WO2018151580A1 - Préparation pharmaceutique à libération immédiate et à libération prolongée contenant du chlorhydrate d'itopride - Google Patents

Préparation pharmaceutique à libération immédiate et à libération prolongée contenant du chlorhydrate d'itopride Download PDF

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WO2018151580A1
WO2018151580A1 PCT/KR2018/002079 KR2018002079W WO2018151580A1 WO 2018151580 A1 WO2018151580 A1 WO 2018151580A1 KR 2018002079 W KR2018002079 W KR 2018002079W WO 2018151580 A1 WO2018151580 A1 WO 2018151580A1
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weight
release portion
sustained
acid
hydrochloride
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PCT/KR2018/002079
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Korean (ko)
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김승균
성윤진
이봉상
전홍렬
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주식회사 씨티씨바이오
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • Itopride hydrochloride (N-[[4- [2- (dimethylamino) ethoxy] phenyl] methyl] -3,4-dimethoxybenzamide hydrochloride) inhibits acetylcholine esterase and inhibits dopamine D2 It acts as an antagonist of receptors to increase the amount of acetylcholine, and this acetylcholine promotes gastrointestinal peristalsis, which is used for digestive symptoms such as bloating, epigastric pain, anorexia, chest pain and vomiting due to functional dyspepsia to be.
  • This drug is suitable for long-term use because peripheral dopamine D2 antagonism shows little side effects such as gynecomastia and milk secretion, which is a side effect of gastrointestinal function improving agents such as domperidone.
  • Itopride Hydrochloride (N-[[4- (2-Dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide) has an effect time of 30 minutes oral administration orally and reaches a peak blood concentration. 0.5-1.5 hours, duration is about 12 hours. Etoprid is known to excrete about 80% in the urine during oral administration and the rate of excretion (half life) is about 6 hours.
  • the present invention can reduce the side effects that can be experienced by initially releasing excess drug.
  • the present invention relates to pharmaceutical preparations containing active ingredients such as etofried or pharmaceutically acceptable salts of etofried (preferably etopried hydrochloride), which is administered once daily to increase the drug compliance while expressing initial drug efficacy. It provides this excellent pharmaceutical formulation.
  • active ingredients such as etofried or pharmaceutically acceptable salts of etofried (preferably etopried hydrochloride), which is administered once daily to increase the drug compliance while expressing initial drug efficacy. It provides this excellent pharmaceutical formulation.
  • the present invention relates to oral preparations formulated with etoprid or a pharmaceutically acceptable salt thereof, which is a very useful drug for treating gastrointestinal abnormalities. More specifically, the present invention relates to etoprid or a pharmaceutically acceptable salt thereof for 24 hours. Provided is an oral pharmaceutical preparation with improved medication compliance that can be taken once daily by eluting at a constant rate.
  • the formulation of the present invention provides a pharmaceutical formulation comprising etoprid or a pharmaceutically acceptable salt of etoprid, preferably etoprid hydrochloride, which has excellent initial drug expression but is capable of continuous dissolution at a constant rate.
  • Pharmaceutically acceptable salts of the etoprid include acid addition salts and quaternary ammonium salts.
  • Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, iodide, sulfate, phosphate, oxalate, maleic acid, fumaric acid salt, lactic acid salt, malic acid salt, succinic acid salt, tartaric acid salt, benzoic acid salt and methane.
  • Organic acid salts such as a sulfonic acid salt and a citric acid salt
  • a quaternary ammonium salt Lower alkylhalogenides, such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, methylmethanesulfonate
  • lower alkyl sulphonates such as ethylmethanesulfonate, lower alkyl aryl sulfonates such as methyl-p-toluene sulfonate, and the like
  • topofid hydrochloride Etoprided hydrochloride can be used for sustained release with excellent initial drug expression rate, including immediate release and sustained release.
  • the topofrid or pharmaceutically acceptable salt of the topofrid may be used as the topofrid hydrochloride.
  • the inventors of the present invention have completed the present invention by investigating a method for sustaining the effect simply by taking once a day while showing a quick effect including the etoprid or a pharmaceutically acceptable salt thereof.
  • sustained release as used herein may be understood to mean an agent that is slowly dissolved in the body after administration and slowly elutes the drug.
  • immediate release may be understood to mean an agent in which the drug is eluted rapidly in the body after administration.
  • the sustained release portion of the present invention may use a sustained release polymer in order to effectively control the release of the etoprid hydrochloride having a very high water solubility.
  • the sustained-release polymer means a material used to slowly release the drug over a long time, and can be used without limitation as long as it is used in the industry as a sustained-release polymer, preferably the sustained-release polymer is hydroxypropyl methyl cellulose, At least one selected from the group consisting of hydroxypropyl cellulose and povidone may be used, and more preferably hydroxypropyl methyl cellulose (HPMC) may be used.
