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WO2000043041A1 - Compositions medicamenteuses presentant une meilleure absorption orale - Google Patents

Compositions medicamenteuses presentant une meilleure absorption orale Download PDF

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Publication number
WO2000043041A1
WO2000043041A1 PCT/JP2000/000251 JP0000251W WO0043041A1 WO 2000043041 A1 WO2000043041 A1 WO 2000043041A1 JP 0000251 W JP0000251 W JP 0000251W WO 0043041 A1 WO0043041 A1 WO 0043041A1
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WO
WIPO (PCT)
Prior art keywords
amidino
phenyl
naphthyl
oxy
drug
Prior art date
Application number
PCT/JP2000/000251
Other languages
English (en)
Japanese (ja)
Inventor
Shunsuke Watanabe
Kazuhiro Sako
Shigeo Takemura
Hiromu Kondo
Toyohiro Sawada
Keiichi Yoshihara
Tatsunobu Yoshioka
Masataka Katsuma
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to JP2000594494A priority Critical patent/JP4599714B2/ja
Priority to AU30747/00A priority patent/AU3074700A/en
Publication of WO2000043041A1 publication Critical patent/WO2000043041A1/fr

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Classifications

    • 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
    • A61K9/1635—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • composition for improving oral absorption is provided.
  • the present invention relates to a pharmaceutical composition for improving the absorption of a drug from the gastrointestinal mucosa. Further, the present invention provides a method for improving the absorption of a drug from the gastrointestinal mucosa by using a substance having an inhibitory action on the formation of a poorly absorbable complex formed by the drug and bile acid or a dissociating action of the complex. It is about.
  • the present invention provides a spray-dried pharmaceutical composition containing aminoalkyl methacrylate copolymer E prepared by dissolving aminoalkyl methacrylate copolymer E and a surfactant in a solvent and then spray-drying the composition, and the composition. It relates to the manufacturing method. Background art
  • Oral administration and injection administration are widely used for drug administration, but oral administration is the most common because of the ease of taking by the patient himself.
  • oral administration is a convenient route of administration or an administration route that is excellent in safety, for drugs that are difficult to be absorbed through the gastrointestinal mucosa, even if they have excellent pharmacological effects, the development of oral preparations is necessary. Or abandon the development itself as a drug.
  • the absorption of the drug from the gastrointestinal mucosa is affected by the pH and the diet in the gastrointestinal tract of the patient, so that not only does the bioavailability of the drug vary, but its pharmacological effect cannot be expected. Things can happen.
  • drugs since many anionic substances are present in the gastrointestinal cavity and in the mucous layer, drugs, especially basic drugs, are difficult to pass through the mucus layer, and thus generally have poor absorption from the gastrointestinal mucosa. Inferior.
  • JP-A-9-129777 discloses a method using cyclodextrins.
  • International Publication No. WO98 / 0322 discloses a method using an anion exchange resin such as cholestyramine.
  • Japanese Patent Application Laid-Open No. H10-231254 discloses a method using a lipophilic substance such as a fatty acid glycerin ester.
  • an object of the present invention is to improve the absorption from the gastrointestinal mucosa to the extent that pharmacologically therapeutic effects can be expected for drugs that are hardly absorbed from the gastrointestinal mucosa by oral administration, especially basic drugs.
  • An object of the present invention is to provide a pharmaceutical composition and a method for improving absorption.
  • the technical level at the time of filing a patent application of the present invention is to improve the solubility of an invention based on a technical recognition that is completely contrary to the present invention, i.e., a compound that is hardly soluble and therefore hardly absorbed from the digestive tract. Therefore, a method of improving the solubility of a molecular compound in which a hardly soluble compound and bile acids are combined and a method of improving the solubility of the hardly soluble compound are known (see JP-A-8-48638).
  • aminoalkyl methacrylate copolymer E is used as a base for forming a film layer for masking bitterness or a film layer for controlling release, and then dissolving the polymer in a solvent such as ethanol to coat tablets. It is known that it is used in particular. After dissolving the polymer in a solvent such as ethanol, the powder obtained by the spray drying method is used as an excipient for improving the absorption of a drug from the gastrointestinal mucosa, for example, for a spray-dried pharmaceutical. Composition), a spray-dried pharmaceutical composition which is easy to handle in production such as improvement in water repellency, and a method for producing the composition have not been known so far. Disclosure of the invention
  • the present inventors conducted an in vivo test with a dog on a basic drug that was expected to have a certain degree of bioavailability according to the pH profile relating to solubility. I knew it was low. Thus, the present inventors have proposed that the intestinal mucosa absorb The purpose of improving the absorption through the gastrointestinal mucosa of such a drug, which is difficult to be absorbed, has been studied diligently. As a result, the cause of the poor absorption is that a basic drug and bile acid form a poorly absorbable complex.
  • the substance and a bile acid form a poorly absorbable complex, but a substance having an inhibitory effect on the formation of the poorly absorbable complex, for example, an aminoalkyl methacrylate copolymer
  • a substance having an inhibitory effect on the formation of the poorly absorbable complex for example, an aminoalkyl methacrylate copolymer
  • E or the like can improve the absorption of a drug from the gastrointestinal mucosa.
  • the substance having the formation inhibitory action also has an action of dissociating the once formed poorly-absorbable complex, thereby completing the present invention.
  • the orally absorbable pharmaceutical composition of the present invention is particularly preferable as a substance having an inhibitory effect on the formation of a poorly absorbable complex formed by a drug and bile acid or a dissociating effect on the complex.
  • aminoalkyl methacrylate copolymer E was prepared by the spray drying method, the spray-dried product consisting of the polymer had problems in handling such as water repellency during the study of scale-up from lab scale to plant scale. I knew that there was. Therefore, the present inventors have studied and found that the above problem can be solved by adding a surfactant such as polysorbate 80 to ethanol in which the polymer is dissolved and spray-drying it. Was completed.
  • the present invention relates to a pharmaceutical composition for improving oral absorption comprising a drug and a substance having an inhibitory action on the formation of a poorly absorbable complex formed by the drug and bile acid or a dissociation action of the complex.
  • the present invention also relates to a method for improving the absorption of a drug from the gastrointestinal mucosa by using a substance having an inhibitory action on the formation of a poorly absorbable complex formed by the drug and bile acid or a dissociation action of the complex. Things.
