-coated particles will deform during the compression process. This results in unsatisfactory one-sided appearance, which requires film coating, and Opadry's strong hiding power can make the final tablet look uniform and beautiful.
  • gastric-soluble Opadry film coating premix can The main drug is released from the stomach and absorbed stably throughout the gastrointestinal tract.
  • the invention also provides a method for preparing trimetazidine sustained-release tablets, which comprises the following steps:
  • the prescription amount of the protective pellets, the prescription amount of the filler, the prescription amount of the disintegrating agent and the prescription amount of the lubricant are mixed in a final mixer, and then compressed in a tablet press to obtain a tablet core.
  • tablets are prepared by using multi-dose dosage form pellets. Even if the preparation defects of individual pellets do not seriously affect the drug release behavior of the overall preparation, the recurrence of the drug release law is ensured as a whole.
  • the consistency (different batches) and consistency (same batch) reduce the possibility of burst release.
  • FIG. 1 is an in vitro release profile of trimetazidine hydrochloride sustained-release tablets of Examples 1, 2, 3, 4, and 5 in a pH 6.8 dissolution medium.
  • FIG. 2 is an in vitro release profile of trimetazidine hydrochloride sustained-release tablets of Examples 1, 2, 3, 4, and 5 in a dissolution medium at pH 1.2.
  • FIG. 3 is an in vitro release profile of trimetazidine hydrochloride sustained-release tablets of Examples 1, 2, 3, 4, and 5 in a pH 4.0 dissolution medium.
  • FIG. 4 is an in vitro release curve diagram of trimetazidine hydrochloride sustained-release tablets of Example 1, 2, 3, 4, and 5 in dissolution medium water.
  • the instruments used in the present invention can be obtained through formal commercial means.
  • the specific conditions are as follows:
  • the coating material for protective pellet coating and the plasticizer for protective pellet coating are dissolved in an aqueous solution; the sustained-release pellets are placed in a Glatt fluidized bed for protective coating, and the air intake volume is 300 to 500 m 3 / h, inlet air temperature is 40 to 70 ° C, atomization pressure is 3.0 to 5.0 bar, peristaltic pump speed is 40 to 80 rpm, material temperature is controlled at 25 to 45 ° C, and protective pellets are prepared.
  • the tablet core is placed in a high-efficiency coating pan, and the film is coated with Opadry.
  • the Opadry solid content is 10 to 15%, and the weight gain of the coating is 3 to 5%.
  • the coating material for protective pellet coating and the plasticizer for protective pellet coating are dissolved in an aqueous solution; the sustained-release pellets are placed in a Glatt fluidized bed for protective coating, and the air intake volume is 300 to 500 m 3 / h, inlet air temperature is 40 to 70 ° C, atomization pressure is 3.0 to 5.0 bar, peristaltic pump speed is 40 to 80 rpm, material temperature is controlled at 25 to 45 ° C, and protective pellets are prepared.
  • the tablet core is placed in a high-efficiency coating pan, and the film is coated with Opadry.
  • the Opadry solid content is 10 to 15%, and the weight gain of the coating is 3 to 5%.
  • the coating material for protective pellet coating and the plasticizer for protective pellet coating are dissolved in an aqueous solution; the sustained-release pellets are placed in a Glatt fluidized bed for protective coating, and the air intake volume is 300 to 500 m 3 / h, inlet air temperature is 40 to 70 ° C, atomization pressure is 3.0 to 5.0 bar, peristaltic pump speed is 40 to 80 rpm, material temperature is controlled at 25 to 45 ° C, and protective pellets are prepared.
  • the tablet core is placed in a high-efficiency coating pan, and the film is coated with Opadry.
  • the Opadry solid content is 10 to 15%, and the weight gain of the coating is 3 to 5%.
  • the coating material for protective pellet coating and the plasticizer for protective pellet coating are dissolved in an aqueous solution; the sustained-release pellets are placed in a Glatt fluidized bed for protective coating, and the air intake volume is 300 to 500 m 3 / h, inlet air temperature is 40 to 70 ° C, atomization pressure is 3.0 to 5.0 bar, peristaltic pump speed is 40 to 80 rpm, material temperature is controlled at 25 to 45 ° C, and protective pellets are prepared.
  • the tablet core is placed in a high-efficiency coating pan, and the film is coated with Opadry.
  • the Opadry solid content is 10 to 15%, and the weight gain of the coating is 3 to 5%.
