WO2020135491A1 - Microcomprimé de propafénone, forme posologique à unités multiples comprenant un microcomprimé de propafénone, leurs procédés de préparation et leurs utilisations - Google Patents

Microcomprimé de propafénone, forme posologique à unités multiples comprenant un microcomprimé de propafénone, leurs procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2020135491A1
WO2020135491A1 PCT/CN2019/128249 CN2019128249W WO2020135491A1 WO 2020135491 A1 WO2020135491 A1 WO 2020135491A1 CN 2019128249 W CN2019128249 W CN 2019128249W WO 2020135491 A1 WO2020135491 A1 WO 2020135491A1
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WIPO (PCT)
Prior art keywords
propafenone
microchip
microplate
microtablets
microchips
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Ceased
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PCT/CN2019/128249
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English (en)
Chinese (zh)
Inventor
钱晓明
盛小茜
方云
万建胜
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SINOTHERAPEUTICS Inc
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SINOTHERAPEUTICS Inc
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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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention relates to a propafenone microchip, a multi-unit dosage form containing the microchip, and a preparation method and use thereof.
  • Propafenone is a broad-spectrum and high-efficiency membrane inhibitory antiarrhythmic drug. It has a membrane stabilizing effect and a competitive ⁇ receptor blockade. It can reduce myocardial excitability, extend the duration of action potential and effective refractory period, and prolong conduction. Clinically, it can be used to prevent and treat ventricular and supraventricular ectopic beats, ventricular or supraventricular tachycardia, irritability syndrome, and ventricular fibrillation after electrical cardioversion. Its chemical name is 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone, and its structural formula is shown in formula (I).
  • Propafenone formulations currently in clinical use have a variety of release forms, mainly immediate-release tablets, immediate-release capsules, and sustained-release capsules. Because propafenone is a highly variable drug, the variability within an individual is greater than 30%, and its blood concentration in the body fluctuates greatly. Therefore, it is difficult for immediate release tablets and capsules to maintain a stable therapeutic effect, and it will bring Certain side effects. Propafenone sustained-release capsules can achieve a relatively stable blood concentration in the body, but conventional sustained-release capsules still fail to solve the problem of large drug release due to the influence of food delivery rhythm when taken before or after meals. The problem of difference.
  • Multi-unit dosage form refers to a drug delivery system composed of multiple dosage units, and is a concept opposite to "single-unit dosage form” (SUDF).
  • examples of multi-unit dosage forms such as microcapsule capsules, micropellet tablet compression, microtablet (or mini-tablet) capsules, or multiple drug units (e.g., multiple microtablets) )
  • a special package such as a sachet.
  • the solid multi-unit dosage form for oral administration can be taken in the form of whole capsules or tablets, or can be taken in the form of multiple drug units (for example, multiple micro-tablets) dispersed in liquid or soft food.
  • US 5,681,588 discloses a phenylpropionyl benzalkonium chloride HCl (Propafenone hydrochloride) sustained-release granule tablet, and gelatin capsules containing phenylpropionyl benzalkonium chloride sustained-release granule tablets and phenylpropionyl benzalkonium chloride quick-release granule tablets And the preparation method, compared with the sustained-release pill with similar in vitro release, the fluctuation of the blood drug concentration after administration of the sustained-release microparticle tablet of the invention is small, which improves the treatment safety.
  • HCl Propafenone hydrochloride
  • the dosage form disclosed in US 5,681,588 has insurmountable problems.
  • the maximum specification of the capsule (trade name Rythmol SR) contained in this application is 425 mg, the dose is relatively large. If a large amount of medicinal supplements are added during the preparation process, the cost will increase and the volume of the medicine will increase, resulting in patients taking Inconvenience, therefore, the capsule of this application uses a smaller amount of auxiliary materials, and the active ingredient content in the microtablets is higher, which is 80% to 90% or more.
  • the higher content of active ingredients in the microtablets makes the control of the granulation process of the active ingredients and the compression process of the microtablets higher in the preparation process, which increases the difficulty of the preparation.
  • the microchip of the capsule disclosed in US 5,681,588 has a uniform shape, so the release characteristics of its multi-unit drug delivery system cannot be adjusted.
  • the dosage form disclosed in US 5,681,588 still does not solve the problem of food affecting drug release.
  • the maximum blood concentration of Rythmol SR taken after meals can reach 4 times that taken before meals (see its instructions). Such fluctuations in blood drug concentration are very unfavorable for the treatment of arrhythmia.
  • the present invention provides a new sustained-release multi-unit dosage form of propafenone that is easy to prepare, has good dissolution-release characteristics, and can adjust the release characteristics, as well as the pharmaceutical monomer and preparation of the multi-unit dosage form method.
  • the present invention relates to a propafenone microtablet comprising the active ingredient propafenone or a pharmaceutically acceptable salt thereof, a binder and a lubricant.