  • the present invention relates to a pharmaceutical composition for improving oral absorption comprising a drug and an aminoalkyl methacrylate copolymer E.
  • the present invention relates to a method for improving the absorption of a drug from the gastrointestinal mucosa by using an aminoalkyl meta-atalylate copolymer E.
  • the present invention relates to a spray-dried pharmaceutical composition containing aminoalkyl methacrylate copolymer E, obtained by dissolving or suspending aminoalkyl methacrylate copolymer E and a surfactant in a solvent, and spray-drying the solution. Things. Furthermore, the present invention discloses that aminoalkyl methacrylate copolymer E and a surfactant are dissolved in a solvent. After suspension or suspension, the solution is spray-dried from the solution.
  • the present invention relates to a method for producing a spray-dried pharmaceutical yarn-containing composition containing E-latelate copolymer.
  • a pharmaceutical composition for improving oral absorption a method for improving the absorption of a drug from the gastrointestinal mucosa, a pharmaceutical composition comprising aminoalkyl methatalylate copolymer E as a formulation component, and spray-drying the composition, and The method for producing the spray-dried pharmaceutical composition will be described in detail.
  • the drug used in the pharmaceutical composition for improving oral absorption is poor in absorbability from the gastrointestinal mucosa, and is poorly absorbed by the composition of the present invention, that is, the drug and bile acid are formed.
  • Composition for improving oral absorption comprising a substance having an inhibitory action on the formation of an acidic complex or dissociating action of the complex, or a medicament for improving oral absorption comprising a drug and aminoalkyl methacrylate copolymer
  • the drug is not particularly limited as long as it is a drug whose absorbability is improved by forming a composition for use, or a drug which can achieve another object of the present invention.
  • the drug used in the above-mentioned spray-dried pharmaceutical composition is prepared by spray-drying the aminoalkyl methacrylate copolymer E for various formulation purposes and blending it with the composition to be applied.
  • the drug is not particularly limited as long as it is a drug that can be applied to a composition that can improve the water repellency of the polymer by making it into a dry pharmaceutical composition and that can be easily formulated.
  • the drug used in the pharmaceutical composition for improving oral absorption or spray-dried pharmaceutical composition of the present invention includes, for example, extracts derived from animals and plants existing in nature (eg, extracts, tinctures, etc.), extracts and the like.
  • An isolated compound or a chemically synthesized compound is included in the present invention.
  • the drug may be a single component or a mixture of two or more.
  • the present invention includes salts of the compound, various pharmaceutically acceptable solvates of the compound (eg, water), and solvates of the salt of the compound. Also, these crystalline polymorphs are included.
  • any of these optical isomers, stereoisomers and a mixture of these isomers may be used in the present invention.
  • the salt of the compound is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include hydrochloride, hydrobromide, hydroiodide, and phosphoric acid.
  • Mineral salts such as salt, nitrate, sulfate, etc., organic sulfonic acid salts such as methanesulfonic acid salt, ethanesulfonic acid salt, 2-hydroxyethanesulfonic acid salt, p-toluenesulfonic acid salt, acetate, propionic acid
  • Organic carboxylates such as salts, oxalates, malonates, succinates, glutarates, adipates, tartrates, maleates, malates, mandelates and the like can be mentioned.
  • Examples of the drug used in the pharmaceutical composition for improving oral absorption of the present invention include a sedative-hypnotic, a sleep-inducing agent, an anxiolytic, an antiepileptic agent, an antidepressant, an antiparkinson agent, a psychotropic agent, and a central nervous system.
  • Systemic drugs local anesthetics, skeletal muscle relaxants, autonomic nervous drugs, antipyretic analgesics and anti-inflammatory drugs, anticonvulsants, antihypertensives, inotropics, arrhythmias, diuretics, antihypertensives, vasoconstrictors, vasodilators, Cardiovascular drugs, hyperlipidemia drugs, respiratory stimulants, antitussives, expectorants, antiseptics, bronchodilators, arrest agents, intestinal preparations, peptic ulcer agents, stomachic digesters, Antacids, laxatives, bile drugs, gastrointestinal drugs, adrenal hormones, hormonal drugs, urinary drugs, vitamins, hemostats, liver diseases, gout treatments, diabetes, antihistamines, antibiotics , Antibacterial, anti-neoplastic, chemotherapy Drugs, general cold remedies, nourishing tonics, osteoporosis drugs, etc.
  • the drug used in the aminoacryl methacrylate copolymer E-containing spray-dried pharmaceutical composition of the present invention all medicaments that can be prepared by spray-drying in combination with aminoacryl methacrylate copolymer E, for example, Specific indications below the hypnotic sedative as described above are mentioned, and particularly preferred drugs are basic drugs as described above.
  • more preferred basic drugs include amino groups, amidino groups and other basic groups. There may be mentioned those having one or two or more in the chemical structure, but the position of the basic group in the chemical structure is not particularly limited.
  • Particularly preferred basic drugs in the oral absorption-improving pharmaceutical composition or the aminoacrylmethalarylate copolymer E-containing spray-dried pharmaceutical composition of the present invention include (1) JP-A-5-208946, And (2) International publications WO 96 Z1 6940, (3) 99Z051 24, (4) 991 1617, and (5) Activation described in each pamphlet of 99,37643 Examples thereof include aromatic amidine derivatives of the following general formulas which have platelet aggregation inhibitory activity based on factor X inhibitory activity and are useful as antithrombotic agents and the like.
  • R 1 represents a hydrogen atom or a lower alkoxy group
  • R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group
  • 3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group
  • R 4 represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group.
  • n represents a number from 0 to 4
  • A represents an alkylene having 1 to 2 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl groups.
  • X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group
  • Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or a cyclic carbon group which may have a substituent.
  • R 1 is a hydrogen atom or a group represented by the formula—A—W—R 4
  • A a group represented by the formula -C-, a group represented by the formula -C-C- or a group represented by the formula
  • W a single bond or a group represented by the formula — NR 5 —
  • R 4 a hydroxyl group, a lower alkoxy group, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group,
  • R 4 may further be a hydrogen atom, but is not a hydroxyl group or a lower alkoxy group.
