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WO2011111818A1 - Mosapride et composition médicinale à libération lente comprenant un sel de mosapride - Google Patents

Mosapride et composition médicinale à libération lente comprenant un sel de mosapride Download PDF

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Publication number
WO2011111818A1
WO2011111818A1 PCT/JP2011/055772 JP2011055772W WO2011111818A1 WO 2011111818 A1 WO2011111818 A1 WO 2011111818A1 JP 2011055772 W JP2011055772 W JP 2011055772W WO 2011111818 A1 WO2011111818 A1 WO 2011111818A1
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release
mosapride
pharmaceutical composition
sustained
tablet
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PCT/JP2011/055772
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English (en)
Japanese (ja)
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イ・ミンスク
チャン・ヘチュル
カン・ボッキ
キム・ジュンク
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大日本住友製薬株式会社
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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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/20—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to a sustained-release pharmaceutical composition
  • a sustained-release pharmaceutical composition comprising mosapride or a salt thereof having a controlled dissolution profile.
  • Mosaprid (mosapride, ( ⁇ ) 4-amino-5-chloro-2-ethoxy-N-((4- (4-fluorobenzyl) -2-morpholinyl) methyl) benzamide) represented by the following chemical formula 1 is disclosed in Patent Document 1 and Patent Document 2 discloses a gastrointestinal motility promoter.
  • Mosapride is a selective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist, acting on the cholinergic gut cholinergic, neuronal serotonin (5-HT) receptor, and acetylcholine By promoting release, the acetylcholine promotes gastrointestinal smooth muscle movement, thereby exerting a strong gastrointestinal motility and gastric emptying promoting action.
  • mosapride Since mosapride does not have a dopamine D2 receptor blocking action, it has no side effects on pyrethral symptoms, high prolactin plasma (lactation, gynecomastia), QT prolongation and deep veins.
  • Mosapride is generally taken three times a day and is safely absorbed regardless of diet. The medicinal effect is rapidly manifested after taking, and administration for about two weeks can bring about an excellent improvement effect on symptoms of abnormal digestive function.
  • Mosapride also has a short ecological half-life of 1.4 to 2.0 hours, C max (maximum plasma concentration after drug administration) and AUC (area under the plasma drug concentration-time curve) from 5 to 40 mg Increases in proportion to capacity.
  • Mosapride is absorbed approximately 93% in the gastrointestinal tract, but it is not highly soluble in aqueous solution, has low bioavailability, and has a short half life (eg, several times a day) Mosaprid 5mg x 3).
  • Patent Document 3 proposes a sustained-release tablet produced by using mosapride as a sustained-release matrix tablet using a water-soluble hydrogel.
  • the one-matrix tablet form has the disadvantage that it is difficult to quickly achieve an effective plasma concentration of mosapride.
  • the present inventor manufactured a mosapride-containing sustained-release pharmaceutical composition having a biphase that satisfies a unique dissolution profile, and reached the initial effective plasma concentration of mosapride and the late-stage efficacy according to the dissolution profile. It was confirmed that the plasma concentration could be maintained, and the present invention was completed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an immediate release part and a sustained release part of mosapride comprising mosapride or a salt thereof and a pharmaceutically acceptable carrier
  • an aqueous buffer pH 1.2
  • the second release method piaddle method
  • the Korean Pharmacopoeia the following elution profile: 1) 10% to 50% of the total weight of mosapride or its salt is released within 30 minutes, 2) Provide a pharmaceutical composition characterized in that a release of 50% to 95% of the total weight of mosapride or a salt thereof is achieved between 6 and 16 hours.
  • the following elution profile 1) 20% to 40% of the total weight of mosapride or its salt is released within 30 minutes, 2)
  • the above pharmaceutical composition is provided wherein a release of 60% to 90% of the total weight of mosapride or a salt thereof can be achieved in 8-14 hours.
  • the immediate release portion comprises 20-40% of the total weight of mosapride or a salt thereof
  • the sustained release portion comprises 60-80% of the total weight of mosapride or a salt thereof
  • the sustained-release portion comprises a cellulose derivative, gums, a hydrophilic or hydrophobic (meth) acrylate copolymer, a hydrophilic or hydrophobic polyvinyl derivative, a polyethylene derivative, a carboxyvinyl compound, and a polysaccharide.
  • a pharmaceutical composition as described above comprising one or more pharmaceutically acceptable modified release agents selected from the group.
  • the above pharmaceutical composition is provided wherein the release controlling agent is contained in an amount of 5 to 80% by weight based on the total weight of the sustained release part.
  • the above-mentioned pharmaceutical composition is provided, wherein the composition is a dosage form of a powder, a pellet, a capsule, a tablet, a coated tablet or a preparation thereof.
  • the above-mentioned pharmaceutical composition is provided, wherein the tablet is a two-layer tablet comprising an immediate release part layer and a sustained release part layer.
  • the pharmaceutical composition is provided as described above, wherein the tablet is a tablet comprising delayed release coated pellets contained in a matrix.
  • the pharmaceutical composition according to claim 1 which is administered once a day, is provided.
  • the sustained-release part comprises one or more pharmaceuticals selected from the group consisting of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, xanthan gum, serfia and ethylcellulose.