  • the coating material for protective pellet coating and the plasticizer for protective pellet coating are dissolved in an aqueous solution; the sustained-release pellets are placed in a Glatt fluidized bed for protective coating, and the air intake volume is 300 to 500 m 3 / h, inlet air temperature is 40 to 70 ° C, atomization pressure is 3.0 to 5.0 bar, peristaltic pump speed is 40 to 80 rpm, material temperature is controlled at 25 to 45 ° C, and protective pellets are prepared.
  • the tablet core is placed in a high-efficiency coating pan, and the film is coated with Opadry.
  • the Opadry solid content is 10 to 15%, and the weight gain of the coating is 3 to 5%.
  • Trimetazidine Hydrochloride Sustained-Release Tablets prepared by measuring the in vitro release method (Chinese Pharmacopoeia 2010 Edition Two Appendix XD first method) and dissolution measurement method (Chinese Pharmacopoeia 2010 Edition Two Appendix XC first method) device The release characteristics of Trimetazidine Hydrochloride Sustained-Release Tablets and the reference commercially available Trimetazidine Hydrochloride Sustained-Release Tablets (Name Wanshuangli, 35mg / tablet).

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Abstract

一种曲美他嗪缓释片及其制备方法。该缓释片包括片剂薄膜包衣用包衣材料和由其包衣的片芯，片芯包括微丸和辅料，微丸从内至外依次包括载药包衣层、缓释包衣层和保护包衣层，载药包衣层包括曲美他嗪和载药微丸包衣用粘合剂，缓释包衣层包括缓释微丸包衣用包衣材料、致孔剂、增塑剂和抗粘剂，保护包衣层包括保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，辅料包括填充剂、崩解剂和润滑剂。该缓释片由于在缓释层之外又包裹了保护层，解决了微丸在压片过程中易出现的因缓释层遭到破坏而导致的缓释能力下降以及因流动性过剩而导致的含量均匀度不合格等问题，同时解决了易溶性药物曲美他嗪在水中存在的突释问题。

Description

一种曲美他嗪缓释片及其制备方法 技术领域
本发明属于药物制剂领域，涉及曲美他嗪缓释片的制备工艺。
背景技术
心绞痛是一种常见的心血管疾病，是由于冠状动脉粥样硬化、狭窄，导致冠状动脉供血不足，心肌暂时缺血与缺氧所引起的，以心前区疼痛为主要临床表现的一组综合征，是发生率最高的冠心病的一种，严重威胁着人类的健康和生活。其主要分为稳定型心绞痛和不稳定型心绞痛。心绞痛可在24小时任何时间发作，但以清晨至上午居多，变异性心绞痛多在夜间定时发作。因此，要求治疗药物在24h内可以一直维持有效治疗浓度，以保证治疗的有效性、安全性和稳定性。盐酸曲美他嗪属于其他类抗心绞痛心血管药物，是第一个作用于心肌细胞代谢、通过使心脏能量代谢合理化发挥直接细胞保护作用而广泛应用于抗心绞痛的药物。