  • R 5 hydrogen atom, carbamoyl group, lower alkoxycarbonyl group, mono- or di-lower alkylaminocarbonyl group, lower alkylsulfonyl group, mono- or di-lower alkylaminothiocarbonyl group, substituted Lower alkyl group which may be substituted or lower alkyl group which may be substituted
  • R 2 lower alkyl group
  • R 3 hydrogen atom, halogen atom, carboxyl group, amino group, cyano group, nitro group, hydroxyl group, lower alkoxy group, lower alkyl group or lower alkoxycarbonyl group
  • B lower alkylene group or carbonyl group
  • n an amidinonaphthyl derivative represented by 0 or 1) or a pharmaceutically acceptable ⁇ ⁇ thereof.
  • A a phenylene or pyridylene group (which may have a substituent);
  • B a 5- or 6-membered aryl or heteroaryl;
  • X — CO—, CONH—, —CSNH—, one S ⁇ 2 —, — S ⁇ 2 NH—, or a group represented by the formula —S0 2 N (one lower alkyl) —
  • R 2 hydrogen atom, 1-lower alkyl, —C ⁇ OH, 1 COO—lower alkyl, 1 CONH 2 , 1 CONH—lower alkyl, 1 CON—di-lower alkyl group, or aryl or heteroaryl Groups (these may have substituents),
  • R 3 an amidino group or a group which can be converted into an amidino group in a living body
  • R 4 and R 5 the same or different, a hydrogen atom or a lower alkyl group
  • R 6 and R 7 the same or different, a hydrogen atom or a lower alkyl group
  • L a bond or a lower alkylene group
  • R is a lower alkyl group, wherein the lower alkyl group is a halogen atom, COOH,
  • - COO- lower alkyl One NH 2, - CN, - N0 2, one OH, -O- lower alkyl, - CONH 2, -CONH- (lower alkyl), -CON- (lower alkyl) 2, -CONH -(S ⁇ 2 -lower alkyl), and optionally substituted aryl, optionally substituted with one or the same or different two substituents,
  • R 2 a hydrogen atom or a group represented by the formula z, lower alkyl
  • R 3 hydrogen atom, halogen atom, one COOH, one COO—lower alkyl, NH,
  • n a naphthamide derivative represented by 0 or 1) or a salt thereof.
  • R 3 hydrogen Atom or group represented by the formula
  • X a bond, a group represented by the formula —CO—, one CO—O— or —so 2 —
  • R 2 , R 4 the same or different, a hydrogen atom or lower alkyl, or together form —CH CHCH—,
  • R 5 hydrogen atom or lower alkyl
  • R 6 hydrogen atom or lower alkyl optionally substituted with carboxyl or lower alkyl_0—CO—
  • R 7 A benzene-condensed heterocyclic derivative represented by a hydrogen atom, carboxyl or lower alkyl—O—CO— or a salt thereof.
  • the aromatic amidine derivatives represented by the above general formulas and the like, salts of these derivatives, solvates of these derivatives, and solvates of the salts of the derivatives are included in the definitions.
  • specific groups to be used include those described in the gazette or the pamphlet which discloses them.
  • aromatic amidine derivative used in the present invention specifically, 2- [4-[(1-acetimidoyl-1-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) Propionic acid, (+) — 2— [4 — [((3S) 1-1-acetimidoyl—3-pyrrolidinyl) oxy] phenyl] —3- (7-Amidinol 2-naphthyl) propionic acid, (2 S ) —2— [4— [((3S) 1-111acetimidoyl-1-3-pyrrolidinyl) oxy] phenyl] —3— (7-amidino-2-naphthyl) propionic acid, (2R) —2— [4 — [((3 R) — 1 asset Imidoyl-3-pyrrolidinyl) oxy] phenyl] -3
  • Salts of these derivatives such as the aromatic amidine derivatives represented by the above general formulas of the present invention, solvates of these derivatives, and solvates of the salts of the derivatives include asymmetric carbon atoms.
  • optical isomers or stereoisomers based on asymmetric carbon atoms exist, and these optical isomers, stereoisomers, and mixtures thereof are all included in the present invention. included.
  • the drug used in the pharmaceutical composition for improving oral absorption or the spray-dried pharmaceutical composition containing aminoalkyl methacrylate copolymer E of the present invention can also include peptides, proteins and derivatives thereof.
  • the peptides and proteins include not only those of natural origin but also pharmacologically active derivatives and analogs thereof.
  • the calcitonin of the present invention includes not only naturally-occurring products such as salmon calcitonin, human calcitonin, porcine calcitonin, penis calcitonin, and nitricalcitonin, but also analogs such as genetically modified forms thereof.
  • the body is also included.
  • Insulin includes not only human insulin, porcine insulin, and insulin but also analogs thereof such as recombinants thereof.
  • the drug of the present invention can be obtained by using a formulation technique that allows the drug to be delivered without degradation to the lower gastrointestinal tract, such as the jejunum, ileum, colon, and large intestine, where the effect of digestive enzymes is small.
  • Composition can be applied.
  • the formulation techniques include sustained-release preparations (see, for example, WO94 / 06414 pamphlet) and colon release preparations (for example, WO95 / 28963). Pamphlet), time-release or pulse-release preparations (see, for example, International Publication WO93 / 05771 pamphlet).
  • the drug of the present invention includes not only a spray-dried pharmaceutical composition containing aminoalkyl methacrylate copolymer E, but also a pharmaceutical composition for improving oral absorption, which is hardly absorbed from the gastrointestinal mucosa.
  • the present invention can be applied to a drug that exerts a clinical pharmacological effect by administering a large amount by the oral route. included. In this case, a clinically expected pharmacological effect can be achieved with a smaller dose, and the occurrence of side effects due to the administration of a large amount can be expected.
  • the compounding amount of the drug of the present invention is not particularly limited as long as it is a therapeutically effective amount.
  • a substance having an inhibitory action on the formation of a poorly absorbable complex formed by the drug of the present invention and bile acid or a dissociation action of the complex (hereinafter may be simply abbreviated as a complex formation inhibitory substance) is usually used. Limited as long as it is pharmaceutically acceptable and has the effect.