  • a pharmaceutical composition as described above is provided comprising an acceptable release modifier.
  • the sustained-release portion contains hydroxypropylmethylcellulose as a release regulator, and is further selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, xanthan gum, serfia and ethylcellulose.
  • a pharmaceutical composition as described above which may comprise one or more pharmaceutically acceptable controlled release agents, wherein the controlled release agent is 10-30% by weight relative to the total weight of the sustained release part .
  • the sustained-release portion contains (A) an excipient composed of lactose and microcrystalline cellulose, and (B) at least one binder selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose. And (A) 60 to 85% by weight and (B) 1 to 7% by weight based on the total weight of the sustained release portion.
  • the immediate release part comprises (C) an excipient composed of lactose and corn starch, and (D) hydroxypropylcellulose, (E) a low-substituted hydroxypropylcellulose. Offer things.
  • the pharmaceutical composition of the present invention can reach the effective plasma concentration of mosapride early in the early stage by satisfying the unique two-phase elution profile (immediate release phase and delayed release phase) and It can be maintained continuously and as a single tablet, not only can the mosapride be effective just once a day, but also improve the compliance.
  • FIG. 1 is a graph showing the dissolution rate in water of bilayer tablets produced by changing the mosapride ratio in the immediate-release part and the sustained-release part in Examples 1 to 3 of the present invention.
  • FIG. 2 is a graph showing the dissolution rates at pH 1.2 of bilayer tablets produced by changing the mosapride ratio in the immediate release part and the sustained release part in Examples 1 to 3 of the present invention. is there.
  • FIG. 3 is a graph showing the dissolution rates of bilayer tablets in water produced in Comparative Examples 1 and 2 with different mosapride ratios in the immediate-release part and the sustained-release part.
  • FIG. 1 is a graph showing the dissolution rate in water of bilayer tablets produced by changing the mosapride ratio in the immediate-release part and the sustained-release part in Examples 1 to 3 of the present invention.
  • FIG. 2 is a graph showing the dissolution rates at pH 1.2 of bilayer tablets produced by changing the mosapride ratio in the immediate release part and the sustained release part in Examples 1 to 3
  • FIG. 4 is a graph showing the dissolution rate at pH 1.2 of bilayer tablets produced in Comparative Examples 1 and 2 with different mosapride ratios in the immediate release part and the sustained release part.
  • FIG. 5 is a graph showing the dissolution rate in water of bilayer tablets produced by changing the type of controlled release polymer in Examples 4 to 8 of the present invention.
  • FIG. 6 is a graph showing the dissolution rates at pH 1.2 of bilayer tablets produced by changing the type of release controlling polymer in Examples 4 to 8 of the present invention.
  • FIG. 7 is a graph showing the dissolution rate in water of capsules containing delayed release pellets produced in Example 9 of the present invention.
  • FIG. 8 is a graph showing the dissolution rate at pH 1.2 of capsules containing delayed release pellets produced in Example 9 of the present invention.
  • FIG. 5 is a graph showing the dissolution rate in water of bilayer tablets produced by changing the type of controlled release polymer in Examples 4 to 8 of the present invention.
  • FIG. 6 is a graph showing the dissolution rates
  • FIG. 9 is a graph showing the dissolution rate in water of the bilayer tablet containing delayed release pellets produced in Example 10 of the present invention.
  • FIG. 10 is a graph showing the dissolution rate at pH 1.2 of the bilayer tablet containing delayed release pellets produced in Example 10 of the present invention.
  • FIG. 11 is a graph showing the dissolution rate in water of a tablet produced in Example 11 of the present invention and containing a drug coating layer that is an immediate release phase.
  • FIG. 12 is a graph showing the dissolution rate at pH 1.2 of the tablet produced in Example 11 of the present invention and containing a drug coating layer that is an immediate release phase.
  • FIG. 13 is a graph showing the dissolution rate in water of a tablet manufactured as a core tablet including a delayed release core layer in Example 12 of the present invention.
  • FIG. 10 is a graph showing the dissolution rate at pH 1.2 of the bilayer tablet containing delayed release pellets produced in Example 10 of the present invention.
  • FIG. 11 is a graph showing the dissolution rate in water
  • FIG. 14 is a graph showing the dissolution rate at pH 1.2 of a tablet produced as a core tablet containing a delayed release core layer in Example 12 of the present invention.
  • FIG. 15 is a graph showing the dissolution rate in water of capsules containing immediate release partial mini-tablets and sustained-release partial mini-tablets produced in Example 13 of the present invention.
  • FIG. 16 is a graph showing the dissolution rate at pH 1.2 of capsules containing immediate release partial mini-tablets and sustained-release partial mini-tablets produced in Example 13 of the present invention.
  • FIG. 17 is a graph showing changes in plasma concentration with time during administration of the bilayer tablets produced in Examples 1 to 3 of the present invention.
  • FIG. 18 is a graph showing changes in plasma concentration according to the time when bilayer tablets produced in Comparative Examples 1 and 2 were administered.
