WO2015055130A2 - Micropastille durable à libération prolongée et procédé de préparation associé - Google Patents

Micropastille durable à libération prolongée et procédé de préparation associé Download PDF

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WO2015055130A2
WO2015055130A2 PCT/CN2014/088743 CN2014088743W WO2015055130A2 WO 2015055130 A2 WO2015055130 A2 WO 2015055130A2 CN 2014088743 W CN2014088743 W CN 2014088743W WO 2015055130 A2 WO2015055130 A2 WO 2015055130A2
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release
sustained
coating layer
drug
trimetazidine hydrochloride
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PCT/CN2014/088743
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English (en)
Chinese (zh)
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WO2015055130A3 (fr
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刘锋
周伟杰
赖树挺
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广州帝奇医药技术有限公司
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Publication of WO2015055130A3 publication Critical patent/WO2015055130A3/fr

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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
    • A61K9/48—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
    • 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
    • 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
    • A61K9/5026—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
    • A61K9/48—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
    • 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
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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 relates to a sustained release preparation, in particular to a long-acting trimetazidine hydrochloride sustained-release pellet with a sustained release time of up to 24 hours.
  • the invention also relates to a process for the preparation of the formulation.
  • Trimetazidine Dihydrochloride (TMZ), as a new class of drugs for the effective prevention and treatment of angina pectoris, has been widely used in many countries and regions, and has a good effect on the treatment of angina pectoris.
  • Oral tablet of trimetazidine hydrochloride entered China in 2000, and the product has been listed in the National Essential Drugs List.
  • Trimetazamine Hydrochloride is 1-(2,3,4-trimethylphenyl)piperazine dihydrochloride with a molecular weight of 339.3 and a molecular formula of C 14 H 22 N 2 O 3 .2HCl, which is highly soluble in water.
  • Trimetazidine hydrochloride has a fast absorption rate in the body, and the half-life is about 6 hours. Therefore, the plasma concentration reaches a peak in the short time after taking the drug, and the blood drug is taken before the next administration, especially in the early morning when the ischemia is most severe. The concentration is very low.
  • Oral tablet of trimetazidine hydrochloride the specification is 20mg/tablet, in order to provide sufficient blood concentration to ensure good therapeutic effect, the patient needs to take the medicine 3 times a day.
  • Trimetazidine hydrochloride sustained-release tablets the specification is 35mg / tablet, the patient needs to take 2 times a day, reducing the dose once a day than the ordinary tablets, the compliance is higher.
  • most of the patients with angina pectoris are middle-aged and elderly. These patients have many forgetfulness characteristics. It is easy to cause busy patients to forget to take medicine on time.
  • the sustained release preparation can provide a constant blood concentration, which not only improves the safety, effectiveness and patient compliance of the medication, but also controls the blood concentration and reduces the number of medications. Therefore, the development of sustained release of trimetazidine hydrochloride has received increasing attention and is becoming more and more popular.
  • CN1124140A discloses an oral orally delayed release of trimetazidine pharmaceutical composition for ensuring controlled release of trimetazidine via a depot system using a system selected from the group consisting of ethyl cellulose, a water insoluble polymer of a polymethacrylic acid polymer.
  • the film formed by the mixture of acetyl tributyl citrate and the wet granulation method are used to granulate the film-coated tablets or pellets.
  • the preparation process of the composition is to prepare a blank pill core by spheroidizing technology, and then spray the drug-containing solution on the blank pill core. The method is easy to cause crystallization of the drug by the method, and the drug content is low.
  • CN102133195A discloses a sustained-release pellet of trimetazidine hydrochloride and a preparation method thereof, wherein the content of trimetazidine hydrochloride is 4.65% to 51.62%.
  • Trimetazidine Hydrochloride is applied to a blank pellet core, followed by a sustained release coating with ethyl cellulose or acrylic resin, using a plasticizer selected from the group consisting of dibutyl sebacate, triglyceride or triethyl citrate. , prepared trimetazidine hydrochloride sustained-release pellets.
  • the invention patent preparation blank blank core preparation process is long and the process is cumbersome, and the use of the spray liquid medicine form to prepare the drug-containing pellet core, which is also easy to cause drug crystallization, resulting in insufficient content of trimetazidine hydrochloride in the drug-containing pellet core.