  • the weight ratio of the active ingredient propafenone or a pharmaceutically acceptable salt thereof to the lubricant is about 1:0.05 to about 1:0.5, preferably about 1:0.1 to about 1: 0.3.
  • the lubricant is selected from stearic acid, stearate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid ester, micronized silica gel, One or more of talc, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid and hydrogenated vegetable oil.
  • the lubricant is selected from stearic acid, magnesium stearate, zinc stearate, calcium stearate, sodium stearate fumarate, glyceryl behenate and glyceryl monostearate One or more of them.
  • the lubricant is one or more selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, and magnesium stearate. In a particular embodiment, the lubricant is magnesium stearate and/or glyceryl behenate.
  • the weight ratio of the active ingredient propafenone or a pharmaceutically acceptable salt thereof to the binder is about 1:0.01 to about 1:0.05, preferably about 1:0.02 to about 1. :0.04.
  • the density of propafenone microplatelets is not less than about 1.1 g/cm 3 . In a preferred embodiment, the density of propafenone microtablets is not less than about 1.2 g/cm 3 . In another preferred embodiment, the density of propafenone microplatelets is not greater than about 1.3 g/cm 3 .
  • the active ingredient in the propafenone microtablets of the present invention releases no more than about 15% within 2 hours. In yet another preferred embodiment, the The release of the active ingredient within 2 hours is not higher than about 10%.
  • the active ingredient of the propafenone microtablets of the present invention is propafenone hydrochloride.
  • the present invention relates to a method for preparing propafenone microtablets, including the following steps:
  • the present invention relates to a multi-unit dosage form of propafenone, which comprises a plurality of propafenone microplates each independently having the same or different shapes.
  • the multi-unit dosage form of the present invention is a microtablet capsule.
  • FIG. 1 is an example of the shape of the edge of the top surface of propafenone microplate, showing examples of circular, elliptical, peanut-shaped and petal-shaped.
  • measuring ratio refers to the ratio of various substances according to a certain weight.
  • the active ingredients are mixed with fillers, binders, and lubricants at a specified weight ratio.
  • pharmaceutically acceptable refers to contact with the patient's tissues within normal medical judgment without improper toxicity, irritation, allergic reactions, etc. It has a reasonable pros and cons ratio and can be effectively used for its intended purpose.
  • propafenone also includes propafenone salts, polymorphs, solvates (including, for example, hydrates and mixed solvates and salt hydrates), co-crystals, amorphous and anhydrous forms, and mixtures thereof .
  • the above-mentioned form is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts, especially acid addition salts.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts, especially hydrochloride.
  • suitable salts see, for example, "Remington's Pharmaceuticals", Mack Publishing Company, Easton, Pa., (2005). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • polymorph refers to a single polymorph or a mixture of more than one polymorph in any ratio.
  • crystalline form or “crystal” refers to any solid substance that exhibits a three-dimensional order, as opposed to an amorphous solid substance, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.
  • co-crystal refers to a crystal formed by combining an active pharmaceutical ingredient and a co-crystal former under the action of hydrogen bonds or other non-covalent bonds.
  • amorphous refers to any solid substance that is unordered in three dimensions.
  • hydrate describes a solvate containing a drug and stoichiometric or non-stoichiometric amounts of water.
  • pharmaceutically acceptable excipients refers to those carrier substances that have no significant stimulating effect on the organism and that do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable excipients” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, disintegrating agents, Stabilizer, solvent or emulsifier.
  • Non-limiting examples of the carrier include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol, and the like.
  • tablette refers to a solid pharmaceutical dosage form that contains the active ingredient, and optionally suitable excipients such as diluents, binders, etc., and is prepared by compression or molding techniques.
  • suitable excipients such as diluents, binders, etc.
  • examples of tablets are, for example, compressed tablets, multiparticulate tablets, multi-layer tablets, coated tablets, matrix tablets, osmotic pump tablets and caplets, and the like.
  • microtablet refers to microtablets.
  • the microchips currently used in clinical treatment and research are several millimeters in diameter, usually 1-3 mm.
  • capsule refers to a dosage form containing a plurality of solid particles encapsulated in a shell, which is usually made of gelatin, but can also be made of other materials.
  • the shell of the capsule disintegrates after digestion, thereby releasing particulate content.
  • Capsules include hard shell capsules and soft shells such as soft gel capsules.
  • the capsule used in the present invention refers to a hard shell, or a one-piece, sealed soft shell, which is usually made of gelatin, but can also be made of other film-forming materials.
  • microtablet capsules refers to capsules filled with microtablets. Capsules filled with multiple microchips belong to a multi-unit dosage form. The contents released by the capsule after the shell is degraded are multiple drug units in the form of multiple microchips.
  • time to peak plasma drug concentration ( Tmax ) refers to the average time to reach the peak plasma drug concentration ( Cmax ) after administration of the drug.