  • FIG. 19 is a graph showing changes in plasma concentration with time during administration of a bilayer tablet and a commercially available control drug (gasmotin tablet) produced according to Example 2 of the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an immediate release portion and a sustained release portion of mosapride comprising mosapride or a salt thereof and a pharmaceutically acceptable carrier,
  • the following elution profile when measured with an aqueous buffer solution (pH 1.2) at 37 ° C. by the second release method (paddle method) by the Korean Pharmacopoeia: 1) 10% -50% of the total weight of mosapride or its salt is released within 30 minutes, 2) Provide a pharmaceutical composition characterized in that a release of 50% to 95% of the total weight of mosapride or a salt thereof is achieved between 6 and 16 hours.
  • the pharmaceutical composition of the present invention has the following elution profile: 1) The total weight of mosapride or a salt thereof is released within 20 minutes from 20% to 40%, 2) Release of 60% to 90% of the total weight of mosapride or its salts can be achieved within 8-14 hours.
  • the composition of the present invention elutes mosapride or a salt thereof by a biphasic profile
  • the first phase is an immediate-release (or immediate-release, immediate-release) phase with an immediate-release part
  • the second phase is controlled and released by the immediate release portion as a sustained release (or delayed release) phase. Since the mosapride-containing composition of the present invention can separate the immediate release phase and the release mode of the sustained release portion of each of the immediate release portion and the sustained release portion within one dosage form, the release from each other. Controlled release of tablets that do not affect the release and must exhibit other release modalities is possible.
  • the sustained-release pharmaceutical composition of the present invention quickly reaches the initial effective plasma concentration of mosapride that is therapeutically effective by rapid dissolution by including an immediate-release part and a sustained-release part in an appropriate ratio. Thereafter, mosapride is gradually released, so that the effective plasma concentration can be maintained continuously.
  • the release pattern composed of the two phases of the present invention does not mean that the general release pattern is extended, and that the regularity of the medicinal effect appears by producing a specific range of release in a specific time interval. means.
  • the first phase or the immediate-release type phase is a portion of the dissolution profile obtained in 0 to 30 minutes in a suitable in vitro dissolution test.
  • PH 1.2 a method that is carried out with a general apparatus according to the second elution method (paddle method) by the Korean Pharmacopoeia (or US Pharmacopoeia, Japanese Pharmacopoeia), or some modifications known to those skilled in the art Is a way to give
  • the aqueous buffer (pH 1.2) used here can be prepared as 1000 mL by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water, for example, according to the preparation of the first solution of the Japanese Pharmacopoeia dissolution test.
  • the total weight of mosapride or a salt thereof is released within 10 to 30%, desirably 20 to 40% within 30 minutes.
  • the above-mentioned second phase or sustained-release type phase is a part of the dissolution profile after 30 minutes measured by a suitable in vitro dissolution test.
  • the time required for the release of 50% to 95% of the total weight of mosapride or a salt thereof is 6 to 16 hours, preferably 60% to 90% release. The time required is 8 to 14 hours.
  • An exemplary composition of the present invention as shown in FIG. 1, has about 30% of the total weight of mosapride or salt thereof released into the immediate release phase and the second phase is the total weight of mosapride or salt thereof. Approximately 90% elutes around 12 hours in the sustained release phase. The rapid release of the first phase allows mosapride to be rapidly eluted to achieve a therapeutically effective amount of mosapride concentration initially, while the sustained release of the second phase allows this effective amount to be sustained over time. To maintain.
  • the PK profile of the sustained release type is generally used to logarithmically convert it as a perfect primary release mode rarely seen. It is characterized by maintaining almost linearity (r 2 > 0.85) after the half-life of the drug (about 3 hours) has passed after reaching C max on the graph. This means that the rate of disappearance of commercially available general immediate release dosage forms has been completely changed. By controlling the rate of disappearance in the body, which is a drug-specific feature, as a dosage form, it is possible to induce certain gastrointestinal motility. It was confirmed that it was possible.
  • the present invention not only simply maintains the effect of repeated cessation of the effect that appears repeatedly throughout the day due to the very short half-life of mosapride, but also allows the constant release of the gastrointestinal tract to be induced by constant release. It is the greatest feature. Moreover, it is very important to set the release time of the drug so that the gastrointestinal motility is not continuously activated due to the development of the drug effect until the sleep time is reached after the release is completed. This can eliminate the inconvenience of the patient who may induce sleep disturbance.
  • the composition of the present invention may contain the active ingredient of mosapride or a salt thereof in an effective amount of 0.1 to 500 mg, desirably 0.5 to 100 mg per unit dose.
  • the immediate-release part may contain 20 to 40% of the total weight of mosapride or a salt thereof
  • the sustained-release part may contain 60 to 80% of the total weight of mosapride or a salt thereof. desirable.
  • the immediate release part and the sustained release part each contain mosapride or a salt thereof and a pharmaceutically acceptable carrier, so that the intended elution profile can be achieved as the carrier used in each part.
  • a pharmaceutically acceptable carrier such as a pharmaceutically acceptable carrier, so that the intended elution profile can be achieved as the carrier used in each part.
  • one that is normally used can be appropriately selected and an appropriate amount commonly used for tableting can be used.