  • the hydroxypropyl methyl cellulose may be used hydroxypropyl methyl cellulose 2910, hydroxypropyl methyl cellulose 2208, or a mixture thereof.
  • the hydroxypropyl methyl cellulose may be preferably used in the formulation of the present invention because there is little change in viscosity or release pattern depending on pH.
  • the hydroxypropyl methylcellulose may have 100 to 100,000 cps to form a drug release matrix, preferably HPMC having an average viscosity of 5,000 to 30,000 cPs may be used. The viscosity is measured at 20 ° C. with a 2% by weight aqueous solution by the USP.
  • the formulation of the present invention further comprises a CO 2 feed ingredient and an organic acid in the sustained release portion.
  • the CO 2 supply component is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate in consideration of compatibility with the drug of the present invention, in consideration of excellent bubble generation effect, the purpose of minimizing gastric pH change, etc.
  • One or more may be used, but for the purposes of the present invention, sodium bicarbonate is preferably used.
  • the CO 2 feed component may comprise 1 to 10% by weight, preferably 3 to 8% by weight, even more preferably 4 to 7% by weight relative to the total weight of the sustained release portion.
  • the organic acid may be used together with the CO 2 supply component to use at least one selected from the group consisting of oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, and citric acid, which may be bubbled.
  • Citric acid may be preferably used for the purposes of the present invention.
  • the organic acid may be included 1 to 10% by weight, preferably 3 to 8% by weight, even more preferably 4 to 7% by weight relative to the total weight of the sustained-release portion.
  • the CO 2 feed ingredient and the organic acid can float the preparation in gastric juice, which can allow the drug to remain in the stomach for a long time.
  • the CO 2 feed component and the organic acid can achieve excellent flotation effects in the above content range.
  • when the content ratio of the CO 2 feed component and the organic acid is in the above range can be expected excellent floating effect, slow release effect.
  • a formulation comprising the etoprid of the present invention or a pharmaceutically acceptable salt thereof includes a CO 2 feed ingredient and an organic acid, so that the formulation of the present invention may be capable of long-term gastrointestinal retention.
  • the filler may be any one or more selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, glucose, sorbitol, dextrin, and sucrose, but is not limited thereto.
  • the lubricant is used to improve the moldability of the formulation, and examples thereof may be any one or more selected from the group consisting of hard silicic anhydride, silicon dioxide, talc, stearic acid, magnesium stearate or mixtures thereof. It is not limited to this.
  • Immediate release portions of the formulations of the present invention may be etoprid or a pharmaceutically acceptable salt of etoprid; And pharmaceutically acceptable fillers.
  • the rapid release part may further include a disintegrant, a lubricant, and the like.
  • the disintegrant may be at least one selected from the group consisting of sodium croscarmellose sodium, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, crospovidone, starch, copovidone, low-substituted hydroxypropyl cellulose.
  • croscarmellose sodium may be used.
  • the filler included in the immediate release portion may be the same kind as the filler included in the sustained release portion, or other types of fillers may be used.
  • the preparation preferably comprises an itofried hydrochloride as an active ingredient, and the content of the itofried hydrochloride contained in (a) the sustained release portion may include 3 to 5 times more than the itoprid hydrochloride contained in the (b) immediate release portion. And preferably 3.5 to 4.5 times more.
  • the content of itopride hydrochloride contained in the sustained release portion may be included in four times the weight of the topofrid hydrochloride contained in (b) the immediate release portion.
  • the formulation comprises (a) 45 to 60% by weight of etoprid hydrochloride relative to the total weight of the sustained release portion; 20-25% by weight of hydroxypropylmethylcellulose; 12-20% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 3.5 to 8% by weight of a CO 2 feed component which is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof; 3 to 6% by weight of an organic acid which is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid or mixtures thereof; and 0.5 to 3% by weight of glidants which are magnesium stearate, stearic acid, hard silicic acid or a mixture thereof Sustained release; and
  • etopri hydrochloride 35-50% by weight of etopri hydrochloride relative to the total weight of the immediate release portion; 25-40% by weight of a filler which is microcrystalline cellulose, lactose, starch, calcium dihydrogen phosphate or a mixture thereof; 20-28% by weight of croscarmellose sodium; And an immediate release portion containing 0.5 to 2% by weight of a lubricant, such as hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof, is provided for a daily oral administration.
  • a lubricant such as hard silicic anhydride, magnesium stearate, stearic acid, or a mixture thereof
  • in another embodiment of the present invention can provide a method for preparing a formulation comprising the active ingredient is itoprid or a pharmaceutically acceptable salt thereof.