  • peak plasma drug concentration ( Cmax ) refers to the average peak concentration of the drug reached in the plasma after administration of the drug.
  • AUC 0-t refers to the average integrated area under the plasma drug concentration versus time curve from time 0 to t after administration of the drug.
  • active ingredient refers to a chemical entity that can effectively treat or prevent a target disorder, disease or disorder.
  • the terms "effective amount”, “therapeutically effective amount” or “preventively effective amount” refer to a sufficient amount of drugs or agents that have acceptable side effects but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine tests.
  • the present invention relates to a microtablet, which contains the active ingredient propafenone or a pharmaceutically acceptable salt thereof, a binder and a lubricant.
  • the active ingredient of the propafenone microtablets of the present invention is propafenone hydrochloride.
  • the microtablets of the present invention optionally further comprise one or more of the following: glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, disintegrants , Stabilizer, pH adjuster or emulsifier.
  • the weight ratio of the active ingredient propafenone or a pharmaceutically acceptable salt thereof to the lubricant is about 1:0.05 to about 1:0.5, preferably about 1:0.1 to about 1: 0.3, for example about 1:0.1, about 1:0.2 or about 1:0.3.
  • the lubricant is selected from stearic acid, stearate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, sodium benzoate, sucrose fatty acid ester, micronized silica gel, Talc, glyceryl monostearate, and glyceryl behenate (e.g., commercially available products from France's Carfaxai) ATO888), glyceryl palmitoyl stearate (such as the product under the trade name Precirol TM ), one or more of stearic acid and hydrogenated vegetable oil.
  • the lubricant is selected from the group consisting of stearic acid, magnesium stearate (e.g., the commercially available product LIGAMED MF-2-V of the Dutch company Petrograd), zinc stearate, calcium stearate, One or more of sodium stearyl fumarate, glyceryl behenate and glyceryl monostearate.
  • the lubricant is one or more selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, and magnesium stearate.
  • the lubricant is magnesium stearate and/or glyceryl behenate.
  • the weight ratio of the active ingredient propafenone or a pharmaceutically acceptable salt thereof to the binder is about 1:0.01 to about 1:0.05, preferably about 1:0.02 to about 1. :0.04, for example about 1:0.02, about 1:0.03 or about 1:0.04.
  • the binder may be selected from polyethylene glycol, starch, pregelatinized starch, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl One or more of Hydroxypropyl methylcellulose (HPMC), methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, gum arabic and gelatin.
  • the binder is one or more of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone.
  • the binder is one or more of hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
  • the binder hydroxypropyl methylcellulose is selected from hydroxypropyl methyl having an average methoxy content of 28.0-30.0% by weight and an average hydroxypropyloxy content of 7.0-12.0% by weight Based cellulose, wherein the weight percentage is based on the weight of hydroxypropyl methyl cellulose.
  • the binder hydroxypropyl methylcellulose can be selected from, for example, commercially available products of Shin-Etsu Corporation 60 SH-50 and Dow's commercially available products E3 Premium LV, E5 Premium LV, E6 Premium LV, E15 Premium LV, One or more of E50 Premium LV, but not limited to this.
  • the binder hydroxypropyl methyl cellulose is selected from E5 Premium LV, One or more of E6 Premium LV.
  • the binder hydroxypropyl cellulose is selected from hydroxypropyl cellulose having an average hydroxypropyloxy content of not more than 80.5% by weight, wherein the weight percentage is based on hydroxypropyl cellulose the weight of.
  • the binder hydroxypropyl cellulose may be selected from one of the commercially available products of Ashland Corporation, Klucel TM EF, Klucel TM LF, Klucel TM GF, Klucel TM JF, or Many, but not limited to this.
  • An exemplary method for measuring the density of propafenone microchips of the present invention is the liquid immersion method: using a 100mL graduated cylinder to accurately measure 60mL of liquid paraffin, weigh about 10g of propafenone microchips, and slowly add to the above liquid paraffin, add all After waiting for 2 minutes to read the total volume, calculate the density of the microplate according to the calculated actual volume of the propafenone microplate.
  • the density of propafenone microplate is not less than about 1.0 g/cm 3 .
  • the density of propafenone microplatelets is not less than about 1.1 g/cm 3 .
  • the density of propafenone microtablets is not less than about 1.2 g/cm 3 . In another particular embodiment, the density of propafenone microplatelets is not greater than about 1.3 g/cm 3 .
  • An exemplary method for measuring the friability of propafenone microtablets of the present invention is the "Chinese Pharmacopoeia" 2015 edition 0923 tablet friability check method.
  • the propafenone microtablets have a friability not greater than about 0.8%.
  • the propafenone microtablets have a friability not greater than about 0.5%.
  • the propafenone microtablets have a friability of about 0.1 to about 0.5%.