曲美他嗪口服后吸收迅速，半衰期相对较短[t 1/2＝(6.0±1.4)h]，曲美他嗪浓度可在24h内稳定，且在给药期间(15d)浓度可维持相对不变。单次口服曲美他嗪20mg，1.8h达到血浆浓度峰值，血浆浓度峰值为53.6μg/L，浓度时间曲线下面积可达508.9μg/(h·L)。每次口服曲美他嗪20mg，每日2次，连服15d后，血浆浓度峰值可达到84.8μg/L，浓度时间曲线下面积可达831.4μg/(h·L)。曲美他嗪生物利用度高，可达88.7％，蛋白结合率约为16％，血浆分布容积为318.6L，清除半衰期为6h，80％药物从肾脏排泄(其中62％为原形)，总清除率为37.45L/h。曲美他嗪不影响心脏的血流动力学，犬的动物实验表明静脉注射0.25-1.0mg曲美他嗪对心率、血压、心排血量及左室压力均无明显影响。
普通曲美他嗪片每日单次服用剂量为20mg，每天至少需服用3次，故体内的血药浓度容易出现“峰谷”现象，有效血药浓度维持时间短，毒副作用大，患者依从性差。
2010年施维雅(天津)制药有限公司在国内正式上市销售盐酸曲美他嗪缓释片，英文名称Trimetazidine Dihydrochloride Modified Release Tablets，活性成分为盐酸曲美他嗪，规格35mg/片，商品名万爽力，每天服药2次。口服5小时后达到最大浓度，血药浓度不低于75％的时间超过24小时，60小时达到稳态。减少服用次数，提高患者顺应性。
专利CN00138060.5提供了口服给药后能够长时间释放曲美他嗪的基质片，其特征在于基质片中不含有疏水性成分并且长时间释放是通过与占片剂总重25-50％的羟丙甲纤维素(HypromelloseCellulose，HPMC)混合进行控制。片剂中曲美他嗪二盐酸盐占片剂总重 15-30％，粘合剂PVP占片剂总重3-12％，稀释剂CaHPO 4·2H 2O占片剂总重25-75％，其余是润滑剂硬脂酸镁和流动剂无水胶态SiO 2，采用湿法造粒。
专利CN95103558.4公开了口服延缓释放的曲美他嗪药物组合，通过贮存库系统来确保曲美他嗪的控制释放，所述系统选自EC和聚甲基丙烯酸聚合物的水不溶性聚合物和增塑剂乙酰基柠檬酸三丁酯的混合物形成膜，该膜包裹着药片或药丸小颗粒。
专利ZL200610166205.2公开曲美他嗪缓释微丸及其制备方法，提供了含药丸芯控制药物释放的薄膜衣层的重量比为20：1-5：1，丸芯中曲美他嗪的含量是10-60％，主要采用挤出滚圆法制备丸芯，流化床进行缓释包衣。
专利20111005676.5公开了一种盐酸曲美他嗪缓释片及其制备方法，采用聚醋酸乙烯酯和聚维酮混合物与乙基纤维素的混合物作为缓释骨架材料，其特征在于：以重量百分比计，各组分占片剂总重量如下：15-25％盐酸曲美他嗪、45-55％KollidonSR与乙基纤维素混合物、25-35％填充剂、0-2％润滑剂及0-1％其他辅料，采用湿法制粒。
上述缓释片、缓释微丸和缓释膜包片的配方或制备工艺存在以下问题：
(1)专利CN00138060.5使用较高比例的HPMC为缓释材料，CaHPO 4·2H 2O为填充剂，该专利使用大量的磷酸氢钙二水合物为稀释剂，过高用量的磷酸氢钙，在较低的pH下，药物释放速度会显著加快，因此药物进入胃后，可能会受胃酸影响而加快药物释放。
(2)专利CN95103558.4提供了一种口服延缓释放的曲美他嗪药物组合物，为包有控释膜的片或颗粒，发明人目的是每日单剂量服用。所以该组合物累积释放16h只有80％，释放不完全，未达到药典规定的要求(≥85％)。此外，药物在胃肠道有效吸收时间只有9-12h，设计持续释放16h以上是无必要的。
(3)专利ZL200610166205.2提供一种含活性药物成分曲美他嗪缓释微丸的制备方法，其特征是由含药丸芯和控制药物释放的薄膜衣层组成，主要采用挤出滚圆制备丸芯，流化床进行包衣，在该专利中，微丸优选直径为0.6mm-1.5mm，该丸芯直径较大，和辅料粒径相差较大，只能供胶囊填充使用，原研为缓释片，如用于微丸压片，则可能出现混合不均匀的现象，同时该专利采用挤出滚圆制备载药丸芯，所制得的丸芯粒径分布范围较广，放大生产重现性需采取更严格的措施。
(4)专利20111005676.5，采用聚醋酸乙烯酯和聚维酮混合物与乙基纤维素的混合物作为缓释骨架材料，该组合物释放时间长，但药物在16小时释放约75％，释放不完全，未达到药典规定的要求(≥85％)。
(5)现有的曲美他嗪缓释片较少采用多单元微粒或微丸系统而削弱了释药规律的重现性 (不同批次)和一致性(同一批次)，盐酸曲美他嗪在水中极易溶解，存在突释问题。
盐酸曲美他嗪在水中极易溶解，其溶解度大于1000mg/ml，因此控制高溶解度药物的突释是本发明的关键。所谓突释，就是指缓、控释制剂在释放初期出现的药物大剂量释放现象。
目前国外已有日服2次的盐酸曲美他嗪缓释片上市，国内外也在研制中，曲美他嗪水溶性非常好，单纯骨架型缓释制剂很难控制药物的释放速率，需要添加大量的骨架材料和阻滞剂，专利CN00138060.5所述的长时间释放曲美他嗪的基质片控制药物释放达3-4h。