  • the complex formation inhibitors such as sodium bicarbonate (N a HC0 3), carbonate Natoriumu (Na 2 C_ ⁇ 3), chloride Natoriumu (N a C 1), sodium sulfate (Na 2 S ⁇ 4), sodium phosphate (Na 3 P0 4), 1 disodium hydrogen phosphate (N a 2 HP0 4), sodium hydroxide (N a OH), benzoic acid sodium ⁇ arm (C 6 H 5 - COONa)
  • Inorganic or organic sodium salts such as sodium citrate, sodium acetate (CH 3 CO ON a); organic or inorganic potassium salts such as potassium chloride (KC 1), potassium carbonate (K 2 C ⁇ 3 ); or and lithium salts such as lithium chloride (L i C 1), 1 monovalent organic or inorganic salt comprising a metal ion, nitrate Anmoniumu (NH 4 N0 3), arginine or a salt thereof (e.g., hydrochloric acid arginine
  • aminoalkyl methacrylate copolymer E polysorbate 80, sodium hydroxide, sodium phosphate, disodium monohydrogen phosphate, sodium carbonate, potassium carbonate, sodium chloride, sodium benzoate, lithium chloride, ammonium nitrate, salt And sodium bicarbonate, sodium citrate, sodium acetate, and sodium sulfate.
  • aminoalkyl methacrylate copolymer E, polysorbate 80 sodium hydroxide, sodium phosphate, sodium hydrogen phosphate monobasic, sodium carbonate, sodium carbonate carbonate, sodium chloride, sodium benzoate, sodium chloride, sodium chloride And ammonium nitrate, and more preferably aminoalkyl methacrylate copolymer E, polysorbate 80, and sodium chloride.
  • These complex formation inhibitors can be used alone or in combination of two or more.
  • the pharmaceutical composition of the present invention has an inhibitory action on the formation of a poorly-absorbable complex between the drug and bile acid, and once It also has a function of dissociating the formed poorly absorbable complex, and can provide a method for improving the absorption of a drug from the gastrointestinal mucosa.
  • the “poorly absorbable complex” of the present invention refers to the gastrointestinal mucosa because it forms an insoluble complex. Means those that are difficult to be absorbed from the body, or those that form micelles and apparently dissolve, but are less likely to be absorbed from the gastrointestinal mucosa.
  • the aminoalkyl methacrylate copolymer E of the present invention is a copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate.
  • the state when the aminoacryl methacrylate copolymer E used as the complex formation inhibitor of the present invention is incorporated into the pharmaceutical composition is not particularly limited.
  • examples thereof include a solid such as a powder, and a liquid such as an aqueous solution in which the polymer is dissolved in water.
  • the powder can be prepared by a method known per se, and examples thereof include a pulverization method and a spray drying method.
  • an inorganic acid such as hydrochloric acid, an organic acid such as citric acid, or an acidic additive such as L-glutamic acid hydrochloride can be added.
  • the aminoacryl methacrylate copolymer E-containing spray-dried pharmaceutical composition of the present invention is obtained by dissolving or suspending the aminoacryl methacrylate copolymer E and a surfactant in a solvent and spray-drying the solution.
  • a pharmaceutical composition comprising:
  • the surfactant is not particularly limited as long as it is generally pharmaceutically acceptable and can improve the water repellency of the polymer.
  • Such surfactants include, for example, nonionic surfactants (eg, polyoxyethylene surfactants (eg, polysorbate 80, polyoxyl stearate 40, lauromacrogol, polyoxyethylene hydrogenated castor) Oils (HCO-60), sucrose fatty acid esters, etc.), ionic surfactants (eg, sodium lauryl sulfate, etc.), cationic surfactants (eg, benzalkonium chloride, etc.), Amphoteric surfactants (such as lecithin), etc. These can be used alone or in combination of two or more. The amount of the surfactant used is usually determined based on the water repellency of the polymer.
  • nonionic surfactants eg, polyoxyethylene surfactants (eg, polysorbate 80, polyoxyl stearate 40, lauromacrogol, polyoxyethylene hydrogenated castor) Oils (HCO-60), sucrose fatty acid esters, etc.
  • ionic surfactants eg,
  • the amount is not particularly limited as long as it can be improved, but is preferably 1 to 150% (weight) with respect to the polymer.
  • the solvent for dissolving or suspending the acrylic methacrylate copolymer E and the surfactant is not particularly limited as long as it is generally a pharmaceutically acceptable solvent. Examples thereof include water and organic solvents (eg, methanol). , Ethanol, isopropanol, acetone, etc.), and a mixture of water and an organic solvent.
  • the dry pharmaceutical composition can also contain various excipients and other additives usually used as pharmaceutical additives.
  • hydrochloric acid may be appropriately added as a solubilizing aid for the polymer, and sodium hydroxide, which itself acts as a complex formation inhibitor, adjusts the pH. Can also be added for the purpose.
  • sodium hydroxide which itself acts as a complex formation inhibitor, adjusts the pH.
  • hydrochloric acid and sodium hydroxide sodium chloride having a complex formation-inhibiting action is produced by salting, so that the desired effects of the present invention can be further enjoyed.
  • any concentration may be used, and the amount thereof may be an amount enough to neutralize a part or all of the basic groups of the polymer.
  • the excessively added hydrochloric acid can be neutralized using sodium hydroxide or the like.
  • sodium hydroxide used herein any concentration may be used, and the amount thereof may be such that the polymer does not precipitate.
  • the aminoacryl methacrylate copolymer E is prepared by adding a surfactant, After dissolving or suspending in a solvent such as water, an organic solvent, or a mixture of water and an organic solvent together with an additive, a step of spraying and drying the solution is employed.
  • a surfactant such as water, an organic solvent, or a mixture of water and an organic solvent together with an additive.
  • the organic solvent used at this time is not particularly limited as long as it is generally pharmaceutically acceptable, and examples thereof include methanol, ethanol, isopropanol and acetone.
  • the amount of the organic solvent used here is not particularly limited as long as it can dissolve or suspend the aminoacryl methacrylate copolymer E and the surfactant.
  • the amount is 0.1 to 99.9 parts by weight, preferably 1 to 99 parts by weight, more preferably 2 to 69 parts by weight, per part by weight of the activator.
  • the mixing ratio is not particularly limited as long as it is a pharmaceutically acceptable ratio, but is usually 1:99 to 999: 1, preferably 1: 1. From 1:99 to 99: 1.
  • the amount of the mixed solution is usually 0.1 to 99.9 parts by weight, preferably 1 to 9 parts by weight, based on 1 part by weight of the aminoacryl methacrylate copolymer E and the surfactant, similarly to the amount of the organic solvent.
  • the amount is 9 parts by weight, and more preferably 2 to 69 parts by weight.
  • amino acrylic meta As a device for spraying the solution containing the acrylate copolymer E, a device usually used in a formulation process can be used.