  • the propafenone microtablets have a friability of about 0.2 to about 0.4%.
  • An exemplary method for measuring the hardness of the propafenone microplates of the present invention is to use the Sotax Multitest50 high sensitivity hardness tester.
  • the hardness of propafenone microplatelets is from about 3 to about 15N.
  • the propafenone microplate has a hardness of about 5 to about 12N.
  • the propafenone microplate has a hardness of about 5 to about 8N.
  • the weight of propafenone microtablets is about 6 to about 10 mg, and each microtablet contains about 4.5 to about 7 mg of the active ingredient propafenone or a pharmaceutically acceptable salt thereof.
  • the propafenone microplate is a microplate having the following shape: the top and bottom surfaces of the microplate are independently flat or convex, and the side of the microplate is a curved surface with a curvature, or is composed of multiple side areas Composition, where each side area is independently flat or curved.
  • the side of the propafenone microplate consists of a curved surface with curvature.
  • the side of the propafenone microplate consists of multiple side regions.
  • the line connecting the center points of the top and bottom surfaces of the propafenone microchip is the axis of the microchip.
  • the boundary between the lateral regions is substantially parallel to the axis of the rapamone microplate.
  • the side of the propafenone microplate consists of 2-6 side regions. In another preferred embodiment, the side of the propafenone microplate consists of 2-3 side regions. In a preferred embodiment, the propafenone microplate has a lateral spread width of about 1.5 to about 9.5 mm. In a more preferred embodiment, the propafenone microplate has a lateral spread width of about 2.5 to about 8.5 mm. In a preferred embodiment, the propafenone microtablets are about 1.5 mm to about 3.0 mm high. In a more preferred embodiment, the propafenone microplate is about 2 mm high. In one embodiment, the top and bottom surfaces of the propafenone microplate have the same edge shape.
  • the shape of the edges of the top surface and bottom surface of the propafenone microplate depends on the shape formed by the top surface and the bottom surface intersecting the side surface of the microplate.
  • the top and bottom edges of the propafenone microplate are round in shape.
  • the propafenone microplate is cylindrical.
  • the shape of the edges of the top surface and bottom surface of the propafenone microplate is composed of multiple straight lines and/or curves.
  • the edge shape of the top and bottom surfaces of the propafenone microplate is selected from the group consisting of circular, elliptical, peanut-shaped, and petal-shaped.
  • the top and bottom edges of the microchip are round in shape, and the diameter of the round is from about 1.5 to about 2.5 mm.
  • the side of the microchip consists of a side area.
  • the shape of the top and bottom edges of the microplate is elliptical, the long diameter of the oval is about 1.5 to about 2.5 mm, and the side of the microplate consists of a side area.
  • the top and bottom edges of the microchip have a peanut shape, and the top and bottom edges of the peanut have a long diameter of about 1.5 to about 2.5 mm.
  • the side of the microchip has two sides Area composition.
  • the boundary between multiple side regions of the peanut-shaped microchip is a line composed of points closest to the axis of the microchip in the portion where the peanut-shaped shape is recessed toward the axis of the microchip, the boundary line and the microchip
  • the axis is parallel.
  • the top and bottom edges of the microchip are petal-shaped, and the points farthest from the axis of the microchip in the petal shape are distributed on the virtual cylindrical side, the virtual cylindrical side
  • the diameter is about 1.5mm to about 2.5mm, and the virtual cylindrical axis coincides with the microchip axis.
  • the shape of the top and bottom edges of the microplate is selected from 3-petal, 4-petal or 5-petal petal shapes, wherein the sides of the 3-petal microchip are composed of three side regions, 4 petals
  • the side of the microchip is composed of four side regions
  • the side of the 5-petal microchip is composed of five side regions.
  • the dividing line between the side regions of the petal-shaped microchip is a line composed of the points closest to the microchip axis in the part where the petal shape is recessed toward the microchip axis, the boundary line and the microchip axis parallel.
  • the invention also relates to a method for preparing pharmaceutical microchips, which is used to prepare propafenone microchips of the invention.
  • the method of preparing the drug microchip is a compression method.
  • the method of preparing the drug microchip is a lamination method.
  • the method of preparing the drug microchip is a 3D printing method.
  • a method of preparing a microchip of medicine includes the following steps:
  • the solution in the above step (i) is one or more selected from pure water, aqueous ethanol solution, absolute ethanol, and isopropanol.
  • the wet granulation method in step (ii) above is selected from fluidized bed granulation, high-speed agitation shear granulation and rocking granulation.
  • the drying method in step (iii) above is selected from rotary evaporation, vacuum drying, freeze drying, and spray drying.
  • the pulverization method in the above step (iii) is selected from blade pulverization, hammer pulverization, and roller pulverization.
  • the mixing method in step (iv) above is selected from V-shaped mixing, conical mixing, and hopper mixing.