  • CN1994280A discloses a trimetazidine sustained-release pellets with a daily dose of 20 to 40 mg and a preparation method thereof, and a preparation method thereof
  • the weight ratio of the sustained-release coating layer for controlling drug release by the drug-containing pellet core is 20:1 to 5:1
  • the sustained-release coating material is Kollicoat SR30D
  • the content of trimetazidine in the drug-containing core is 10% to 60%.
  • the preparation method mainly comprises preparing a drug-containing pellet core by an extrusion-spheronization method, and then using a fluidized bed for a sustained-release coating.
  • the pellets of the invention patent contain both immediate release and sustained release pellets, and the immediate release pellets and the sustained release pellets have different bulk density and volume difference due to the inconsistent thickness of the wrapping material and the package, which inevitably leads to The drug content of the pellets is different, which affects the stability of the therapeutic effect.
  • sustained-release preparations are convenient for patients to some extent, but due to gastric emptying and normal metabolism of the human body, the time for staying in the body after oral sustained-release preparations is generally less than 10 hours, which also leads to the existing oral sustained-release preparations. At least twice a day, to ensure adequate blood levels.
  • Long-acting trimetazidine hydrochloride sustained-release pellets which are composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, and an optional coating layer between the drug-containing pellet core and the sustained-release coating layer
  • the quality of the isolated coating layer is 0-15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5-30% of the drug-containing pellet core, and the sustained-release coating layer contains the gastrointestinal adhesive.
  • the quality of the release coating layer is 0 to 10% of the core containing the pellet, and the mass of the sustained release coating layer is 5 to 25% of the core containing the pellet; the quality of the better coating coating layer is the core containing the pellet. 0 to 10%, the quality of the sustained-release coating layer is 10 to 20% of the drug-containing pellet core.
  • composition of the drug-containing pellet core is as follows:
  • composition of the medicated pellet core is as follows:
  • composition of the medicated pellet core is as follows:
  • the composition of the barrier coating layer is as follows:
  • the release coating material is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, Opadry, acrylic resin, povidone, and yake.
  • composition of the barrier coating layer is as follows:
  • Plasticizer 0.1% to 18%.
  • composition of the sustained-release coating layer is as follows:
  • composition of the sustained release coating layer is as follows:
  • composition of the sustained release coating layer is as follows:
  • a long-acting trimetazidine hydrochloride sustained-release pellet which is composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, is provided between the drug-containing pellet core and the sustained-release coating layer.
  • the optional isolating coating layer has a quality of 0.1 to 15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5 to 30% of the drug-containing pellet core, and the sustained-release coating layer contains the stomach and the intestine.
  • a road adhesive wherein the composition of the drug-containing core is as follows:
  • composition of the barrier coating layer is as follows:
  • Plasticizer 0.1% to 18%
  • composition of the sustained release coating layer is as follows:
  • the gastrointestinal adhesive used in any of the above pellets is selected from the group consisting of carbomer, polycarboxyvinyl pentaerythritol ester, hydroxypropyl methylcellulose, high molecular weight (300,000 to 400,000) polyethylene oxide, high molecular weight. (2500 to 4000) at least one of sodium carboxymethylcellulose, liposome, methylcellulose, gelatin, and pectin.
  • the sustained-release coating material used in any of the above pellets is selected from one or more of ethyl cellulose, acrylic resin, silicone elastomer, shellac, cellulose acetate phthalate, and Sulis.
  • the sustained release coating material is an acrylic resin, specifically a low permeability Eudragit series sustained release coating material.
  • a method for preparing the above-mentioned long-acting trimetazidine hydrochloride sustained-release pellets comprising preparing a drug-containing pellet core, directly coating the sustained-release coating layer in the medicine-containing pellet core, or coating the separation coating layer in the medicine-containing pellet core, and then
  • the preparation method of the coated sustained-release coating layer containing the pill core comprises the following steps:
  • a long-acting sustained-release oral preparation of trimetazidine hydrochloride the preparation being a dispersible tablet or capsule containing the long-acting trimetazidine hydrochloride sustained-release pellet according to any one of the above, single dose containing hydrochloric acid Mitazine 70mg ⁇ 90mg, more preferably, a single dose of trimetazidine hydrochloride 75mg ⁇ 85mg.