  • a spray dryer manufactured by Okawara Seisakusho Co., Ltd., manufactured by Yamato Co., Ltd.
  • the compounding amount of the complex formation inhibitor in the present invention is not particularly limited, and is usually appropriately adjusted in relation to the compounding amount of the drug.
  • the compounding amount is not particularly limited as long as it is within a certain range of use as a pharmaceutical additive, but is usually 0.1 part by weight or more per 1 part by weight of the drug. Further, the compounding amount is usually adjusted within a range that can be taken as an oral preparation, preferably 1 to 50 parts by weight per 1 part by weight of the drug, and more preferably 2 parts by weight per 1 part by weight of the drug. Parts to 30 parts by weight. The higher the compounding amount of the complex formation inhibitor, the higher the absorption improvement effect is expected.
  • the amount of the aminoacryl methacrylate copolymer E which is particularly preferred in the present invention, is also appropriately adjusted in general in relation to the amount of the drug, as described above. 1 part by weight or more, preferably 1 part by weight to 30 parts by weight with respect to 1 part by weight of the drug, and more preferably 3 parts by weight to 10 parts by weight with respect to 1 part by weight of the drug.
  • a surfactant may be added to the oral absorption-improving pharmaceutical composition or the aminoalkyl methacrylate copolymer E-containing spray-dried pharmaceutical composition of the present invention for the purpose of further enhancing absorption.
  • surfactants include nonionic surfactants (eg, polyoxyethylene surfactants (eg, polysorbate 80, polyoxyl stearate 40, lauromacrogol, polyoxyethylene hydrogenated castor oil (HCO — 60), sucrose fatty acid esters, etc.), ionic surfactants (anionic surfactants (eg, sodium lauryl sulfate, etc.)), cationic surfactants (eg, salt, etc.) ), Amphoteric surfactants (such as lecithin)), etc. These surfactants may be used alone or as a mixture of two or more.
  • the form of the preparation that the oral absorption-improving pharmaceutical composition or the aminoalkyl methacrylate copolymer E-containing spray-dried pharmaceutical composition of the present invention can take is not particularly limited. Examples thereof include powders, tablets, and capsules. Orally administrable dosage forms such as drugs, solutions, suspensions and emulsions. Preparations prepared from the pharmaceutical composition of the present invention
  • the granulated product obtained by granulating the pharmaceutical composition of the present invention is preferably an enteric substance (eg, methatalylic acid) so that the complex formation inhibitor of the present invention is present near the drug.
  • the polymer dissolves at a low pH, that is, dissolves in the stomach, so that the polymer does not dissolve in the stomach.
  • an enteric substance In the case of formulation, it can be produced by a method known per se.
  • pharmaceutical additives such as excipients, disintegrants, binders, lubricants, fluidizers, dispersants, suspending agents, emulsifiers, preservatives, and stabilizers are added to the pharmaceutical composition of the present invention. Things can be added as appropriate.
  • the pharmaceutical composition for oral absorption improvement or the spray-dried pharmaceutical composition containing aminoacryl methatalyle copolymer E of the present invention may be, for example, a sustained-release preparation (for example, International Publication W09464041). No. 4 pamphlet), colon release preparation (for example, International Publication W095 X 28 963 pamphlet), time release type or pulse release type preparation (for example, International Publication WO 93/057771) No. pamphlet), fine-particle preparations (see, for example, Japanese Patent Application Laid-Open No. 10-511970), mucoadhesive preparations (for example, see Japanese Patent Application Laid-Open No. 5-132416) And the like.
  • the oral absorption-improving pharmaceutical composition or the aminoacryl methacrylate copolymer E-containing spray-dried pharmaceutical composition of the present invention can be generally applied to various preparations such as the above-mentioned preparations. It is a formulation with little chance of forming a poorly absorbable complex.
  • Such pharmaceutical preparations include, for example, a colon release preparation described in International Publication WO95 / 28963, that is, the oral absorption-improving pharmaceutical composition of the present invention.
  • the mixture of the granulated product obtained by granulating the spray-dried pharmaceutical composition containing the noacryl methatalylate copolymer E and a saccharide that is decomposed by intestinal bacteria to generate an organic acid (for example, ratatulose) is mixed with an organic compound.
  • Can be The sugars that are degraded by intestinal bacteria used to generate organic acids at this time include lactulose, raffinose, cellobiose, stachyose, fructooligosaccharides (eg, lactose fructose (eg, lactose oligo LS-55p, Hayashibara), Examples thereof include sucrose, gnorecose, xylose, fnorectose, manoletose, galactose, etc. These can be used alone or in appropriate combination of two or more kinds. The amount is not particularly limited as long as it is used as a form, but is usually 1% to 99.9%, preferably 5% to 99.9%, and more preferably 10% to 99.9%.
  • the polymer substance soluble in the organic acid used at this time is not particularly limited as long as it is generally pharmaceutically acceptable.
  • it is preferably a polymer substance that dissolves below pH 6. More preferably, it is a polymer substance that dissolves below pH 5.5.
  • a polymer substance for example, dimethylamino methacrylate Ethyl / methyl methacrylate / butyl methacrylate copolymer (trade name: Eudragit® E, RShm GmbH), polybutylacetal getylaminoacetate (trade names: AEA® Sankyo, Sankyo), chitosan, etc.
  • the coating film made of a powerful polymer substance may contain a water-permeable release controlling substance, if necessary.
  • the release controlling substance is not particularly limited as long as it is generally a pharmaceutically acceptable substance.
  • ethyl acrylate and methacrylic acid are used.
  • ethylcellulose trade name: Ethocel, Da Chemicals
  • hydroxypropyl methylcellulose trade name
  • Product Name: TC-5 Shin-Etsu Chemical, Hydroxypropyl Cellulose (Product Name: HPC, Japan Soda), Polyet Lenoxide, polyvinylpyrrolidone and the like.
  • a plasticizer can be contained as required.
  • the plasticizer is not particularly limited as long as it is generally a pharmaceutically acceptable substance, and examples thereof include triacetin, macrogol 400, triethyl tenoate, polysorbate 80, and castor oil.
  • a release controlling substance may be coated between a coating layer made of a polymer substance dissolved by an organic acid and a coating layer made of an enteric polymer substance.
  • the coating amount of the polymer substance dissolved by the organic acid is not particularly limited as long as it is generally used as the coating amount of the polymer substance for preparation, and is usually 1% to 50%, preferably It is 2.5% to 40%.