  • the sustained-release part is a pharmaceutically acceptable (A) diluent (excipient) as lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous phosphoric acid
  • diluent excipient
  • lactose dextrin
  • mannitol sorbitol
  • starch microcrystalline cellulose
  • calcium hydrogen phosphate calcium hydrogen phosphate
  • anhydrous phosphoric acid anhydrous phosphoric acid
  • B polyvinylpyrrolidone, copopidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, Those selected from the group consisting of hydroxypropylcellulose, hydroxypropylalkylcellulose and mixtures thereof can be used.
  • a lubricant stearic acid, stearate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, Macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, talc and mixtures thereof can be used, and cellulose derivatives, gums as release modifiers (controlled release substrates) And a hydrophilic or hydrophobic (meth) acrylate copolymer, a hydrophilic or hydrophobic polyvinyl derivative, a polyethylene derivative, a carboxyvinyl compound, and a polysaccharide can be used.
  • Specific release modifiers include hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, methylhydroxyethylcellulose, guar gum, locust bean gum, tragacanth gum, Carrageenan, acacia gum, xanthan gum, gum arabic, gellan gum, caraya gum, tara gum, tamarind gum, cutch gum, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetyl diethyl amino acetate, polyethylene derivatives, polyethylene glycol, polyethylene oxide, cabomo, dextrin, poly Xistrin, dextran, pectin, pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl star
  • a component used for the sustained release portion As a component used for the sustained release portion, more preferred specific examples are shown below.
  • A As a diluent (excipient), lactose, mannitol, starch, and microcrystalline cellulose are preferable. More preferably, lactose and microcrystalline cellulose are mentioned.
  • B As a binder, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose are preferable. More preferably, hydroxypropylcellulose and hydroxypropylmethylcellulose are mentioned.
  • release modifiers include hydroxypropyl methylcellulose, polyethylene oxide, hydroxypropylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, xanthan gum, serfia and ethylcellulose. Furthermore, it is preferable to contain hydroxypropylmethylcellulose as an essential component in order to produce the sustained release portion of the present invention.
  • contents of (A) diluent (excipient), (B) binder and release modifier are usually 60-85 wt%, 1-7 wt% and 10 to 30% by weight. More preferably, they are 65 to 80% by weight, 2 to 6% by weight and 10 to 25% by weight, respectively.
  • the pharmaceutical composition of the present invention can be manufactured as a powder, pellet, capsule, tablet, coated tablet or dosage form of these preparations. Desirably, it can be manufactured in the form of a two-layer tablet made up of a layer of immediate release part and a layer of sustained release part, or it can be configured as a tablet comprising delayed release coated pellets contained within a matrix. it can.
  • the immediate release part is not particularly limited as long as it is a combination of components satisfying the elution characteristics, but as components used in the immediate release part, (C) excipient, (D) binder and (E) disintegrant
  • the combination containing is mentioned, A preferable specific example is shown below.
  • the excipient is selected from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sugars and mixtures thereof. More preferred are lactose, mannitol, starch and microcrystalline cellulose. Particular preference is given to lactose and corn starch.
  • a binder selected from the group consisting of polyvinylpyrrolidone, copopidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose, and mixtures thereof can be used. . More preferably, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose are mentioned, and hydroxypropylcellulose is particularly preferred.
  • Disintegrants include croscarmellose sodium, carboxymethyl starch sodium, partially pregelatinized starch, starches, carmellose sodium, carmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, crospovidone, etc. Is mentioned. More preferred are corn starch, low substituted hydroxypropyl cellulose and carmellose, and particularly preferred are low substituted hydroxypropyl cellulose.
  • the immediate release portion in the pharmaceutical composition of the present invention is an immediate release in the form of a capsule or tablet as a single agent pharmaceutical immediate release unit such as an immediate release tablet or pellet as in the examples of the present invention.
  • a single agent pharmaceutical immediate release unit such as an immediate release tablet or pellet as in the examples of the present invention.
  • the sustained release portion in the pharmaceutical composition of the present invention can be prepared in several capsules or tablets formulated as a pharmaceutical delayed release unit such as a delayed release tablet or pellet, as in the examples of the present invention.
  • a delayed release unit as a delayed release layer that can be incorporated into a multilayer tablet, a multilayer tablet coated with one or more layers is understood as a delayed release core or delayed release coating layer, or as an in-table delayed release pellet that disintegrates be able to.
  • the immediate-release part and the sustained-release part constitute a single dosage form at the same time, but tablets that are separated in the body and exhibit a specific release form are also included in the present invention.
  • the compositions of the present invention can be formulated by conventional mixing methods such as granulation, mixing, filling and compression.
  • tablets can be produced by a wet granulation process, where the immediate release part and the sustained release part can be produced separately.
  • the active ingredient and pharmaceutically acceptable carrier are screened for either one of the immediate release part or the sustained release part and mixed in a high shear mixing granulator or induction layer dryer. it can.
  • This mixture can be dissolved in or dispersed in a distillate (generally purified water) sprayed into a high shear mixing granulator or induction layer dryer, or in purified water or a suitable solvent. Granulated by adding dissolved / dispersed drug. If necessary, wetting agents such as surfactants can be added. The resulting (optionally pelletized) granulation can be dried to a normal residual moisture of 1-5% by tray, fluidized bed or microwave drying techniques. Grind the dried granulation to make the particle size constant, and if necessary, extragranular excipients, generally lubricants and glidants (eg magnesium stearate) , Silicon dioxide).