  • the trimetazidine hydrochloride sustained-release pellet of the invention is carefully designed and coated, and the drug-containing pellet core is evenly wrapped by the sustained-release coating material to maintain a slow and uniform release property, reduce the release rate of the active ingredient, and delay the peak time.
  • the pellets can be stably released for 24 hours, maintaining stable blood concentration and avoiding insufficient blood concentration in early morning ischemia; the frequency of administration can be reduced to once a day, which helps to improve patient compliance.
  • the sustained-release pellets prepared by the method of the invention not only have uniform size, high true sphericity, small difference between batches of pellets, good quality stability and good reproducibility of the coating process, and the preparation process is simple and reliable.
  • the production equipment is simple, easy to operate and low in production cost.
  • Example 1 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 1 in a medium water;
  • Example 2 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 2 in a medium of 0.1 mol of HCl;
  • Figure 3 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 3 in a medium of water;
  • Figure 4 is a comparison diagram of in vitro release of trimetazidine hydrochloride sustained-release pellets of Example 4 and Wanshuangli in 0.1 mol of HCl;
  • Figure 5 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 5 in a medium at pH 6.8;
  • Figure 6 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 6 in a medium of water;
  • Figure 7 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 7 in a medium at pH 4.5;
  • Figure 8 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 8 in a medium of 0.1 mol of HCl;
  • Figure 9 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 9 in a medium of water;
  • Figure 10 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of pH 6.8;
  • Figure 11 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl;
  • Figure 12 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl.
  • Figure 13 is a graph showing the concentration of trimetazidine hydrochloride in plasma at different times after administration of the trimetazidine hydrochloride sustained-release pellets of Example 4 and the commercially available trimetazidine hydrochloride sustained-release tablets.
  • Long-acting trimetazidine hydrochloride sustained-release pellets which are composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, and an optional coating layer between the drug-containing pellet core and the sustained-release coating layer
  • the quality of the isolated coating layer is 0-15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5-30% of the drug-containing pellet core, and the sustained-release coating layer contains the gastrointestinal adhesive.
  • the quality of the release coating layer is 0 to 10% of the core containing the pellet, and the mass of the sustained release coating layer is 5 to 25% of the core containing the pellet; the quality of the better coating coating layer is the core containing the pellet. 0 to 10%, the quality of the sustained-release coating layer is 10 to 20% of the drug-containing pellet core.
  • composition of the drug-containing pellet core is as follows:
  • composition of the medicated pellet core is as follows:
  • composition of the medicated pellet core is as follows:
  • the composition of the barrier coating layer is as follows:
  • the release coating material is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, Opadry, acrylic resin, povidone, and yake.
  • composition of the barrier coating layer is as follows:
  • Plasticizer 0.1% to 18%.
  • composition of the sustained-release coating layer is as follows:
  • composition of the sustained release coating layer is as follows:
  • composition of the sustained release coating layer is as follows:
  • a long-acting trimetazidine hydrochloride sustained-release pellet which is composed of a drug-containing pellet core and a sustained-release coating layer from the inside to the outside, is provided between the drug-containing pellet core and the sustained-release coating layer.
  • the optional isolating coating layer has a quality of 0.1 to 15% of the drug-containing pellet core, and the quality of the sustained-release coating layer is 5 to 30% of the drug-containing pellet core, and the sustained-release coating layer contains the stomach and the intestine.
  • a road adhesive wherein the composition of the drug-containing core is as follows:
  • composition of the barrier coating layer is as follows:
  • Plasticizer 0.1% to 18%
  • composition of the sustained release coating layer is as follows:
  • the gastrointestinal adhesive used in any of the above pellets is selected from the group consisting of carbomer, polycarboxyvinyl pentaerythritol ester, hydroxypropyl methylcellulose, high molecular weight (300,000 to 400,000) polyethylene oxide, high molecular weight. (2500 to 4000) at least one of sodium carboxymethylcellulose, liposome, methylcellulose, gelatin, and pectin.
  • the sustained-release coating material used in any of the above pellets is selected from one or more of ethyl cellulose, acrylic resin, silicone elastomer, shellac, cellulose acetate phthalate, and Sulis.