  • the compression method in step (iv) above is selected from hydraulic compression, mechanical compression, and pneumatic compression.
  • the pressing device in the above step (iv) is a single punch tablet machine, for example, Shanghai Tianfan Pharmaceutical Machine DP-5 type can be used.
  • the drug release of propafenone microtablets of the present invention within 2 hours is not higher than about 15%, for example, about 4.7%, about 8.6%, about 13.6%, about 3.9%, about 6.5% , About 10.9%, about 7.5%, about 14.9%, about 7.2%, about 7.9% or about 3.3%, or for example about 7.5%, about 9.8%, about 8.6%, about 9.6%, about 10.2% or about 12.6 %.
  • the drug release of propafenone microtablets of the invention within 2 hours is not higher than about 10%, for example, about 4.7%, about 8.6%, about 3.9%, about 6.5%, About 7.5%, about 7.2%, about 7.9% or about 3.3%, or for example about 7.5%, about 9.8%, about 8.6% or about 9.6%.
  • the drug release of the propafenone microtablets of the invention within 2 hours is not higher than about 5%, for example, about 4.7%, about 3.9%, or about 3.3%.
  • the drug release of propafenone microtablets of the present invention within 2 hours ranges from about 5% to about 10%, for example, about 4.7%, about 8.6%, about 6.5%, about 7.5 %, about 7.2% or about 7.9%, or for example about 7.5%, about 9.8%, about 8.6% or about 9.6%.
  • the release time can be measured in vitro, for example, can be measured by the dissolution method of USP II, or at different pH values (such as 1-5, 1.2-4.5, 6-7, including but not limited to 1.2, 4.5, 6.8, etc. ).
  • the surface of the microplate of the present invention is optionally substantially covered by a film coating.
  • the film-forming material of the film coating may, for example, contain a water-insoluble polymer, or a mixture of a water-insoluble polymer and a water-soluble polymer.
  • the water-insoluble polymer may be selected from ethyl cellulose, cellulose acetate, and the like, for example.
  • the water-soluble polymer can be selected, for example, from hydroxypropyl cellulose, and the like.
  • “Substantial coverage” means that any coating used covers about 40% to about 100% of the surface of the microtablet.
  • Multi-unit dosage form containing propafenone microtablets and preparation thereof
  • the invention also relates to a multi-unit dosage form, which contains a plurality of propafenone microtablets.
  • multiple propafenone microplatelets in a multi-unit dosage form have the same shape.
  • the multiple propafenone microplatelets in the multi-unit dosage form each independently have the same or different shapes.
  • the multi-unit dosage form contains multiple propafenone microtablets prepared by different methods.
  • the multi-unit dosage form contains a plurality of propafenone microplatelets with different shapes, and the number of propafenone microplatelets of each shape is the total number of all propafenone microplatelets in the multi-unit dosage form The proportions in are independently the same or different from each other.
  • the multi-unit dosage form of the present invention is a capsule filled with multiple propafenone microtablets.
  • the multi-unit dosage form of the present invention is a capsule prepared using two-piece gelatin hollow hard capsules.
  • the capsule of the present invention can be prepared by using the propafenone microtablets of the present invention by any method known in the art, and the preparation method includes but is not limited to a fully automatic mold filling method and a semi-automatic filling method. Therefore, the present invention also relates to a method for preparing a capsule, which comprises filling the capsule with the micro-tablet of propafenone of the present invention.
  • a full-automatic mold filling method is used to fill a fixed number of propafenone microtablets into the capsule.
  • the equipment used may be, for example, a fully automatic capsule filling machine (eg Indian ACG AF90T, etc.).
  • a semi-automatic filling method is used to fill a fixed number of propafenone microtablets into the capsule.
  • the equipment used can be, for example, a semi-automatic capsule filling machine (eg Italian Multi Pharma MC-50, etc.).
  • the theoretical indicated amount of propafenone hydrochloride filled is 425 mg, and 61-85 microchips are filled per capsule. In another embodiment, the theoretical labeled amount of propafenone hydrochloride filled is 325 mg, and each capsule is filled with 47-65 microchips. In yet another embodiment, the theoretical indicated amount of propafenone hydrochloride filled is 225 mg, and each capsule is filled with 33-45 microchips.
  • the release of propafenone in the capsule of the present invention within 2 hours is not higher than about 15%, for example, about 10.2%, about 9.8%, or about 8.9%. In another embodiment, the release of the drug in the capsule of the invention within 2 hours is not higher than about 10%, such as about 9.8% or about 8.9%. In another embodiment, the release of the drug in the capsule of the present invention within 2 hours is in the range of about 5% to about 10%, for example, about 9.8% or about 8.9%. In yet another embodiment, the release of the drug in the capsule of the invention within 2 hours is not higher than about 5%.