  • a distillate generally purified water
  • a high shear mixing granulator or induction layer dryer or in purified water or a suitable solvent.
  • Granulated by adding dissolved / dispersed drug. If necessary, wetting agents such as surfactants can be added.
  • the resulting (optionally pelletized) granulation can be
  • immediate release and sustained release granules can be compressed simultaneously using a rotary tablet press (same as a double layer tablet press), typically in the range of 100-600 mg. it can.
  • a rotary tablet press typically in the range of 100-600 mg. it can.
  • the resulting tablets can be coated in a pan coating apparatus, typically 1-5% water-soluble film coat, and then polished with wax.
  • tablets can be produced as a direct tableting process.
  • the active ingredient and pharmaceutically acceptable carrier are separately screened against the immediate release part and the sustained release part, followed by a suitable mixer such as a cone, hexahedron or V-shape. Mix in a mixer. Otherwise, otherwise, a pharmaceutically acceptable carrier is added and mixed further.
  • the separately manufactured immediate release and sustained release parts can be combined and compressed simultaneously using a rotary tablet press as described above. The resulting tablets can be coated with a pan coating apparatus.
  • a tablet can also be manufactured using a wet granulation process and a direct tableting process.
  • the sustained release portion can be produced by wet granulation as described above, while the immediate release portion can be produced by mixing directly with a tableting excipient.
  • a commercially available mixture of immediate release mosapride can also be used for direct tableting.
  • the two phases can then be combined and tableted simultaneously as described above.
  • the active ingredient and the pharmaceutically acceptable salt are screened and mixed in a suitable mixer such as a cone, regular hexahedron or V-shaped mixer to give immediate release part and sustained release type Capsules can be made by making the parts separately.
  • the mixture is typically mixed after the addition of a lubricant and other pharmaceutically acceptable carriers such as a glidant.
  • a lubricant and other pharmaceutically acceptable carriers such as a glidant.
  • the separately produced immediate release and sustained release portions can then be mixed and filled into the capsules in the appropriate amount using a standard capsule filling machine.
  • the composition of the present invention can provide an excellent therapeutic effect of mosapride as a single dosage form, unlike a conventional method of taking three times a day, and can be taken only once a day. The degree of adaptation can also be greatly improved.
  • Examples 1-3 Manufacture of bilayer tablet by ratio of mosapride content in immediate-release part and sustained-release part
  • mosapride contained in immediate-release part and sustained-release part Bilayer tablets were produced in varying amounts.
  • the mosapride content in the immediate release part was 20% with respect to the total weight of mosapride
  • Example 2 was 30%
  • Example 3 was 40%.
  • the specific manufacturing process is as follows.
  • Step 1 Production of immediate-release partial granules After dissolving hydroxypropylcellulose in purified water to obtain a binding solution, mosapride citrate, lactose hydrate and corn starch are sifted through 24 mesh and mixed. did. Thereafter, a wet granulated product was obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then passed through a 35 mesh sieve with low-substituted hydroxypropylcellulose, magnesium stearate and An immediate release part was manufactured by mixing light anhydrous silicic acid.
  • MIC Developer-5 MIC Developer-5, COMASA
  • ⁇ Step 2> Manufacture of sustained release partial granule After dissolving hydroxypropylcellulose (low substitution degree) in purified water to obtain a binding solution, mosapride citrate, lactose hydrate, microcrystalline cellulose and Then, hydroxypropylmethylcellulose (high substitution degree) as a release controlling polymer was sieved with 24 mesh and mixed. After that, wet granulated material is obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then mixed with light anhydrous silicic acid and magnesium stearate sieved with 35 mesh. Thus, a sustained release portion was obtained.
  • MIC Developer-5, COMASA high speed mixer
  • Comparative Examples 1 and 2 Manufacture of a bilayer tablet according to the immediate release part and the sustained release partial mosapride content ratio
  • Table 2 In order to compare the effects of the immediate release part and the sustained release partial mosapride content, Table 2 below and A bilayer tablet was prepared with the same composition as in the above example.
  • the mosapride content in the immediate release part was 10% with respect to the total weight of mosapride, and Comparative Example 2 was 50%.
  • Examples 4 to 8 Production of mosapride-containing bilayer tablet with controlled release polymer
  • Mosaprid-containing bilayer tablets were produced with the components and contents shown in Table 3 below, while changing the controlled release polymer.
  • a wet granulated product was obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then passed through a 24-mesh low-substituted hydroxypropyl cellulose, magnesium stearate and An immediate release part was manufactured by mixing light anhydrous silicic acid.
  • MIC Developer-5 MIC Developer-5, COMASA
  • ⁇ Step 2> Manufacture of sustained-release partial granules After dissolving hydroxypropylcellulose (low substitution degree) in purified water to obtain a binding solution, mosapride citrate, lactose hydrate, microcrystalline cellulose and release Polyethylene oxide (Example 4), hydroxypropylcellulose (high substitution degree, Example 5), crosslinked sodium carboxymethylcellulose (Example 6), crosslinked polyvinylpyrrolidone (Example 7) or xanthan gum (Example) as a regulating polymer 8) was sieved with 24 mesh and mixed.