  • the sustained release coating material is an acrylic resin, specifically a low permeability Eudragit series sustained release coating material.
  • Acrylic resin is a kind of polymer formed by two or more kinds of monomers.
  • the acrylic resin used as a film coating material is copolymerized by monomers such as methacrylate, acrylate and methacrylic acid in different proportions. A large class of polymers.
  • Acrylic resin is a safe, non-toxic polymer material.
  • the acrylic resin produced by Evonik Industries has good film-forming properties, including E, L, S, RL and RS.
  • E type is gastric soluble
  • L and S are enteric
  • RL and RS are insoluble in water
  • Eudragit is the trade name.
  • the Eutec RL has a pore diameter of 1 to 5 ⁇ m and the Eudragit RS has a diameter of 0.1 to 0.6 ⁇ m. Drugs on the inside of the coating are released through these channels, and the ratio of the two materials can be adjusted to adjust the release rate. It is formed by copolymerization of neutral methacrylic acid with a small amount of trimethylammonium methacrylate chloride. The molar ratio of the quaternary amine group to the neutral ester group is 1:20 (equivalent to 50 meq/100 g), and The corresponding ratio is 1:40 (equivalent to 25 mg equivalents per 100 g).
  • the quaternary amine group determines the swelling and permeability of the film in water, it contains less quaternary amine groups.
  • the formed film has low permeability and has a long delay effect on drug release, and is suitable for a sustained release coating of a water-soluble drug.
  • a method for preparing the above-mentioned long-acting trimetazidine hydrochloride sustained-release pellets comprising preparing a drug-containing pellet core, directly coating the sustained-release coating layer in the medicine-containing pellet core, or coating the separation coating layer in the medicine-containing pellet core, and then
  • the preparation method of the coated sustained-release coating layer containing the pill core comprises the following steps:
  • a long-acting sustained-release oral preparation of trimetazidine hydrochloride the preparation being a dispersible tablet or capsule containing the long-acting trimetazidine hydrochloride sustained-release pellet according to any one of the above, single dose containing hydrochloric acid Mitazine 70mg ⁇ 90mg, more preferably, a single dose of trimetazidine hydrochloride 75mg ⁇ 85mg.
  • the bioadhesive drug delivery system is a new branch of modern drug delivery forms.
  • the bioadhesive preparation is a kind of pharmaceutical preparation which uses a bioadhesive material as a drug carrier and adheres to the mucosa for a long time through bioadhesion.
  • Bioadhesive formulations have the following major advantages over other dosing forms:
  • the carrier is composed of bioadhesive materials, which have different degrees of adhesion to the mucosa, which can prolong the release time and improve the absorption of the drug;
  • the site of action is the tissue mucosa of the human body.
  • the drug directly enters the systemic blood system through mucosal transport, avoiding the first-pass effect of the liver and improving the bioavailability of the drug;
  • 3 has a targeting function, for local diseases, can greatly increase the local drug concentration, to avoid the difficulty of oral drugs in the lesions to achieve effective concentrations.
  • the biological adhesion preparation can be divided into oral adhesion preparation, nasal adhesion preparation, gastrointestinal oral adhesion preparation, eye adhesion preparation, uterine and vaginal adhesion preparation, rectal adhesion preparation and the like.
  • the current technical methods for prolonging the transit time of drugs in the gastrointestinal tract are mainly intragastric floating drug delivery systems and gastrointestinal mucosal drug delivery systems.
  • Sources of bioadhesives are available in a variety of synthetic and natural sources. Natural such as: gelatin, pectin, western gum, gum arabic, sodium alginate and so on. Synthetic are: methyl cellulose (MC), sodium carboxymethyl cellulose (CMC ⁇ Na), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methacrylic acid Ester, polyvinyl alcohol (PVA), Carbopol, polycarbophil, and the like.
  • Natural such as: gelatin, pectin, western gum, gum arabic, sodium alginate and so on.
  • Synthetic are: methyl cellulose (MC), sodium carboxymethyl cellulose (CMC ⁇ Na), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methacrylic acid Ester, polyvinyl alcohol (PVA), Carbopol, polycarbophil, and the like.