  • the weight percentage is based on the theoretically labeled amount of the capsule. The above release characteristics can be measured in vitro, for example, can be measured by USP II dissolution method, or at different pH values (such as 1-5, 1.2-4.5, 6-7, including but not limited to 1.2, 4.5, 6.8, Etc.).
  • the present invention also relates to a method of preventing and treating disease, which method comprises administering to a subject in need thereof an effective amount of propafenone microtablets of the present invention or a multi-unit dosage form containing propafenone microtablets.
  • the propafenone microtablets of the present invention or the multi-unit dosage form containing propafenone microtablets can be used for the prevention and treatment of diseases.
  • the invention also relates to the use of the propafenone microtablets or the multi-unit dosage form containing propafenone microtablets in the preparation of a medicament for preventing and treating diseases.
  • the disease includes prevention and treatment of ventricular and supraventricular ectopic beats, ventricular or supraventricular tachycardia, pre-excitation syndrome, ventricular fibrillation after electrical cardioversion, and the like.
  • propafenone microtablets and multi-unit dosage forms containing propafenone microplates of the present invention is simple and controllable, and is suitable for commercial production.
  • Propafenone microchips can have a variety of preset shapes, and the proportion of the total amount of propafenone microchips in a multi-unit dosage form can be adjusted by adjusting the number of propafenone microchips of each shape To adjust the release characteristics of multi-unit dosage forms.
  • the multi-unit dosage form comprising propafenone microtablets of the present invention has unique release characteristics.
  • the release rate of the capsule of the present invention in the first 2 hours after oral administration is extremely slow, the release rate after 2 hours increases, and finally the release of propafenone is completed.
  • This release mode makes the release of oral propafenone less affected by the gastrointestinal environment.
  • this release mode may be particularly beneficial for reducing the effect of gastric emptying on the release of propafenone.
  • the clinical test results show that the capsule of the present invention has excellent release characteristics, reduces the release difference of propafenone when taken before or after meals, and obtains a more stable fluctuation of blood drug concentration, so it can reduce side effects and achieve Better treatment effect.
  • Hardness testing equipment Sotax Multitest50 high sensitivity hardness tester
  • Dissolution sample analysis The solution obtained in the dissolution test was filtered with a 0.45 ⁇ m filter membrane, and the filtrate was collected, measured by UV spectrophotometry, the measurement wavelength was 305 nm, and the detection instrument was Shimadzu UV-2550.
  • Microchip Dissolve the binder in purified water according to the specific composition in Table 1 to prepare a binder solution; add the active ingredient to the wet granulator (German DIOSNA P1-6), stir it evenly, and then stick the above The mixture solution is added to the wet granulator for wet granulation; after granulation, the wet granules are dried in a vacuum drying oven (Shanghai Yiheng DZF-6050); the mixture obtained after drying is crushed using a blade grinder (QUADRO L1A) 1.
  • microchip Pass the sieve with a mesh size of 30 mesh; add the above dry particles to the lubricant and mix using a V-type mixer (Nantong Beite HBD-200); after mixing, use a tablet press (Nanjing Feite P2020) to prepare micro sheet.
  • the microchip weighs 6-10 mg and contains 5-7 mg propafenone hydrochloride.
  • the top surface of the microchip is round, the diameter of the circle is about 1.5-2.5 mm, the side of the microchip is a curved surface with a curvature, and the height of the microchip is about 2 mm. According to the above method, the microchip 1-1 to the microchip 1-11 of the present invention are prepared.
  • Physical mixture Mix the active ingredients propafenone hydrochloride, binder, and lubricant according to the specific composition and dosage of Table 1 using a V-type mixer (Nantong Beite HBD-200) to obtain a physical mixture.
  • V-type mixer Nelosine HBD-200
  • the physical mixture obtained by mixing through the above steps is the physical mixture 1-1.
  • the physical mixture obtained through the above steps is physical mixture 1-11.
  • Other physical mixtures were also prepared according to the corresponding composition and dosage in Table 1 according to the above method.
  • the density of propafenone microplatelets of different compositions prepared above is about 1.1 g/cm 3 to about 1.3 g/cm 3 , which is higher than the density of microplatelets of Rythmol SR capsules.
  • the propafenone microtablets of different compositions have a friability range of 0.1% to 0.5% and a hardness range of 5 to 12N, and show good physical properties.
  • microchips 1-8 and microchips 1-10 with a weight ratio of active ingredient to lubricant of about 1:0.1 have a friability of 0.1% and 0.2%, respectively, and the weight ratio of active ingredient to lubricant is about 1 : 0.2 microchips 1-1 to 1-7 have a friability of 0.1% to 0.4%, and the weight ratio of active ingredient to lubricant is about 1:0.3 microchips 1-9 and microchips 1-11 The friability is 0.1% and 0.5% respectively.
  • the microchip of the invention has the characteristics of high density, good physical properties and simple preparation.