发明内容
现有的曲美他嗪缓释片因未采用多单元微粒或微丸系统而削弱了释药规律的重现性(不同批次)和一致性(同一批次)，盐酸曲美他嗪在水中极易溶解，存在突释问题。
本发明提供了一种曲美他嗪缓释片，其由空白丸芯、曲美他嗪和载药微丸包衣用粘合剂形成载药微丸，由载药微丸、缓释微丸包衣用包衣材料、致孔剂、增塑剂和抗粘剂形成缓释微丸，由缓释微丸、保护微丸包衣用包衣材料和保护微丸包衣用增塑剂形成保护微丸，由微丸、填充剂、崩解剂和润滑剂形成片芯，由片芯和片剂薄膜包衣用包衣材料形成最终的曲美他嗪缓释片。该片有限成分质量可控，在各种介质中药效释放行为均能达到预期效果，与参比制剂相似因子均大于70以上。
在本发明的技术方案中，所述载药微丸为以流化床将包含载药微丸包衣用粘合剂和曲美他嗪的水溶液液相层积在空白丸芯上制得。
在本发明的技术方案中，所述缓释微丸为以流化床将包含致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂的溶液通过液相层积在载药微丸上制得。
在本发明的技术方案中，所述保护微丸为以流化床将包含保护微丸包衣用包衣材料和保护微丸包衣用增塑剂溶液通过液相层积在缓释微丸上制得。
在本发明的技术方案中，所述片芯为将保护微丸、填充剂、崩解剂和润滑剂混合，然后压片制得。
在本发明的技术方案中，所述曲美他嗪缓释片为通过液相层积法将片剂薄膜包衣用包衣材料的溶液液相沉积在片芯表面制得。
在本发明的技术方案中，各组分的比例按质量份数计为曲美他嗪10～20份、空白丸芯10～15份、载药微丸包衣用粘合剂3～5份、缓释微丸包衣用包衣材料8～14份、致孔剂1～5份、增塑剂0.5～5份、抗粘剂0.5～2份、保护微丸包衣用包衣材料10～17份、保护微丸包衣用增塑剂1～5份、填充剂25～35份、崩解剂3～4份、润滑剂0.1～1份、片剂薄膜包衣用包衣材料2～5份。
在本发明的技术方案中，该缓释片由以下重量百分比计的下列组分：
组分 质量份数
曲美他嗪 10～20
空白丸芯 10～15
载药微丸包衣用粘合剂 3～5
缓释微丸包衣用包衣材料 8～14
致孔剂 1～5
增塑剂 0.5～5
抗粘剂 0.5～2
保护微丸包衣用包衣材料 10～17
保护微丸包衣用增塑剂 1～5
填充剂 25～35
崩解剂 3～4
润滑剂 0.1～1
片剂薄膜包衣用包衣材料 2～5
本发明另一个方面提供一种曲美他嗪缓释微丸压片的制备方法，其包括如下步骤：
1)向纯化水中依次加入载药微丸包衣用粘合剂、曲美他嗪，得到载药微丸包衣液；将空白丸芯通过液相层积将载药微丸包衣液包衣在空白丸芯表面，得到载药微丸；
2)向纯化水中依次加入致孔剂、缓释微丸包衣用包衣材料、醇溶剂、增塑剂和抗粘剂，搅拌均匀后得到缓释微丸包衣液；将载药微丸通过液相层积将所述缓释微丸包衣液包衣在载药微丸表面，得到缓释微丸；
3)向纯化水中依次加入保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，搅拌均匀后得到保护微丸包衣液；将缓释微丸通过液相层积将所述保护微丸包衣液包衣在缓释微丸表面，得到保护微丸；
4)将保护微丸、填充剂、崩解剂和润滑剂混合，压片，得到片芯；
5)向纯化水中加入片剂薄膜包衣用包衣材料，搅拌均匀后得到片剂薄膜包衣液；将片芯通过液相层积法将片剂薄膜包衣液包衣在片芯表面，得到曲美他嗪缓释片。
本发明所使用的空白丸芯，为淀粉丸芯或微晶纤维素丸芯，优选微晶纤维素丸芯，因为微晶纤维素丸芯不溶于大多数有机溶剂和水，适用于溶液层积上药法，并且微晶纤维素丸芯的表面光滑、硬度较高，是微丸包衣和压片的最好选择，优选粒径为50～1000μm，更优选粒 径为50～500μm的微晶纤维素丸芯，因为较小的粒径和较窄的粒径分布有利于微丸包衣和压片。
本发明所使用的载药微丸包衣用粘合剂，为羟乙基纤维素(HEC)或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素，因为羟丙基甲基纤维素具有较好的分散能力，更加适合于喷雾包衣。
本发明所使用缓释微丸包衣用包衣材料，为醋酸纤维素(CA)或乙基纤维素(EC)，优选乙基纤维素，因为乙基纤维素为致密性较高的缓释材料，配合有机溶剂进行包衣的衣膜耐压性较好，更适合于微丸压片，更优选低粘度的乙基纤维素，因为低粘度的乙基纤维素往往需要更多的缓释聚合物包衣，从而能够获得具有一定厚度的缓释衣膜，更有利于压片。
本发明所使用的致孔剂，为聚乙二醇(PEG)、聚维酮(PVP)、蔗糖或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素，因为羟丙基甲基纤维素具有适宜的水溶性，将其作为致孔剂来配合高致密性且水不溶性的乙基纤维素，能够保证药物的合理释放。