  • the tableting of the sustained release part of the step (S1) may be performed such that the sustained release part may be formed of at least two tablets.
  • orthopred hydrochloride as an active ingredient, it is possible to rapidly release the topofrid hydrochloride, and at the same time characterized in that the continuous release of itoprid hydrochloride from the matrix polymer, oral once a day
  • formulations for administration are provided.
  • the formulation may be characterized by the following dissolution profiles.
  • the formulation may be provided as an oral formulation for once-a-day administration, and etoprid hydrochloride is used as an elution medium by using 900 ml of pH 1.2 buffer and rotating the paddle at 50 rpm, measuring 15-40% at 30 minutes. , Eluting at 41-70% in 3 hours, 80% or more in 9 hours.
  • the term 'Tmax' means a time to peak plasma concentration rat ion, and the plasma concentration of the drug (itopred hydrochloride) is maximum after administration of the pharmaceutical preparation of the present invention. It means the time until
  • 'Cmax' in the present invention means the maximum plasma concentrat ion, and means the maximum concentration in the plasma of the drug (itopred hydrochloride) due to the administration of the pharmaceutical preparation of the present invention.
  • the term 'AUC' means the area under the plasma concentration-time curve, and in pharmacokinetics, the term “AUC” refers to the time measured from the start time of the administration to the time “t” after the start of the administration.
  • the area under the curve obtained in the subject by plotting the serum concentration of the benefit agent (drug or active ingredient).
  • the AUC is the area under the curve during the administration period with doses administered periodically to infinity time.
  • AUC can be obtained by analyzing serum samples of the subject to be administered.
  • the pharmaceutical preparations of the present invention include itofried or a pharmaceutically acceptable salt thereof, and include three doses of drug fast-acting and fast-acting preparations that allow the patient to be rapidly exposed to a sufficient amount of drug early for expression. It is characterized by satisfying the same drug persistence at the same time.
  • the present invention is a formulation having both characteristics of a fast-acting oral formulation and a sustained oral formulation, which is characterized by initial high release rate of itoprid or its pharmaceutically acceptable salt after administration of the formulation. Exposure to a sufficient amount of drug, ie an increase in Cmax and a reduction in Time to Peak Plasma Concentration, and an initial AUC increase are achieved.
  • the preparations of the present invention can be easily taken by oral administration once a day.
  • the pharmaceutical preparations according to the present invention can be taken once a day, which is excellent in taking convenience.
  • the pharmaceutical preparations of the present invention can achieve both sustained release and immediate effect expression when administered to a human body.
  • 1 is a diagram showing the process of the inventors of the present invention developed the formulation of the present invention.
  • Figure 2 is a picture showing a pellet type capsule, which is one of the development process of the topofid hydrochloride capsule formulation.
  • 3 is a graph comparing dissolution of P01 and a commercial product Ganaton.
  • Figure 4 is a photograph confirming the degree of floating or swelling in the medium of Preparation Example 1. Pellet was not rich and no swelling was observed.
  • 5 is a graph comparing the pK result of P01 and a commercial product Ganaton.
  • FIG. 6 is a view showing a mini tablet capsule, which is one of the development process of the topofrid hydrochloride capsule formulation.
  • 10 is a graph comparing dissolution of M02-2 and M02-1 and a commercial product Ganaton.
  • 11 is a photograph confirming the degree of floating or swelling in the medium of M02-2.
  • the manufactured mini tablet was partially suspended in the upper layer of the medium and swelling was confirmed.
  • Figure 16 is a graph comparing the pK result of T03-1 and commercially available Ganaton.
  • 21 is a photograph confirming the degree of floating or swelling in the medium of T03-3. The prepared tablets were suspended in the upper portion of the medium, and swelling was confirmed.
  • Figure 23 is one of the processes for the development of the preparation of the Itofried 150mg, a capsule containing two 50 mg tablets of sustained-release itoprid hydrochloride and 50 mg tablets of immediate release itoprid hydrochloride is shown in the figure.
  • 24 is a graph comparing dissolution between T04-1 and Ganaton, a commercial product.
  • 25 is a graph showing the dissolution of T04-1. The degree of dissolution of the immediate release portion alone and the sustained release portion was compared.
  • Figure 26 is a photograph confirming the degree of floating or swelling in the medium of T04-1.
  • the immediate release part of the prepared tablet was neither suspended nor swollen.
  • the sustained release portion was suspended in the upper portion of the medium and the degree of swelling was confirmed.
  • FIG. 27 is a graph comparing pK result of T04-1 and Ganaton which is a commercial product.
  • FIG. 28 is a graph comparing dissolution of T04-2, T04-1, and Ganaton, a commercial product.
  • Fig. 29 is a graph showing the dissolution of T04-2. The degree of dissolution of the immediate release portion alone and the sustained release portion was compared.