  • Example 9 Production of Mosaprid-Containing Capsule Containing Delayed Release Pellets
  • Mosaprid-containing capsules containing delayed release pellets were produced as follows with the components and contents shown in Table 4 below.
  • ⁇ Step 1> Production of immediate-release partial granules After dissolving hydroxypropylcellulose in purified water to obtain a binding solution, mosapride citrate, lactose hydrate and corn starch are sifted through 24 mesh and mixed. did.
  • a wet granulated product was obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then passed through a 35 mesh sieve with low-substituted hydroxypropylcellulose, magnesium stearate and An immediate release part was obtained by mixing light anhydrous silicic acid.
  • MIC Developer-5 COMASA
  • An immediate release part was obtained by mixing light anhydrous silicic acid.
  • Step 2 Formation of sustained release partial drug coating layer 25-30 mesh non-pareil beads are placed in a fluidized bed coating machine, and mosapride, hydroxypropyl methylcellulose (low substitution degree) and hydroxypropylmethylcellulose 4000 cps are added.
  • a coating solution obtained by dissolving in a mixed solution of water and methanol (1: 2, weight ratio) was coated to form a drug coating layer.
  • the coating conditions were spray air pressure 2.7 bar, outlet air temperature 24 ° C., inlet air temperature 34 ° C., flows 4-7 and outlet air frets 28%.
  • the coating conditions were spray air pressure 2.8 bar, outlet air temperature 24 ° C., inlet air temperature 34 ° C., flows 5-18 and outlet air frets 28%.
  • Step 4> Capsule Filling The immediate release granule part and the sustained release pellet part obtained as described above were filled into No. 1 capsules using a capsule filling machine (DMF 1500, Tesampamatech).
  • Example 10 Production of mosapride-containing bilayer tablet containing delayed release pellets
  • Mosaprid-containing bilayer tablets containing delayed release pellets were produced with the ingredients and contents shown in Table 5 below.
  • a wet granulated product was obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then passed through a 35 mesh sieve with low-substituted hydroxypropylcellulose, magnesium stearate and An immediate release part was obtained by mixing light anhydrous silicic acid.
  • MIC Developer-5 MIC Developer-5, COMASA
  • An immediate release part was obtained by mixing light anhydrous silicic acid.
  • ⁇ Step 2> Formation of sustained-release partial drug coating layer 25-30 mesh non-pareil beads are put into a fluidized bed coating machine, and mosapride and hydroxypropylmethylcellulose are mixed with water and methanol (1: 2).
  • the drug coating layer was formed by coating with a coating solution obtained by dissolution in a weight ratio.
  • the coating conditions were atomizing air 2.7 bar, outlet air temperature 24 ° C., inlet air temperature 34 ° C., flows 4-7 and outlet air frets 28%.
  • the pellets on which the drug coating layer is formed are mixed with an induction layer coating machine, and ethylcellulose and hydroxypropylmethylcellulose are mixed with water and methanol (1:41. 5 and a weight ratio) was coated with a coating solution obtained to form a controlled release membrane layer.
  • the coating conditions were spray air pressure 2.8 bar, outlet air temperature 24 ° C., inlet air temperature 34 ° C., flow 5-18, outlet air frets 28%.
  • hydroxypropyl methylcellulose high substitution degree
  • microcrystalline cellulose microcrystalline cellulose
  • light anhydrous silicic acid and magnesium stearate sieved with 35 mesh were mixed to obtain a sustained release portion.
  • BB-11, RIVA two-layer tablet press
  • Two-layer tablets configured as layers were produced.
  • the produced bilayer tablet was placed in a fan coating machine (LDCS, VECTOR), and then film-coated with Opadry.
  • Example 11 Production of mosapride-containing tablet containing drug coating layer
  • Mosaprid-containing coated tablets were produced with the components and contents shown in Table 6 below.
  • ⁇ Step 1> Preparation of sustained-release partial tablet hydroxypropylcellulose was dissolved in purified water to obtain a binding solution, and then mosapride citrate, lactose hydrate, microcrystalline cellulose and hydroxypropylcellulose were sieved with 24 mesh. And mixed. Thereafter, a wet granulated product was obtained using a high speed mixer, and after drying and sieving steps, light anhydrous silicic acid and magnesium stearate sieved with 24 mesh were mixed to obtain a sustained release portion. .
  • the sustained release part was tableted with a continuous tableting machine (Picola D-8, RIVA) to produce tablets.
  • Drug coating step Mosaprid, hydroxypropylmethylcellulose, propylene glycol 6000 and Eudrazi E100 are dissolved in a mixed solution of ethanol (fermented alcohol) and water (65:35, weight ratio) (immediate release part).
  • ethanol fermented alcohol
  • water 65:35, weight ratio
  • Example 12 Production of mosapride-containing tablet containing delayed release core layer
  • Mosaprid-containing tablets containing a delayed release core layer were prepared with the components and contents shown in Table 7 below.
  • ⁇ Step 1> Preparation of sustained-release partial core layer tablet hydroxypropylcellulose was dissolved in purified water to obtain a binding solution, and then mosapride citrate, lactose hydrate, microcrystalline cellulose and hydroxypropylcellulose were added thereto. Sieve through a mesh and mix. After that, a wet granulated product is obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and mixed with light anhydrous silicic acid and magnesium stearate sieved with 35 mesh.