本发明所使用的增塑剂，为邻苯二甲酸二甲酯、癸二酸二丁酯或柠檬酸三乙酯，优选柠檬酸三乙酯，因为单用乙基纤维素所制得的衣膜物理性能较差，延展系数和抗压能力有限，压片过程中经常伴有衣膜的破裂而改变药物的释放行为，作为增塑剂的柠檬酸三乙酯的引入则可以有效解决压片过程中衣膜破裂的问题。
本发明所使用的抗粘剂为二氧化硅、二氧化钛或滑石粉，优选滑石粉，因为选用乙基纤维素作为缓释材料进行包衣时，微丸容易粘连，加入抗粘剂滑石粉后，粘连现象能够得以克服，优选粒度为500～2000目，更优选粒度为500～1500目滑石粉，因为如果滑石粉的粒径过大，其在包衣过程中容易发生沉降，导致喷枪堵塞；另外，粒径较小的滑石粉能够使衣膜更加密实完整。
本发明所使用的保护微丸包衣用包衣材料，为羟乙基纤维素(HEC)或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素，同样因为羟丙基甲基纤维素具有较好的分散能力，更加适合于喷雾包衣。
本发明所使用的保护微丸包衣用增塑剂，为聚乙二醇(PEG)、聚维酮(PVP)或羟丙基甲基纤维素(HPMC)，优选聚乙二醇，因为聚乙二醇具有非常强的弹性形变能力，压片过程中对缓释衣膜具有较好的保护作用，更优选弹性形变能力优异且常见易得的聚乙二醇。
本发明所使用的填充剂，为淀粉、糊精、乳糖或微晶纤维素(MCC)，优选微晶纤维素，因为微晶纤维素是微丸压片的理想填充剂，在压缩时起缓冲作用，可以避免微丸之间直接接触，在较小的压力下即可获得较大的硬度，从而避免压力对衣膜的破坏。
本发明所使用的崩解剂，为羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)或交联羧甲基纤维素钠(CCMC-Na)，优选交联羧甲基纤维素钠，因为交联羧甲基纤维素钠的纤维特性能够产生强烈的毛细管作用，因而具备良好的吸水能力；同时，交联羧甲基纤维素钠的交联化学结构能够形成一种不溶于水的亲水性、高吸水性物质，具有良好的快速膨胀特性。与其他崩解剂相比，这种双重功能使得交联羧甲基纤维素钠在使用时具有超级崩解功能。
本发明所使用的润滑剂，为滑石粉、微粉硅胶或硬脂酸镁，优选硬脂酸镁，因为硬脂酸镁易于与待压片药物颗粒混匀，能够减少颗粒与冲模之间的摩擦力，压片后片面光洁美观。
本发明所使用的片剂薄膜包衣用包衣材料，为胃溶型欧巴代薄膜包衣预混剂，因为在微丸压片时，聚合物包裹的颗粒会在压片过程中发生形变，导致片面外观不理想，需要进行薄膜包衣，而欧巴代的遮盖力较强，能够使最终得到的片剂外观均匀、美观，此外，胃溶型欧巴代薄膜包衣预混剂能够使主药在胃部就开始释放并在胃肠道全程中稳定吸收。
制备工艺
本发明还提供了一种曲美他嗪缓释片的制备方法，其包括下列步骤：
1)在搅拌条件下，向纯化水中依次加入处方量的载药微丸包衣用粘合剂、处方量的曲美他嗪，搅拌均匀后得到载药微丸包衣液；将处方量的空白丸芯置于底喷式流化床包衣机中，通过液相层积法将所述载药微丸包衣液包衣在所述空白丸芯表面，得到载药微丸。
2)在搅拌条件下，向纯化水中依次加入处方量的致孔剂、处方量的缓释微丸包衣用包衣材料、醇性溶剂、处方量的增塑剂和处方量的抗粘剂，搅拌均匀后得到缓释微丸包衣液；将处方量的载药微丸置于底喷式流化床包衣机中，通过液相层积法将所述缓释微丸包衣液包衣在所述载药微丸表面，得到缓释微丸。
3)在搅拌条件下，向纯化水中依次加入处方量的保护微丸包衣用包衣材料和处方量的保护微丸包衣用粘合剂，搅拌均匀后得到保护微丸包衣液；将处方量的缓释微丸置于底喷式流化床包衣机中，通过液相层积法将所述保护微丸包衣液包衣在所述缓释微丸表面，得到保护微丸。
4)将处方量的保护微丸、处方量的填充剂、处方量的崩解剂和处方量的润滑剂置于终混机中混合，然后置于压片机中压片，得到片芯。
5)在搅拌条件下，向纯化水中加入处方量的片剂薄膜包衣用包衣材料，搅拌均匀后得到片剂薄膜包衣液；将处方量的片芯置于高效包衣机中，通过液相层积法将所述片剂薄膜包衣液包衣在所述片芯表面，得到曲美他嗪缓释片。
在本发明的技术方案中，各组分的组成为
Figure PCTCN2018095425-appb-000001
或者
Figure PCTCN2018095425-appb-000002
Figure PCTCN2018095425-appb-000003
或者
Figure PCTCN2018095425-appb-000004
Figure PCTCN2018095425-appb-000005
或者
Figure PCTCN2018095425-appb-000006
或者
Figure PCTCN2018095425-appb-000007