  • the enteric polymer used at this time is not particularly limited as long as it is generally pharmaceutically acceptable, but is preferably a polymer soluble at pH 6 or more.
  • a polymer substance include a 1: 1 copolymer of methyl methacrylate and methacrylic acid (trade name: Eudragit® L, Rmim GmbH), and a 2: 1 copolymer of methyl methacrylate and methacrylic acid (trade name: Eudragit ® S, Rohm GmbH), 1: 1 copolymer of ethyl methacrylate and methacrylic acid (trade name: Eudragit ® LD-55, Rohm GmbH ⁇ ), hydroxypropyl methylcellulose phthalate, Doxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, shellac and the like.
  • the coating amount of the enteric substance is not particularly limited as long as it is generally used as the coating amount of the polymer substance for preparation, but is usually 1% to 60%, preferably 3% to 4%. 0%.
  • FIG. 1 shows the solubility phase diagram of Compound A (see below) with bile.
  • the compound A described in the Examples was prepared by N- [4-[(1-acetimidoyl-4-piperidyl) oxy] produced by the method described in International Publication WO 96/16940. ] Phenyl] — N— [(7-Amidino-2-naphthyl) methyl] sulfamoylacetic acid monomethanesulfonate, which inhibits activated blood coagulation factor X, and acts as a blood coagulation inhibitor or thrombosis prevention / treatment agent It is useful.
  • a 9 mg / m 1 aqueous solution (hereinafter abbreviated as A solution) was obtained.
  • Table 1 shows the results of sodium lauryl sulfate
  • Table 2 shows the results of bile powder.
  • Example 1 10 g of Eudragit® E100 (Rohm GmbH) was dissolved in 19 g of methanol, and 100 g of 1N hydrochloric acid and 50 g of 1N aqueous sodium hydroxide solution were added. Spray dried. Compound A (0.5 mg) and the spray-dried product (1.5 mg) were combined, dissolved in 0.5 ml of purified water, and given to a Wistar male rat (8 weeks old) under anesthesia using an oral sonde to give 2.5 mg of Compound A. A solution equivalent to mgZkg was orally administered. After administration, the mice were anesthetized with ether at 0.5 and 1 hour, blood was collected from the jugular vein, and the plasma unchanged substance concentration (/ igZml) was measured by high performance liquid chromatography.
  • Comparative Example 1 0.5 mg of Compound A was dissolved in 0.5 ml of purified water. Oral administration to rats was performed in the same manner as in Example 1, and the unchanged plasma concentration (// g / ml) was measured. Table 3 shows the concentrations of the unchanged compound in plasma determined in Comparative Example 1 and Example 1.
  • Example 2 Aqueous solution containing compound A and various ratios of Eudragit® E was orally and colonically administered to rats (2.5 mg Zkg as compound A), and the blood concentration 30 minutes later was measured. was compared with a control example to which an aqueous solution containing was administered. Table 4 shows the percentage (the improvement in absorption (%)) of the concentration of the unchanged compound in the plasma of each Example relative to the concentration of the unchanged compound in the plasma of the control example.
  • Example 2 30 g of the spray-dried product obtained in Example 1 was mixed with 10 g of Compound A to obtain a powder.
  • Example 3 10 g of Eudragit® E100 (Rohm GmbH) was dissolved in 190 g of methanol. Separately, after dissolving 2 g of Compound A in 100 g of 1 N hydrochloric acid, 50 g of a 1 N aqueous sodium hydroxide solution was added. After mixing the two solutions, a further 2 g of Tween80 was added and spray dried to obtain a powder.
  • Example 4 100 mg of sodium chloride was added to 55 mg of the powder obtained in Example 3 []. After mixing in a mortar, tableting pressure of 250 kg with an oil press and punching with a Z punch The tablets were obtained to obtain tablets having a diameter of 7 mm.
  • Example 5 Eudragit® E100500g and Tween80500g were dissolved in ethanol30000g. 1250 g of 1N hydrochloric acid was added to the ethanol solution, and spray-dried to obtain a powder. The powder did not agglomerate after storage.
  • Example 6 Lactose (200 mg) was added to powder (128 mg) obtained in Example 5, mixed in a mortar, and then compressed with an oil press at a compression pressure of 250 kg. A tablet having a diameter of 9 mm was obtained.
  • Example 7 Compound A 10 mg was added to powder 128 obtained in Example 5 After adding 20 Omg of loin and mixing, the mixture was tableted with an oil press at a tableting pressure of 250 kgZ punch to obtain a tablet having a diameter of 9 mm. The tablet was coated with an aqueous solution of Eudragit® EZ hydroxypropylcellulose (4: 1) in ethanol (64:26 (parts by weight)), and the weight increased by 26 mg. Coating with an aqueous solution of hydroxypropyl cellulose resulted in an increase of 6. Omg in weight. The tablets were coated with a solution of Viodragit® LZ talc / triethyl atenate (6: 3: 1) in ethanol / water (17: 1 (parts by weight)), and the weight was increased by 26 mg.
  • Example 8 500 g of Eudragit® E and 5 Og of Tween 805 were dissolved in 3000 g of ethanol. 625 g of 1 N hydrochloric acid and 312.5 g of 1 N sodium hydroxide were added to the ethanol solution, and spray-dried to obtain a powder.
  • Example 9 Compound A 1 Omg and lactulose 20 Omg were added to 124 mg of the powder obtained in Example 8 and mixed, and the mixture was compressed with an oil press at a compression pressure of 250 kg to form a tablet having a diameter of 9 mm. Tablets were obtained.
  • the tablets were coated with an aqueous solution of Eudragit® EZ hydroxypropylcellulose (24: 1) in ethanol (64:26 (parts by weight)), and the weight increased by 32 mg. When an aqueous solution of hydroxypropylcellulose was coated thereon, the weight increased by 11. Omg.
  • the tablets were coated with an ethanolic aqueous solution (17: 1 (parts by weight)) of Eudragit® LZ talc quernate (6: 3: 1), and the weight increased by 26 mg.
  • Example 3 phosphate buffer compound Al Omg (and pH3.3 with 50mMKH 2 PO 4 and 5 OmMH 3 P0 4) (comparison).
  • blood was collected from the forearm arm vein, and the plasma unchanged substance concentration was measured by high performance liquid mouth chromatography. From the obtained changes in plasma concentration, the area under the plasma concentration curve (AUC) and the maximum plasma concentration (Cmax) were calculated.