  • sustained release and controlled-release dosage forms prepared by the coating technology control and adjust the release rate of the drug in the body and the outside of the dosage form through the coating film, so the selection of the coating material and the composition of the coating film are largely The success or failure of the sustained release and controlled release of this preparation is determined.
  • Commonly used sustained release coating materials are ethyl cellulose (EC), acrylic resin, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), cellulose acetate phthalate (CAP), polyethylene.
  • Acetaldehyde diethylamine acetate (AEA), polyvinyl acetate (PVAc), cellulose acetate (CA), methacrylic acid copolymer, polyacrylic resin, silicone elastomer, crosslinked alginate, shellac , cellulose acetate phthalate, Eudragit, Su Lisi and so on.
  • AEA Acetaldehyde diethylamine acetate
  • PVAc polyvinyl acetate
  • CA cellulose acetate
  • methacrylic acid copolymer polyacrylic resin
  • silicone elastomer silicone elastomer
  • crosslinked alginate shellac
  • shellac cellulose acetate phthalate
  • Eudragit Su Lisi and so on.
  • the composition of the raw material is an amount of 1000 unit parts, such as 1000 pieces of sustained release disintegrating tablets, or the amount of contents required for 1000 sustained release capsules.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • trimetazidine hydrochloride sustained-release pellets The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:
  • sustained-release coating liquid slow-release coating material, anti-adhesive agent, plasticizer, porogen and gastrointestinal adhesive are added to the purified water under stirring, and stirred to completely dissolve to form a solid content of 10 % of coating liquid;
  • trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • trimetazidine hydrochloride sustained-release pellets The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:
  • a sustained-release coating liquid 1) Formulating a sustained-release coating liquid: adding a sustained-release coating material, an anti-adhesive agent and a gastrointestinal adhesive to purified water in a stirring, stirring to completely dissolve it, and forming a coating liquid having a solid content of 10%;
  • trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • trimetazidine hydrochloride sustained-release pellets The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:
  • sustained-release coating liquid Preparation of sustained-release coating liquid: adding sustained-release coating material, anti-adhesive agent, plasticizer, porogen and gastrointestinal adhesive to 80% ethanol in stirring, stirring to completely dissolve, forming solid 10% of the coating liquid;
  • trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • Triacetin (plasticizer) 2.40g
  • trimetazidine hydrochloride sustained-release pellets The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:
  • a sustained-release coating liquid adding a sustained-release coating material, an anti-adhesive agent, a plasticizer, a porogen and a gastrointestinal adhesive to 80% ethanol in a stirring, and stirring to completely dissolve;
  • trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • trimetazidine hydrochloride sustained-release pellets The method for preparing the above-mentioned trimetazidine hydrochloride sustained-release pellets is as follows:
  • the mixture is wetted with purified water as a wetting agent, and then extruded and spheronized, and the soft material is dried at 50 ° C and sieved to obtain a pill core;
  • Formulating the coating liquid adding the isolation coating and the plasticizer material to the purified water under stirring, and stirring to completely dissolve;
  • the anti-adhesive agent is added to the purified water to be homogenized, and after the homogenization is completed, the suspension is added to the coating liquid, and the stirring is continued;
  • the pellets are sprayed with a fluidized bed to isolate the pellets.
  • Formulating a sustained-release coating liquid adding a sustained-release coating material, an anti-adhesive agent, a plasticizer, a porogen and a gastrointestinal adhesive to a stirred 80% acetone-water mixture, and stirring to completely dissolve;
  • trimetazidine hydrochloride sustained-release pellets were aged in an oven at 40 ° C for 24 hours to obtain sustained-release pellets.
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • Eudragit RSPO Sutained Release Coating Material
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • Eudragit RSPO Sutained Release Coating Material
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • a trimetazidine hydrochloride sustained-release pellet comprising the following components:
  • in vitro release assay Choinese Pharmacopoeia 2010 edition two appendix XD first method
  • dissolution assay Choinese Pharmacopoeia 2010 edition two appendix XC
  • the apparatus of one method measures the trimetazidine hydrochloride sustained-release pellets prepared in Examples 1 to 10 of the present invention and the commercially available trimetazidine hydrochloride sustained-release tablets (named Wan Shuangli, 35 mg/tablet) Drug release characteristics.