有益效果
(1)本发明的通过多剂量剂型微丸来制备片剂，即使个别微丸在制备上的缺陷不至于对整体制剂的释药行为产生严重影响，从整体上保证了释药规律的重现性(不同批次)和一致性(同一批次)，降低了突释的可能性。
附图说明
图1为实施例1、2、3、4、5的盐酸曲美他嗪缓释片在pH6.8溶出介质的体外释放曲线图。
图2为实施例1、2、3、4、5的盐酸曲美他嗪缓释片在pH1.2溶出介质的体外释放曲线图。
图3为实施例1、2、3、4、5的盐酸曲美他嗪缓释片在pH4.0溶出介质的体外释放曲线图。
图4为实施例1、2、3、4、5的盐酸曲美他嗪缓释片在溶出介质水的体外释放曲线图。
具体实施方式
本发明所使用的仪器均可通过正规的商业手段获取，具体情况，如下表：
设备名称 型号 厂家
多功能流化床 FLZB-15 创智机电
三元旋振筛 S49-600-S 河南新乡筛分设备
高效湿法混合制粒机 HLSG-200 温州制药机械
沸腾干燥机 FG-120C 重庆广厦
摇摆颗粒机 YK-160 温州制药机械
离心振荡筛 ZG-550 温州制药机械
粉碎整粒机 FZB-300 温州制药机械
多向运动混合机 HD-600A 江南制药机械
高速压片机 GZPL-620 国药龙立
高效包衣机 BGB-75C 小伦制药机械
实施例1：
Figure PCTCN2018095425-appb-000008
Figure PCTCN2018095425-appb-000009
制备方法：
(1)将载药微丸包衣用粘合剂和曲美他嗪，溶解于水溶液中；空白微晶纤维素丸芯(50～500μm)置于格拉特流化床中，进行溶液层积上药，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到载药微丸；
(2)将致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂，溶解并分散于乙醇水溶液中；载药微丸置于格拉特流化床中，进行缓释包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到缓释微丸；
(3)将保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，溶解于水溶液中；缓释微丸置于格拉特流化床中，进行保护包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到保护微丸。
(4)将微丸与填充剂、崩解剂和润滑剂混合均匀，以高速旋转压片机制备片芯，冲模为9号浅凹，硬度为4.0～6.0kg。
(5)将片芯置于高效包衣锅中，以欧巴代对其进行薄膜包衣，欧巴代固含量为10～15％，包衣增重为3～5％。
实施例2：
Figure PCTCN2018095425-appb-000010
制备方法：
(1)将载药微丸包衣用粘合剂和曲美他嗪，溶解于水溶液中；空白微晶纤维素丸芯(50～500μm)置于格拉特流化床中，进行溶液层积上药，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到载药微丸；
(2)将致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂，溶解并分散于乙醇水溶液中；载药微丸置于格拉特流化床中，进行缓释包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到缓释微丸；
(3)将保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，溶解于水溶液中；缓释微丸 置于格拉特流化床中，进行保护包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到保护微丸。
(4)将微丸与填充剂、崩解剂和润滑剂混合均匀，以高速旋转压片机制备片芯，冲模为9号浅凹，硬度为4.0～6.0kg。
(5)将片芯置于高效包衣锅中，以欧巴代对其进行薄膜包衣，欧巴代固含量为10～15％，包衣增重为3～5％。
实施例3：
Figure PCTCN2018095425-appb-000011
制备方法：
(1)将载药微丸包衣用粘合剂和曲美他嗪，溶解于水溶液中；空白微晶纤维素丸芯(50～500μm)置于格拉特流化床中，进行溶液层积上药，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到载药微丸；
(2)将致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂，溶解并分散于乙醇水溶液中；载药微丸置于格拉特流化床中，进行缓释包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到缓释微丸；