  • Figure 31 is a graph comparing the pK result of T04-2 and commercially available Ganaton.
  • Fig. 33 is a graph showing the dissolution of T04-3. The dissolution degree of the immediate release part alone was compared.
  • FIG. 37 is a graph comparing dissolution of an Itofried 150mg formulation (T05) and commercially available Ganaton, T04-1, T04-2, and T04-3 according to an embodiment of the present invention.
  • 40 is a graph comparing pK results of T05 and Ganaton, a commercial product.
  • Solubility Soluble in water ( ⁇ 48 mg / mL) or methanol. Recording in acetic acid.
  • Etoprid hydrochloride 150 mg was prepared as a hard capsule with the following composition.
  • Etoprid hydrochloride 150mg was prepared as a hard capsule containing a mini tablet of about 2mm in size with the following composition.
  • Figure 6 shows a capsule containing an etofried mini tablet prepared according to Preparation Example 3.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • Itofried hydrochloride, microcrystalline cellulose, hypromellose and povidone are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is sieved to 18 mesh, magnesium stearate is added, tableted in a rotary tableting machine, and the tablets are filled into capsules.
  • FIG. 13 shows a capsule containing three tablets of Itofried SR tablet prepared according to Preparation Example 4.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • FIG. 13 shows a capsule containing three tablets of Itofried SR tablet prepared according to Preparation Example 5.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • Figure 13 shows a capsule containing three tablets of etoprired SR tablet prepared according to Preparation Example 6.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • 150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule.
  • the SR part content below represents the total amount of two tablets.
  • Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.
  • Itofried hydrochloride, microcrystalline cellulose, lactose, croscarmellose sodium, and hard silicic anhydride are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.
  • FIG. 23 shows a capsule including two tablets of Itofried SR tablet and one tablet IR tablet prepared according to Preparation Example 7.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.
  • Itofried hydrochloride, hypromellose, microcrystalline cellulose, lactose, croscarmellose sodium and sodium bicarbonate were sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.
  • FIG. 23 shows a capsule containing two SR tablets of Itofried and one IR tablet prepared according to Preparation Example 8.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • 150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule.
  • the SR part content below represents the total amount of two tablets.
  • Itofried hydrochloride, microcrystalline cellulose, hypromellose, mannitol, and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.
  • Itofried hydrochloride, hypromellose, microcrystalline cellulose, lactose, croscarmellose sodium, sodium hydrogencarbonate, and hard silicic acid were sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours. Do The dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.
  • FIG. 36 shows a capsule including two tablets of etofried SR and one tablet IR prepared according to Preparation Example 9.
  • Dissolution rate was measured by pH 1.2, 50rpm, Paddle test method.
  • 150 mg of etoprid hydrochloride were prepared with two SR tablets and one IR tablet to prepare a formulation filled in a capsule.
  • the SR part content below represents the total amount of two tablets.
  • Itofried hydrochloride, microcrystalline cellulose, hypromellose and lactose are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is sieved to 18 mesh, and sodium bicarbonate and magnesium stearate are added and tableted in a rotary tableting machine. Two tablets are used as sustained-release tablets.
  • Itofried hydrochloride, microcrystalline cellulose, lactose, croscarmellose sodium, and hard silicic anhydride are mixed, sieved through 30 mesh, wet granulated with 80% ethanol, and dried in a 60 degree dryer for 4 hours.
  • the dried product is set to 18 meshes, and magnesium stearate is added to the tablets in a rotary tableting machine, and a fast-soluble tablet is filled into the capsule together with the western portion.
  • FIG. 36 shows a capsule including two tablets of Itofried SR tablet and one tablet IR tablet prepared according to Preparation Example 10.

Abstract

La présente invention concerne une préparation pharmaceutique qui comporte : (a) une partie à libération prolongée comprenant de l'itopride ou un sel de qualité pharmaceutique de celui-ci, un polymère à libération prolongée, un constituant fournissant du CO2, un acide organique, et facultativement une charge de qualité pharmaceutique; (b) une partie à libération immédiate comprenant de l'itopride ou un sel de qualité pharmaceutique de celui-ci, et une charge de qualité pharmaceutique. La présente invention est prise une fois par jour et peut ainsi augmenter l'observance de la prise du médicament.
PCT/KR2018/002079 2017-02-20 2018-02-20 Préparation pharmaceutique à libération immédiate et à libération prolongée contenant du chlorhydrate d'itopride WO2018151580A1 (fr)

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CN115844847A (zh) * 2022-11-17 2023-03-28 云南永安制药有限公司 一种盐酸伊托必利制剂及其制备方法

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CN115844847A (zh) * 2022-11-17 2023-03-28 云南永安制药有限公司 一种盐酸伊托必利制剂及其制备方法
CN115844847B (zh) * 2022-11-17 2023-09-01 云南永安制药有限公司 一种盐酸伊托必利制剂及其制备方法

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