  • Example 1 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 1 in a medium water;
  • Example 2 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 2 in a medium of 0.1 mol of HCl;
  • Figure 3 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 3 in a medium of water;
  • Figure 4 is a comparison diagram of in vitro release of trimetazidine hydrochloride sustained-release pellets of Example 4 and Wanshuangli in 0.1 mol of HCl;
  • Figure 5 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 5 in a medium at pH 6.8;
  • Figure 6 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 6 in a medium of water;
  • Figure 7 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 7 in a medium at pH 4.5;
  • Figure 8 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 8 in a medium of 0.1 mol of HCl;
  • Figure 9 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellet of Example 9 in a medium of water;
  • Figure 10 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium at pH 6.8.
  • Figure 11 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl;
  • Figure 12 is a graph showing the in vitro release profile of the trimetazidine hydrochloride sustained-release pellets of Example 10 in a medium of 0.1 mol of HCl.
  • the sustained-release pellets of Examples 1 to 12 all have long-acting and sustained-release properties, and the release degree is substantially linear with time, and has a good sustained-release property. Meanwhile, the pellets of the respective examples were in about 24 hours.
  • trimetazidine hydrochloride sustained-release pellet of Example 4 has better sustained-release properties than the commercially available trimetazidine hydrochloride sustained-release tablet, and has a longer release time (up to 24 hours) than the commercially available sustained-release tablet. It is about 1 times longer.
  • trimetazidine hydrochloride sustained-release pellet of Example 4 of the present invention The trimetazidine hydrochloride sustained-release pellet of Example 4 of the present invention.
  • mice 12 healthy beagle dogs, half male and half female, weighing about 10 ⁇ 1 kg, were randomly divided into 2 groups;
  • trimetazidine hydrochloride sustained-release tablets (named Wanshuangli, 35 mg/tablet) were orally administered, one tablet was administered for the first time, and one tablet was administered again 12 hours later; the hydrochloric acid of Example 4 was orally administered once.
  • Detection method The concentration of trimetazidine hydrochloride in plasma was measured by high performance liquid chromatography at different times after administration, and the blood concentration-time curve was plotted.
  • Figure 13 is a graph showing the concentration of trimetazidine hydrochloride in plasma at different times after administration of the trimetazidine hydrochloride sustained-release pellets of Example 4 and the commercially available trimetazidine hydrochloride sustained-release tablets.
  • the results showed that the trimetazidine hydrochloride sustained-release pellet of Example 4 effectively delayed the peak time (Tmax) of the concentration of trimetazidine hydrochloride in vivo, and peaked after about 10 hours of oral administration.
  • Tmax peak time
  • the use of gastrointestinal mucoadhesive agents prolongs the elimination half-life of trimetazidine hydrochloride in dogs, reaching the requirement of a one-day sustained-release dosage form.
  • the AUC of the trimetazidine hydrochloride sustained-release pellet of Example 4 was 1398.25 ng ⁇ h/mL, which was similar to the control (1437 ng ⁇ h/mL) and had good bioequivalence.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une micropastille durable à libération prolongée et un procédé de préparation associé. La micropastille durable à libération prolongée de chlorhydrate de trimétazidine comprend, en partant du centre, un noyau contenant un médicament, une couche d'enrobage à libération prolongée et, éventuellement, une couche d'enrobage d'isolation entre le noyau et l'enrobage à libération prolongée. La masse de la couche d'enrobage d'isolation représente 0 à 15 % de celle du noyau, la masse de la couche d'enrobage à libération prolongée représente 5 à 30 % de celle du noyau, et la couche d'enrobage à libération prolongée contient un pansement gastro-intestinal. La micropastille à libération prolongée de chlorhydrate de trimétazidine selon la présente invention est disponible sur prescription, et utilise une matière d'enrobage à libération prolongée qui encapsule de manière uniforme un noyau renfermant un médicament, ce qui permet à l'effet de libération de médicament de la micropastille d'être durable, lent et uniforme. Ce procédé réduit la vitesse de libération des composants actifs et retarde le pic, de sorte que la libération se produit régulièrement et en continu sur 24 heures et que la stabilité de la concentration plasmatique est maintenue, ce qui évite la possibilité d'une concentration plasmatique insuffisante pendant l'ischémie matinale. Ce procédé réduit également la posologie à une seule prise par jour, ce qui favorise l'observance.