(3)将保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，溶解于水溶液中；缓释微丸置于格拉特流化床中，进行保护包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到保护微丸。
(4)将微丸与填充剂、崩解剂和润滑剂混合均匀，以高速旋转压片机制备片芯，冲模为9号浅凹，硬度为4.0～6.0kg。
(5)将片芯置于高效包衣锅中，以欧巴代对其进行薄膜包衣，欧巴代固含量为10～15％，包衣增重为3～5％。
实施例4：
Figure PCTCN2018095425-appb-000012
Figure PCTCN2018095425-appb-000013
制备方法：
(1)将载药微丸包衣用粘合剂和曲美他嗪，溶解于水溶液中；空白微晶纤维素丸芯(50～500μm)置于格拉特流化床中，进行溶液层积上药，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到载药微丸；
(2)将致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂，溶解并分散于乙醇水溶液中；载药微丸置于格拉特流化床中，进行缓释包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到缓释微丸；
(3)将保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，溶解于水溶液中；缓释微丸置于格拉特流化床中，进行保护包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到保护微丸。
(4)将微丸与填充剂、崩解剂和润滑剂混合均匀，以高速旋转压片机制备片芯，冲模为9号浅凹，硬度为4.0～6.0kg。
(5)将片芯置于高效包衣锅中，以欧巴代对其进行薄膜包衣，欧巴代固含量为10～15％，包衣增重为3～5％。
实施例5：
Figure PCTCN2018095425-appb-000014
Figure PCTCN2018095425-appb-000015
制备方法：
(1)将载药微丸包衣用粘合剂和曲美他嗪，溶解于水溶液中；空白微晶纤维素丸芯(50～500μm)置于格拉特流化床中，进行溶液层积上药，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到载药微丸；
(2)将致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂，溶解并分散于乙醇水溶液中；载药微丸置于格拉特流化床中，进行缓释包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到缓释微丸；
(3)将保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，溶解于水溶液中；缓释微丸置于格拉特流化床中，进行保护包衣，进风量为300～500m 3/h、进风温度为40～70℃，雾化压力为3.0～5.0bar，蠕动泵转速为40～80rpm，物料温度控制在25～45℃，制备得到保护微丸。
(4)将微丸与填充剂、崩解剂和润滑剂混合均匀，以高速旋转压片机制备片芯，冲模为 9号浅凹，硬度为4.0～6.0kg。
(5)将片芯置于高效包衣锅中，以欧巴代对其进行薄膜包衣，欧巴代固含量为10～15％，包衣增重为3～5％。
实施例6 曲美他嗪缓释片体外溶出度检测
采用体外释放度测定法(中国药典2010版二部附录XD第一法)和采用溶出测定法(中国药典2010版二部附录XC第一法)的装置测定本发明实施例1～10所制得的盐酸曲美他嗪缓释片以及对照品市售盐酸曲美他嗪缓释片(名万爽力，35mg/片)的药物释放特征。
对实施例1-5的检测，通过结果(图1-4，表1-4)可以看出实施例1、2、3、4、5中曲美他嗪缓释片的批间释放行为重现性及批内释放行为均一性均良好，表明本发明的处方工艺稳定、可控。
表1
Figure PCTCN2018095425-appb-000016
表2
Figure PCTCN2018095425-appb-000017
表3
Figure PCTCN2018095425-appb-000018
表4
Figure PCTCN2018095425-appb-000019

Claims (10)