  • MIC Developer-5 MIC Developer-5, COMASA
  • a sustained release part was obtained.
  • the sustained release part was tableted with a continuous tableting machine (Picola D-8, RIVA) to produce tablets.
  • the sustained-release partial tablet produced as described above was placed in a fan coating machine (LDCS, VECTOR) and then film-coated with Opadry.
  • LDCS fan coating machine
  • Step 2> Immediate release type partial outer layer tablet production Hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution, and then mosapride citrate, lactose hydrate and corn starch were sifted through 24 mesh and mixed. did.
  • a wet granulated product was obtained using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then passed through a 35 mesh sieve with low-substituted hydroxypropylcellulose, magnesium stearate and A mixture of light anhydrous silicic acid and the like was mixed to produce a mixture of immediate release parts.
  • MIC Developer-5 MIC Developer-5, COMASA
  • COMASA high speed mixer
  • MIC Developer-5 MIC Developer-5, COMASA
  • a mixture of light anhydrous silicic acid and the like was mixed to produce a mixture of immediate release parts.
  • ⁇ Step 3> Manufacture of core layer composite tablet
  • the granulated product of the sustained release part of the core tablet and the immediate release part obtained as described above was tableted using a single tableting machine (EKO, Korsch). Were produced.
  • the manufactured core tablet was put into a fan coating machine (LDCS, VECTOR), and film coating was performed with Opadry.
  • Example 13 Production of a mosapride-containing capsule comprising an immediate release part and a sustained release part mini-tablet ⁇ Step 1> Production of immediate-release partial mini-tablets Immediate-release partial mini-tablets were produced with the components and contents shown in Table 8 below. Hydroxypropyl cellulose is dissolved in purified water to obtain a binding solution, then mosapride citrate and microcrystalline cellulose are passed through 35 mesh and granulated with a high speed mixer (MIC Developer-5, COMASA). After the product was obtained and dried and sieved, light anhydrous silicic acid and magnesium stearate sieved with 35 mesh were mixed to obtain an immediate release part.
  • MIC Developer-5 MIC Developer-5, COMASA
  • the immediate release part was tableted with a single tableting machine (EKO, Korsch).
  • the manufactured mini-tablets were placed in a fan coating machine (LDCS, VECTOR) and then film-coated with Opadry.
  • the diameter of the mini-tablet is in the range of 2-4 mm.
  • Hydroxypropylcellulose was dissolved in purified water to obtain a binding solution, and then mosapride citrate, microcrystalline cellulose and hydroxypropylmethylcellulose (high substitution degree) were sieved with 35 mesh, and then a high speed mixer (MIC Developer-5, COMASA) was used to obtain a wet granulated product, and after drying and sieving steps, light anhydrous silicic acid and magnesium stearate sieved with 35 mesh were mixed to obtain a sustained release part. .
  • the sustained release part was tableted with a single tableting machine (EKO, Korsch). The diameter of the mini-tablet is in the range of 4-6 mm.
  • Step 2 After putting the sustained release partial mini-tablet into a fan coating machine (LDCS, VECTOR), mix ethylcellulose and hydroxypropylmethylcellulose with water and methanol. The film was coated with a coating solution obtained by dissolving in a solution (1: 41.5, weight ratio) to form a controlled release membrane layer. The coating conditions were: spray air 1.7 bar, outlet air temperature 24 ° C., inlet air temperature 34 ° C., flow 5-7, fan speed 10-15 rpm. The mini-tablet on which the release controlling layer was formed was film-coated with Opadry. The immediate release partial mini-tablets and the sustained-release partial mini-tablets were filled into hard capsules.
  • LDCS fan coating machine
  • VECTOR fan coating machine
  • Test Example 1 Dissolution Test Using the dissolution tester (Vankel VK 7025 Vk 8000, USA) on the mosapride-containing dosage forms produced in Examples 1 to 13 and Comparative Examples 1 and 2 under the following conditions: The dissolution test was conducted and the results are shown in FIGS.
  • immediate release and delayed release can be easily adjusted by adjusting the ratio of the drug in the immediate release part and the sustained release part. be able to.
  • Comparative Examples 1 and 2 as shown in FIG. 3 and FIG. 4, after the release of mosapride citrate was completed within 30 minutes by rapid disintegration of the immediate release layer, although the release of the sustained release portion occurred, unlike Examples 1 to 3, the elution rate for 30 minutes was very low at about 10% and very high at 50%. This is because in the case of Examples 1 to 3, the ratio of mosapride in the immediate release layer is about 20 to 40%, whereas Comparative Example 1 is about 10% and Comparative Example 2 is about 50%. I think that the. As is apparent from FIGS.
  • the release of the sustained-release portion shows various patterns depending on the type of the controlled-release polymer. In the case of manufacturing, it can be seen that a release phase having various elution patterns can be obtained.
  • the pellets produced by coating the controlled release polymer are delayed-released to provide immediate and delayed release through the capsule or bilayer tablet. Can be adjusted.
  • FIGS. 11 and 12 Example 11
  • Example 12 the immediate release part as the outer layer is immediately eluted, and the sustained release part as the inner layer is released slowly, thereby showing a two-phase elution profile.