PCT/CN2014/088743 2013-10-17 2014-10-16 Micropastille durable à libération prolongée et procédé de préparation associé WO2015055130A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN112999195A (zh) * 2021-02-26 2021-06-22 山东大学第二医院 一种依托考昔缓释胶囊及其制备方法
US11414910B2 (en) 2015-06-11 2022-08-16 Lg Electronics Inc. Refrigerator and control method for refrigerator
CN115569125A (zh) * 2022-09-23 2023-01-06 湖南正清制药集团股份有限公司 盐酸青藤碱口服迟释脉冲微丸及其制剂和制备方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103565751A (zh) * 2013-10-17 2014-02-12 广州帝奇医药技术有限公司 一种长效缓释微丸及其制备方法
CN104473905A (zh) * 2014-11-20 2015-04-01 美吉斯制药（厦门）有限公司 一种盐酸曲美他嗪缓释胶囊及其制备方法
CN105616358B (zh) * 2016-02-17 2018-12-07 南京卓康医药科技有限公司 一种曲美他嗪缓释微丸组合物及其制备方法
CN106085651A (zh) * 2016-06-24 2016-11-09 南京为绿生物科技有限公司 绿色健康缓释型洁厕宝
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CN110237053A (zh) * 2019-07-26 2019-09-17 湖北欣泽霏药业有限公司 一种盐酸曲美他嗪缓释微丸及其制备方法
CN111888476A (zh) * 2020-08-17 2020-11-06 深圳市道科思医药有限公司 盐酸曲美他嗪的改良释放药物组合物

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2717687B1 (fr) * 1994-03-24 1996-06-14 Adir Compositions pharmaceutiques permettant la libération prolongée de trimétazidine après administration par voie orale.
JP2005513057A (ja) * 2001-12-15 2005-05-12 スフェリックス， インコーポレイテッド 胃保持が増加する生体接着性薬物送達システム
WO2006035417A2 (fr) * 2004-09-27 2006-04-06 Sigmoid Biotechnologies Limited Preparations de dihydropyrimidine
CN100571703C (zh) * 2006-12-20 2009-12-23 山东省医药工业研究所 曲美他嗪缓释微丸及其制备方法
WO2009006299A2 (fr) * 2007-06-29 2009-01-08 Dr. Reddy's Laboratories Ltd. Systèmes à multiples particules
HUE027498T2 (en) * 2009-01-30 2016-10-28 Lupin Ltd Pharmaceutical preparations containing trimetazidine
CN102552217A (zh) * 2010-12-20 2012-07-11 天津市凯文生物科技有限公司 曲美他嗪缓释胶囊及其制备方法
CN102133195A (zh) * 2011-03-17 2011-07-27 王国栋 盐酸曲美他嗪的缓控释微丸及其制备方法
CN103565751A (zh) * 2013-10-17 2014-02-12 广州帝奇医药技术有限公司 一种长效缓释微丸及其制备方法

Cited By (9)

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US11414910B2 (en) 2015-06-11 2022-08-16 Lg Electronics Inc. Refrigerator and control method for refrigerator
US11761255B2 (en) 2015-06-11 2023-09-19 Lg Electronics Inc. Refrigerator and control method for refrigerator
US11821249B2 (en) 2015-06-11 2023-11-21 Lg Electronics Inc. Refrigerator and control method for refrigerator
US11851934B2 (en) 2015-06-11 2023-12-26 Lg Electronics Inc. Refrigerator and control method for refrigerator
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CN112545997A (zh) * 2020-12-25 2021-03-26 正大制药（青岛）有限公司 一种氟骨化醇制剂及其制备方法
CN112999195A (zh) * 2021-02-26 2021-06-22 山东大学第二医院 一种依托考昔缓释胶囊及其制备方法
CN115569125A (zh) * 2022-09-23 2023-01-06 湖南正清制药集团股份有限公司 盐酸青藤碱口服迟释脉冲微丸及其制剂和制备方法
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