  1. 一种曲美他嗪缓释片，其由空白丸芯、曲美他嗪和载药微丸包衣用粘合剂形成载药微丸，由载药微丸、缓释微丸包衣用包衣材料、致孔剂、增塑剂和抗粘剂形成缓释微丸，由缓释微丸、保护微丸包衣用包衣材料和保护微丸包衣用增塑剂形成保护微丸，由微丸、填充剂、崩解剂和润滑剂形成片芯，由片芯和片剂薄膜包衣用包衣材料形成最终的曲美他嗪缓释片。
  2. 根据权利要求1所述的曲美他嗪缓释片，所述载药微丸为以流化床将包含载药微丸包衣用粘合剂和曲美他嗪的水溶液通过液相层积法在空白丸芯上制得；所述缓释微丸为以流化床将包含致孔剂、缓释微丸包衣用包衣材料、增塑剂和抗粘剂的溶液通过液相层积在载药微丸上制得；所述保护微丸为以流化床将包含保护微丸包衣用包衣材料和保护微丸包衣用粘合剂的溶液液相层积在缓释微丸上制得；所述片芯为将保护微丸、填充剂、崩解剂和润滑剂混合，然后压片制得；所述曲美他嗪缓释片为通过液相层积法将片剂薄膜包衣用包衣材料的溶液液相沉积在片芯表面制得。
  3. 一种曲美他嗪缓释微丸压片的制备方法，其包括如下步骤：
    1)向纯化水中依次加入载药微丸包衣用粘合剂、曲美他嗪，得到载药微丸包衣液；将空白丸芯通过液相层积将载药微丸包衣液包衣在空白丸芯表面，得到载药微丸；
    2)向纯化水中依次加入致孔剂、缓释微丸包衣用包衣材料、醇溶剂、增塑剂和抗粘剂，搅拌均匀后得到缓释微丸包衣液；将载药微丸通过液相层积将所述缓释微丸包衣液包衣在载药微丸表面，得到缓释微丸；
    3)向纯化水中依次加入保护微丸包衣用包衣材料和保护微丸包衣用增塑剂，搅拌均匀后得到保护微丸包衣液；将缓释微丸通过液相层积将所述保护微丸包衣液包衣在缓释微丸表面，得到保护微丸；
    4)将保护微丸、填充剂、崩解剂和润滑剂混合，压片，得到片芯；
    5)向纯化水中加入片剂薄膜包衣用包衣材料，搅拌均匀后得到片剂薄膜包衣液；将片芯通过液相层积法将片剂薄膜包衣液包衣在片芯表面，得到曲美他嗪缓释片。
  4. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，各组分的比例按质量份数计为曲美他嗪10～20份、空白丸芯10～15份、载药微丸包衣用粘合剂3～5份、缓释微丸包衣用包衣材料8～14份、致孔剂1～5份、增塑剂0.5～5份、抗粘剂0.5～2份、保护微丸包衣用包衣材料10～17份、保护微丸包衣用增塑剂1～5份、填充剂25～35份、崩解剂3～4份、润滑剂0.1～1份、片剂薄膜包衣用包衣材料2～5份。
  5. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，载药微丸包衣用粘合剂，为羟乙基纤维素(HEC)或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素。
  6. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，缓释微丸包衣用包衣材料为醋酸纤维素(CA)或乙基纤维素(EC)，优选乙基纤维素；
    致孔剂为聚乙二醇(PEG)、聚维酮(PVP)、蔗糖或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素；
    增塑剂为邻苯二甲酸二甲酯、癸二酸二丁酯或柠檬酸三乙酯，优选柠檬酸三乙酯；
    抗粘剂为二氧化硅、二氧化钛或滑石粉，优选滑石粉。
  7. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，保护微丸包衣用增塑剂，为聚乙二醇(PEG)、聚维酮(PVP)或 羟丙基甲基纤维素(HPMC)，优选聚乙二醇；
    保护微丸包衣用包衣材料，为羟乙基纤维素(HEC)或羟丙基甲基纤维素(HPMC)，优选羟丙基甲基纤维素。
  8. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，填充剂为淀粉、糊精、乳糖或微晶纤维素(MCC)，优选微晶纤维素；
    崩解剂，为羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)或交联羧甲基纤维素钠(CCMC-Na)，优选交联羧甲基纤维素钠；
    润滑剂，为滑石粉、微粉硅胶或硬脂酸镁，优选硬脂酸镁。
  9. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，薄膜包衣用包衣材料，为胃溶型欧巴代薄膜包衣预混剂。
  10. 根据权利要求1-2任一项所述的曲美他嗪缓释片或者权利要求3所述的制备方法，其中，空白丸芯，为淀粉丸芯或微晶纤维素丸芯，优选微晶纤维素丸芯。
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