  • Table 6 shows the formulation and properties of the resulting spray-dried powder.
  • Example 10 Compound A 1 Omg was mixed with sodium benzoate in a 19-fold amount by weight, and the mixture was filled in a hydroxypropylmethylcellulose capsule (No. 2) and fasted for about 20 hours. Male beadal dog with 1 force psuel with 30 m1 of water Oral administration. Blood was collected from the forelimb arm vein at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 hours after administration, and the unchanged unchanged plasma concentration was measured by high performance liquid chromatography. . AUC and Cmax were calculated from the obtained changes in plasma concentration. The results are shown in Table 7 below.
  • Example 11 10 mg of compound A was dissolved in 10 ml of an isotonic phosphate buffer (0.123 M sodium phosphate monobasic and 0.163 M sodium phosphate monobasic; pH 6.5). did.
  • Blood was collected from the forearm vein at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, and 8 hours after administration, and the unchanged substance concentration in plasma was measured by high performance liquid chromatography. AUC and Cmax were calculated from the obtained changes in plasma concentration. The results are shown in Table 7 below.
  • Example 12 A 50-fold amount of sodium benzoate in a weight ratio of 50 mg was added to 1 mg of compound A, and 10 ml of an isotonic phosphate buffer solution (0.123 M disodium hydrogen phosphate and 0.163 M) was added. It was dissolved in sodium hydrogen phosphate monobasic; pH 6.5) and orally administered to male beagle dogs in the same manner as in Example 11. The unchanged substance concentration in the plasma was measured, and the values of 11 and 111 were calculated. The results are shown in Table 7 below.
  • Table 7 shows AUC and Cmax obtained in Comparative Example 2, Example 10, Example 11, and Example 12 described above. As is clear from the table, It was found that the pharmaceutical composition of the present invention exhibited excellent absorption compared to Compound A alone by the addition of the coalescence inhibitor. It was also suggested that excellent absorption was exhibited depending on the type of the complex formation inhibitor and Z or the amount added.
  • Example 14 2.5% by weight of Gersia®44 / 14 was mixed with 1 Omg of compound A and dissolved in 10 ml of purified water. Wistar males were prepared in the same manner as in Comparative Example 3. The rats were orally administered. At 0.5 and 1 hour after administration, blood was collected from the jugular vein, and the concentration of the unchanged substance in plasma was measured by high performance liquid mouth chromatography.
  • Example 15 A 20 mg amount of arginine hydrochloride was added to 1 mg of compound A in a weight ratio, dissolved in 10 ml of purified water, and applied to Wistar male rats in the same manner as in Comparative Example 3. Oral administration. At 0.5 and 1 hour after administration, blood was collected from the jugular vein, and the concentration of unchanged substance in plasma was measured by high performance liquid mouth chromatography.
  • Example 16 Compound A 1 Omg was mixed with a 20-fold amount by weight of salted chickpeas, dissolved in 10 ml of purified water, and applied to Wistar male rats in the same manner as in Comparative Example 3. Oral administration. At 0.5 and 1 hour after administration, blood was collected from the jugular vein, and the concentration of unchanged substance in plasma was measured by high performance liquid mouth chromatography.
  • Example 17 1 Omg of Compound A was mixed with 3 times the amount of sodium carbonate and 17 times the amount of sodium hydrogencarbonate in a weight ratio, and dissolved in 10 ml of purified water. was orally administered to Wistar male rats by the method described above. At 0.5 and 1 hour after administration, blood was collected from the jugular vein, and the unchanged substance concentration in plasma was measured by high performance liquid mouth chromatography. (Results and Discussion) Table 8 shows the plasma unchanged compound concentrations determined in Comparative Example 3 and Examples 13 to 17 described above. As is clear from the table, it was found that the pharmaceutical composition of the present invention exhibited excellent absorption compared to Compound A alone by the addition of the complex formation inhibitor.
  • FIG. 1 shows a solubility phase diagram relating to the interaction between compound A and bile acids.
  • the phase diagram is composed of a curved portion forming an insoluble complex and a linear portion indicating bile solubilization.
  • Bile derived from living organisms is a mixture of various components, so detailed analysis is difficult.Power Bile soluble complex is formed in a bile concentration-dependent manner, and compound A is dissolved in a region with a low bile concentration The decrease in degree suggested that Compound A and bile form a complex of about 1 : 1 by weight ratio, and then form a soluble complex with 6 times the amount of bile.
  • an insoluble complex and a soluble complex of compound A and bile acid were prepared, and these were orally administered to rats under fasted conditions to evaluate the absorbability of the complex from the gastrointestinal mucosa.
  • the AUC of the complex was about 20% as compared with the administration of the aqueous solution, so that even the soluble complex, the insoluble complex, and the misaligned complex were complexed with bile acid. It was clear that any substance that forms the body is unlikely to be absorbed from the gastrointestinal mucosa.
  • a drug capable of forming a complex with bile acid that is, a drug that forms an insoluble complex at a molar ratio of 1: 1 or more to the drug and bile acid, or the insoluble complex is found.
  • Those that form a supersoluble complex proved to be poorly absorbed by the gastrointestinal mucosa.
  • the pharmaceutical composition of the present invention is capable of improving absorption from the gastrointestinal mucosa to a drug by forming a poorly-absorbable complex with bile acid, making it difficult to be absorbed from the gastrointestinal mucosa. it can.
  • improving the oral absorption can reduce the dosage and suppress the occurrence of side effects.
  • the expected pharmacological effects can be exhibited.
  • the polymer and the surfactant are dissolved in a solvent, and then prepared by a spray drying method, so that they can be handled in production.
  • An easy spray-dried pharmaceutical composition and a method for producing the same can be provided.

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Abstract

La présente invention concerne des compositions médicamenteuses mieux absorbées par les muqueuses digestives, où un médicament (en particulier, un médicament basique). difficilement absorbable par les muqueuses digestives lorsqu'il est administré oralement, est mélangé à une substance ayant soit une action inhibitrice sur la formation d'un complexe difficilement absorbable formé par le médicament et l'acide biliaire, soit une action de dissociation sur ce complexe. Par ailleurs, cette invention concerne une méthode d'amélioration de l'absorption médicamenteuse par voie digestive. En outre, l'invention concerne des compositions médicamenteuses atomisées contenant un copolymère de méthacrylate aminoalkyle E, préparées de façon appropriée, en dissolvant d'abord le polymère précité avec un tensioactif dans un solvant, et en les atomisant ensuite. Enfin, cette invention concerne un processus de production de ces compositions.