  • the dissolution of the active ingredient propafenone hydrochloride in the microtablets of the present invention is significantly reduced.
  • the release in 0.1N hydrochloric acid at pH 1.2 within 2 hours is less than 15%, wherein the weight percentage is based on the total content of propafenone hydrochloride in microchips.
  • the dissolution rate of the active ingredient propafenone hydrochloride decreased significantly.
  • the weight ratio of propafenone hydrochloride to glyceryl behenate changes from 1:0.1 (microchip 1-8) to 1:0.2 (microchip 1-2)
  • the dissolution of propafenone hydrochloride within 6 hours The degree dropped from 78.5% to 63.8%.
  • the weight ratio of propafenone hydrochloride to glyceryl behenate became 1:0.3 (microchips 1-9), the dissolution of propafenone hydrochloride within 6 hours further decreased to 60.2%.
  • the dissolution of the active ingredient propafenone hydrochloride increased significantly.
  • the weight ratio of propafenone hydrochloride to hydroxypropyl methylcellulose is changed from 1:0.02 (microchip 1-1) to 1:0.03 (microchip 1-2)
  • propafenone hydrochloride is within 6 hours
  • the dissolution rate increased from 58.3% to 63.8%.
  • the weight ratio of propafenone hydrochloride to hydroxypropyl methylcellulose became 1:0.04 (microchips 1-3)
  • the dissolution of propafenone hydrochloride within 6 hours further increased to 89.6%.
  • the binder is dissolved in purified water to prepare a binder solution; the active ingredient is added to a fluidized bed (Glatt GPCG2), and the side spray method is used
  • the above binder solution is sprayed into the fluidized bed, the material temperature is 40-60°C, and the inlet air volume is maintained at 50-100cm 3 /hour. While spraying, stirring and mixing are performed to obtain wet particles, which are then dried to dryness.
  • the weight loss is less than 3.0%, and the dried particles are prepared; the dried particles are crushed using a blade grinder (QUADRO L1A) with a mesh opening of 30 mesh to prepare dry particles; the dry particles and the lubricant are used in a V-type mixer (Nantong HBITE HBD-200) for mixing; after the mixing is completed, a tablet press (Nanjing Feite P2020) is used to prepare microchips. Microchips were prepared using round, oval, peanut-shaped, and petal-shaped molds, respectively. The weight of microchips of different shapes is basically the same, 6-10mg, each microchip contains 5-7mg propafenone hydrochloride.
  • the shape of the edge of the top surface and the bottom surface is a round microchip
  • the diameter of the circle is about 1.5 to about 2.5 mm
  • the side of the microchip is composed of a side area
  • the height of the microchip is about 2 mm.
  • the top and bottom edges of the microplate are elliptical in shape.
  • the long diameter of the oval is about 1.5 to about 2.5 mm.
  • the side of the microplate is composed of a side area, and the height of the microplate is about 2 mm.
  • the edge shape of the top surface and the bottom surface is a peanut-shaped microchip.
  • the long diameter of the shape of the peanut top surface and the bottom surface is about 1.5-2.5 mm.
  • the side surface of the microchip is composed of two side regions, and the height of the microchip is about 2 mm.
  • the dividing line between the multiple side regions of the peanut-shaped microchip is a line composed of the points closest to the microchip axis in the portion where the peanut-shaped shape is recessed toward the microchip axis, and the boundary line is parallel to the microchip axis .
  • the top and bottom edges have petal-shaped microchips with a microchip height of about 2mm.
  • the points farthest from the microchip axis in the petal shape are distributed on the virtual cylindrical side, and the diameter of the virtual cylindrical side is From about 1.5 mm to about 2.5 mm, the virtual cylindrical axis coincides with the microchip axis.
  • the side of the 3-petal microplate is composed of three side areas
  • the side of the 4-petal microplate is composed of four side areas
  • the side of the 5-petal microplate is composed of five side areas.
  • the dividing line between the side regions of the petal-shaped microchip is a line composed of points closest to the microchip axis in the portion where the petal shape is recessed toward the microchip axis, and the dividing line is parallel to the microchip axis.
  • the shapes of circles, ellipses, peanuts, and petals used in this embodiment are shown in FIG. 1.
  • microchips of different shapes have a friability range of 0.2% to 0.4%, a hardness range of 5 to 8N, and good physical properties.
  • the release rate of propafenone microtablets of different shapes in this invention within 2 hours is slow, which is much lower than the microplates in Rythmol SR capsules, for example, the dissolution rate of the round microplates is 27.7 in the microplates of Rythmol SR within 2 hours. %, the release rate of the propafenone microtablets of the present invention increases after 2 hours, for example, the dissolution rate of the round microplates within 3 hours is 47% of the microplates of Rythmol SR.