  • FIGS. 15 and 16 Example 13
  • the immediate-release partial mini-tablet dissolves immediately and the release of the free-release partial mini-tablet occurs.
  • Test Example 2 Evaluation of changes in blood concentration in clinical trials of bilayer tablets by the content of mosapride in immediate-release part and sustained-release part
  • the bilayer tablets of Examples 1-3 were compared with the bilayer tablets of Comparative Examples 1-2.
  • 20 healthy male subjects were administered and the mosapride-containing bilayer tablets (containing 15 mg of mosapride) of Examples 1 to 3 and Comparative Examples 1 and 2 were administered, and the change in blood concentration was measured.
  • the bilayer tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were dosed at the same time as the start of the test, and 0, Blood was collected at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8, 10, 12, 14, 16 and 18 hours, using LC-MS Then, the concentration of mosapride in plasma was measured from a sample in which all blood was treated. The measurement results are shown in Table 9 below and FIGS. As shown in Table 9 above, in the bilayer tablets of Examples 1 to 3, in the case of AUC (area under the curve), no significant difference can be seen, and in the Cmax item, 3961 ng / mL, 51.
  • Comparative Example 1 28.16ng / mL
  • Comparative Example 2 was 81.25ng / mL, which C max of control drug Gasmotin Tablets 5mg currently marketed in (Co. Taewoong Pharmaceutical) Is 50 to 60 ng / mL
  • Comparative Example 1 is about 40% to 50% lower
  • Comparative Example 2 is about 30 to 60% higher.
  • the ratio of the immediate release part to the sustained release part is appropriately 20 to 40%: 60 to 80%.
  • Test Example 3 Evaluation of change in blood concentration in clinical test The absorption pattern of the mosapride-containing bilayer tablet produced in Example 2 was evaluated. Specifically, for 16 healthy men and women, the mosapride-containing bilayer tablet of Example 2 (containing 15 mg of mosapride) and a commercially available mosapride citrate rapid-release tablet (containing 5 mg of gasmotin tablet) as a control group; Taeung Pharmaceutical Co., Ltd.) was administered, and changes in blood concentration were measured. As a dosing method, one group in the first-stage dosing group administers the bilayer tablet of Example 2 at the start of the test, and two groups administer one gasmotin tablet at the start of the test, and the second dosing after 6 hours.
  • a dosing method one group in the first-stage dosing group administers the bilayer tablet of Example 2 at the start of the test, and two groups administer one gasmotin tablet at the start of the test, and the second dosing after 6 hours.
  • the third dose was administered again after 6 hours.
  • it was dosed in the same manner as the 1st-phase dosing method, except that the dosing samples of groups 1 and 2 were replaced for the 2nd-phase dosing group.
  • the dosing samples of groups 1 and 2 were replaced for the 2nd-phase dosing group.
  • plasma was obtained from samples that were fully processed using LC-MS.
  • the mosapride concentration was measured. The measurement results are shown in Table 10 below and FIG.

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Abstract

L'invention concerne Mosapride et une composition médicinale à libération lente comprenant un sel de Mosapride. Plus spécifiquement, la composition de cette invention, puisqu'elle possède un profil d'élution deux-phases spécifique (une phase de libération rapide et une phase de libération retardée), permet d'atteindre rapidement dans un premier temps un niveau sanguin efficace de Mosapride, et dans un deuxième temps de maintenir de façon durable ce niveau sanguin efficace. Elle permet non seulement d'augmenter l'efficacité médicinale de Mosapride même lors d'une unique dose journalière en une prise, mais également d'améliorer le degré d'adaptation à la prise de médicament.
PCT/JP2011/055772 2010-03-12 2011-03-11 Mosapride et composition médicinale à libération lente comprenant un sel de mosapride WO2011111818A1 (fr)

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WO2024063349A1 (fr) * 2022-09-21 2024-03-28 한국유나이티드제약 주식회사 Formulation de mosapride à libération prolongée

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KR101962654B1 (ko) * 2017-06-23 2019-03-27 한국유나이티드제약 주식회사 용출 특성을 조절한 모사프리드 함유 경구 투여 서방제제
KR102334701B1 (ko) * 2019-11-29 2021-12-06 한국유나이티드제약 주식회사 프로톤펌프억제제와 모사프리드를 함유하는 유핵정 제제
KR102334699B1 (ko) * 2019-12-10 2021-12-06 한국유나이티드제약 주식회사 프로톤펌프억제제 및 모사프리드를 포함하는 유핵정 제제

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JP2016053092A (ja) * 2012-02-22 2016-04-14 デュシネイ・インコーポレイテッド ドキシラミンおよびピリドキシン、ならびに／またはその代謝物もしくは塩の製剤
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TWI568455B (zh) * 2014-09-12 2017-02-01 韓國聯合製藥股份有限公司 每日一次投藥之提供藥學及臨床效果之莫沙必利持續釋放製劑
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JP2023510140A (ja) * 2019-12-19 2023-03-13 セルトリオン， インク． シベンゾリンまたはその塩を含む薬学剤形
WO2024063349A1 (fr) * 2022-09-21 2024-03-28 한국유나이티드제약 주식회사 Formulation de mosapride à libération prolongée

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