PCT/JP2000/000251 1999-01-22 2000-01-20 Compositions medicamenteuses presentant une meilleure absorption orale WO2000043041A1 (fr)

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AU30747/00A AU3074700A (en) 1999-01-22 2000-01-20 Medicinal compositions with improved oral absorption

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002005786A1 (fr) * 2000-07-17 2002-01-24 Yamanouchi Pharmaceutical Co., Ltd. Composition pharmaceutique a absorbabilite per os amelioree
WO2003059389A1 (fr) * 2002-01-16 2003-07-24 Yamanouchi Pharmaceutical Co., Ltd. Compositions medicamenteuses presentant une meilleure absorption orale
WO2005032588A1 (fr) * 2003-09-30 2005-04-14 Kyowa Pharmaceutical Ind. Co.,Ltd. Preparation contenant un medicament de base
JP2005533802A (ja) * 2002-06-25 2005-11-10 セエルエル ファルマ 親油性有効成分を含有する固体薬学的組成物およびその製造方法
WO2008066102A1 (fr) * 2006-11-30 2008-06-05 Takeda Pharmaceutical Company Limited Préparation à libération prolongée

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02268178A (ja) * 1989-04-07 1990-11-01 Toyama Chem Co Ltd ３―ホルミルアミノ―７―メチルスルホニルアミノ―６―フェノキシ―４ｈ―１―ベンゾピラン―４―オンまたはその塩を含有する抗炎症製剤
EP0413299A1 (fr) * 1989-08-16 1991-02-20 Mercian Corporation Composition antibiotique
JPH04327529A (ja) * 1991-04-25 1992-11-17 Kyoto Yakuhin Kogyo Kk 矯味経口剤
WO1994010983A1 (fr) * 1992-11-06 1994-05-26 Hisamitsu Pharmaceutical Co., Inc. Preparation pharmaceutique perorale liberable dans le tube digestif inferieur
JPH06256193A (ja) * 1993-02-19 1994-09-13 Tokyo Tanabe Co Ltd ダナゾールの経口用持続性製剤
WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1998005310A1 (fr) * 1996-08-02 1998-02-12 Hisamitsu Pharmaceutical Co., Inc. Gelules destinees a des preparations orales et preparations de gelules destinees a une administration orale
JPH11189531A (ja) * 1997-12-26 1999-07-13 Dai Ichi Seiyaku Co Ltd 経粘膜投与用医薬組成物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62221626A (ja) * 1986-03-20 1987-09-29 Tokyo Tanabe Co Ltd １，４−ジヒドロピリジン化合物の製剤用組成物
JP4227677B2 (ja) * 1996-12-10 2009-02-18 杏林製薬株式会社 被膜形成性抗真菌剤組成物
JP2000169364A (ja) * 1998-09-30 2000-06-20 Taisho Pharmaceut Co Ltd 経口製剤用粒子

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02268178A (ja) * 1989-04-07 1990-11-01 Toyama Chem Co Ltd ３―ホルミルアミノ―７―メチルスルホニルアミノ―６―フェノキシ―４ｈ―１―ベンゾピラン―４―オンまたはその塩を含有する抗炎症製剤
EP0413299A1 (fr) * 1989-08-16 1991-02-20 Mercian Corporation Composition antibiotique
JPH04327529A (ja) * 1991-04-25 1992-11-17 Kyoto Yakuhin Kogyo Kk 矯味経口剤
WO1994010983A1 (fr) * 1992-11-06 1994-05-26 Hisamitsu Pharmaceutical Co., Inc. Preparation pharmaceutique perorale liberable dans le tube digestif inferieur
JPH06256193A (ja) * 1993-02-19 1994-09-13 Tokyo Tanabe Co Ltd ダナゾールの経口用持続性製剤
WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1998005310A1 (fr) * 1996-08-02 1998-02-12 Hisamitsu Pharmaceutical Co., Inc. Gelules destinees a des preparations orales et preparations de gelules destinees a une administration orale
JPH11189531A (ja) * 1997-12-26 1999-07-13 Dai Ichi Seiyaku Co Ltd 経粘膜投与用医薬組成物

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7871644B2 (en) 2000-07-17 2011-01-18 Astellas Pharma Inc. Pharmaceutical composition for oral use with improved absorption
WO2002005786A1 (fr) * 2000-07-17 2002-01-24 Yamanouchi Pharmaceutical Co., Ltd. Composition pharmaceutique a absorbabilite per os amelioree
US7008640B2 (en) 2000-07-17 2006-03-07 Yamanouchi Pharmaceutical Co., Ltd. Pharmaceutical composition for oral use with improved absorption
WO2003059389A1 (fr) * 2002-01-16 2003-07-24 Yamanouchi Pharmaceutical Co., Ltd. Compositions medicamenteuses presentant une meilleure absorption orale
JP5462429B2 (ja) * 2002-01-16 2014-04-02 アステラス製薬株式会社 経口吸収改善用医薬組成物
JPWO2003059389A1 (ja) * 2002-01-16 2005-05-19 山之内製薬株式会社 経口吸収改善用医薬組成物
US7923025B2 (en) 2002-01-16 2011-04-12 Astellas Pharma Inc. Pharmaceutical composition for oral use with improved absorption
CN100450547C (zh) * 2002-01-16 2009-01-14 安斯泰来制药有限公司 改善口服吸收用药物组合物
JP2005533802A (ja) * 2002-06-25 2005-11-10 セエルエル ファルマ 親油性有効成分を含有する固体薬学的組成物およびその製造方法
JP2005104914A (ja) * 2003-09-30 2005-04-21 Kyowa Yakuhin Kogyo Kk 塩基性薬剤含有製剤
WO2005032588A1 (fr) * 2003-09-30 2005-04-14 Kyowa Pharmaceutical Ind. Co.,Ltd. Preparation contenant un medicament de base
JPWO2008066102A1 (ja) * 2006-11-30 2010-03-11 武田薬品工業株式会社 徐放性製剤
WO2008066102A1 (fr) * 2006-11-30 2008-06-05 Takeda Pharmaceutical Company Limited Préparation à libération prolongée

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