  • the different shapes of propafenone microtablets of the present invention can achieve complete release, for example, the dissolution of propafenone microplates of different shapes within 18 hours is 96.3% to 99.6%, which is equivalent to the dissolution rate of Rythmol SR microplates within 18 hours. It can be seen that the present invention not only prepares propafenone microchips with unique release characteristics, but also realizes the preparation of drug microchips of different shapes under high drug loading, and achieves different release effects by controlling the shape of the microchips .
  • microchips of different shapes prepared in Example 2 above, two of them are selected, combined according to a preset ratio, and filled into capsules using a semi-automatic capsule filling machine (Italian Multi Pharma MC-50).
  • the theoretically marked amount of propafenone hydrochloride filled is 425 mg.
  • Each capsule is filled with 61-85 microchips.
  • the configuration of microchips with different shapes is shown in Table 8 below. Capsules (referred to as capsule 3-1, capsule 3-2, capsule 3-3) were prepared according to the ratio.
  • US 5,681,588 discloses the release of capsules when using different compressive forces to prepare sustained-release granule tablets in the production process of Rythmol SR capsules (see Figure 9 of this application), where the release of each batch of capsules within 2 hours is More than 20%, much higher than the capsule of the present invention.
  • the capsules prepared by using the propafenone microtablets of the present invention have unique release characteristics.
  • the results of this example show that the dissolution of the capsule product can be adjusted by controlling the quantity ratio of the microchips of each shape to achieve the required release rate of the capsule, thereby achieving the release characteristics of the multi-unit dosage form Adjustment.
  • Example 4 Dissolution of capsules in different dissolution media
  • the dissolution release of the capsule in different dissolution media was measured.
  • the dissolution medium was selected to be a) phosphate buffer solution of pH 6.8 and pH 6.8 in 0.1N hydrochloric acid at pH 1.2 for 2 hours, and b) acetate buffer solution of pH 4.5 for 2 hours and then transferred to phosphate buffer solution of pH 6.8. See Table 10 for the results.
  • the capsule 3-1 showed a substantially uniform dissolution rate. It shows that the capsules prepared with different shapes of microtablets of the present invention can maintain a similar release rate under different pH conditions and have good dissolution-release characteristics.
  • Test preparation Propafenone hydrochloride capsules prepared according to the prescription and process of capsule 3-1 in Example 3, the specification is 425 mg, and the administration method is oral, once a day.
  • the 10 healthy male subjects selected were randomly divided into 2 groups, each group of 5 people.
  • the grouping scheme is shown in Table 11 below:
  • the maximum blood concentration C max of propafenone capsules administered to the present invention before and after meals is basically the same.
  • the area under the blood concentration curve AUC 0-36h of the blood drug concentration curve of propafenone capsules given to the present invention after meals was slightly higher than before meals.
  • the overall results show that the difference between the propafenone capsules taken before or after a meal is small, and the two are equivalent, indicating that the propafenone capsule of the present invention is less affected by the rhythm of gastrointestinal tract food delivery, and can be obtained more Smooth fluctuations in blood drug concentration.

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Abstract

La présente invention concerne un microcomprimé de propafénone, une capsule comprenant le microcomprimé de propafénone, et leurs procédés de préparation et leurs utilisations.
PCT/CN2019/128249 2018-12-26 2019-12-25 Microcomprimé de propafénone, forme posologique à unités multiples comprenant un microcomprimé de propafénone, leurs procédés de préparation et leurs utilisations Ceased WO2020135491A1 (fr)

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CN109394722B (zh) * 2018-12-26 2020-06-12 上海宣泰医药科技有限公司 普罗帕酮微片、包含该微片的多单元剂型及其制备方法和用途
CN112587506A (zh) * 2020-12-09 2021-04-02 南京森博医药研发有限公司 一种用于制备美沙拉嗪肠溶缓释胶囊的方法

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Publication number Priority date Publication date Assignee Title
WO2010043950A2 (fr) * 2008-10-15 2010-04-22 Aizant Drug Research Solutions Private Limited Composition de propafénone à libération prolongée
CN107441051A (zh) * 2016-05-30 2017-12-08 北京科信必成医药科技发展有限公司 一种盐酸普罗帕酮微片及其制备方法
CN109394722A (zh) * 2018-12-26 2019-03-01 上海宣泰医药科技有限公司 普罗帕酮微片、包含该微片的多单元剂型及其制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043950A2 (fr) * 2008-10-15 2010-04-22 Aizant Drug Research Solutions Private Limited Composition de propafénone à libération prolongée
CN107441051A (zh) * 2016-05-30 2017-12-08 北京科信必成医药科技发展有限公司 一种盐酸普罗帕酮微片及其制备方法
CN109394722A (zh) * 2018-12-26 2019-03-01 上海宣泰医药科技有限公司 普罗帕酮微片、包含该微片的多单元剂型及其制备方法和用途

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