WO2008015959A1 - Composition pharmaceutique permettant une meilleure absorption d'une substance pharmacologiquement active - Google Patents

Composition pharmaceutique permettant une meilleure absorption d'une substance pharmacologiquement active Download PDF

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Publication number
WO2008015959A1
WO2008015959A1 PCT/JP2007/064685 JP2007064685W WO2008015959A1 WO 2008015959 A1 WO2008015959 A1 WO 2008015959A1 JP 2007064685 W JP2007064685 W JP 2007064685W WO 2008015959 A1 WO2008015959 A1 WO 2008015959A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
component
pharmacologically active
fatty acid
active substance
Prior art date
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PCT/JP2007/064685
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English (en)
Japanese (ja)
Inventor
Masateru Miyake
Original Assignee
Otsuka Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to CN2007800283846A priority Critical patent/CN101495150B/zh
Priority to JP2008527720A priority patent/JP5300477B2/ja
Priority to KR1020097004307A priority patent/KR101390695B1/ko
Publication of WO2008015959A1 publication Critical patent/WO2008015959A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • composition with improved absorption of pharmacologically active substances
  • the present invention relates to an oral pharmaceutical composition with improved absorbability of a pharmacologically active substance and capable of efficiently expressing a pharmacological action in a living body.
  • pharmacologically active substances are destabilized in the stomach even if administered orally, and the desired pharmacological action cannot be obtained.
  • certain pharmacologically active substances may cause gastric disorders during residence in the stomach. Therefore, pharmacologically active substances that are required to be absorbed in the gastrointestinal tract today are formulated into enteric preparations that have been devised to reach the lower part of the gastrointestinal tract without being dissolved in the stomach. Has been.
  • pH-dependent products are known as enteric preparations!
  • the pH-dependent enteric preparation is formulated so as to enable selective dissolution in the lower digestive tract by utilizing the difference in pH between the gastric juice and the lower gastrointestinal tract.
  • pH-dependent enteric preparations are coated with polymers that are neutral but not decomposed when acidic (for example, cellulose derivatives, Eudragit, etc.), and the pH is acidic in the stomach. Without dissolving, it is soluble in the lower digestive tract because of its neutral pH (see Non-Patent Documents 1 and 2, for example).
  • Non-Patent Documents 1 and 2, for example see Non-Patent Documents 1 and 2, for example.
  • conventional pH-dependent enteric preparations actually lead to a decrease in the dispersibility of pharmacologically active substances when they pass through the stomach, resulting in reduced bioavailability. It has been.
  • Non-Patent Document 1 1 ⁇ Mharaj et al., J. Pharm. Sci. 73, p.59 (1988)
  • Non-Patent Document 2 S. Y. Lin et al., Pharm. Res., 4, p70 (1987)
  • Non-Patent Document 3 Isabel Gomez-Orellana and Duncan R. Parton, Advances in the oral delivery of proteins. Exptl. Opin. Ther. Patents, 9, 247-253, 1999.
  • Non-Patent Document 4 Rakhi B. Shar, Fukhrul Ahsan & Mansoor A. Khan, Oral delivery of proteins; Progress and prognostication. And Rev. Ther. Drug Carrier Systems, 19, 13 5-169, 2002.
  • Non-Patent Document 5 J. Gordon Still, Development of oral insulin; Progress and current stat us. Diabetes Metab. Res. Rev., 18, suppl. 1, S29-S37, 2002.
  • Non-Patent Document 6 YH Lee, BA Perry, JP Sutyak, W. Stern and PJ Sinko, Regio nal differences in intestinal spreading and pH recovery and the impact on salmon cal citonin in dogs. Pharm. Res., 17, 284-290 2000.
  • Non-Patent Document 7 PJ Sinko, YH Lee, V. Makhey, GD Leesman, JP Gilligan and W. Stern, Biopharmaceutical approaches for developing and assessing oral peptide d elivery strategies and systems; in vitro permeability and in vivo oral absorption of salmon calcitonin (sTC). Pharm. Res., 16, 527-533, 1999.
  • Patent Document 1 Japanese Patent Laid-Open No. 10-231254
  • Patent Document 2 Special Table 2003-506476
  • An object of the present invention is to solve the above-described problems of the prior art. Specifically, an object of the present invention is to provide an oral pharmaceutical composition that has improved absorbability of a pharmacologically active substance and can efficiently express a pharmacological action in vivo.
  • the present inventor conducted extensive studies to solve the above-mentioned problems, and as a result, combined (A) a pharmacologically active substance, (B) a drug absorption promoter, and (C) a wax that dissolves in vivo. It has been found that the ability to absorb the pharmacologically active substance in the lower part of the gastrointestinal tract can be enhanced and the pharmacological action can be effectively exhibited in vivo.
  • the present invention has been completed by making further improvements based on these findings.
  • the present invention provides the following inventions:
  • Item 1 An oral pharmaceutical composition
  • A a pharmacologically active substance
  • B a drug absorption promoter
  • C a wax that dissolves in vivo.
  • Item 2 The oral pharmaceutical composition according to Item 1, wherein the component (A) is a poorly soluble pharmacologically active substance.
  • Item 3 The oral pharmaceutical composition according to Item 1, wherein the component (B) is a medium chain fatty acid salt.
  • Item 4 The oral pharmaceutical composition according to Item 1, wherein the component (B) is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms.
  • Item 5 The oral pharmaceutical composition according to Item 1, wherein the component (C) is an ester of a higher fatty acid.
  • Item 6. The oral pharmaceutical composition according to Item 1, wherein the component (C) is a glycerin fatty acid ester.
  • Item 7. The oral pharmaceutical composition according to Item 1, wherein the component (B) is a medium chain fatty acid salt, and the component (C) is an ester of a higher fatty acid.
  • Item 8 The oral pharmaceutical composition according to Item 1, wherein the component (B) is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms and the component (C) is a glycerin fatty acid ester.
  • Item 9 Per unit amount of oral pharmaceutical composition, (A) component is 0.000;! To 90% by weight, (B) component is 0.0;! To 90% by weight, and (C) component; The oral pharmaceutical composition according to Item 1, which is contained in an amount of 95 to 95% by weight.
  • Item 10 The oral pharmaceutical composition according to Item 1, wherein Component (C) is contained in a ratio of;! To 10,000 parts by weight per 100 parts by weight of Component (B).
  • Item 11 Use of (B) a drug absorption enhancer and (C) a wax that dissolves in vivo for the production of an oral pharmaceutical composition containing (A) a pharmacologically active substance.
  • Item 12 The oral pharmaceutical composition according to Item 11, wherein the component (A) is a poorly soluble pharmacologically active substance.
  • Item 13 The use according to Item 11, wherein component (B) is a medium chain fatty acid salt.
  • Item 14 The use according to Item 11, wherein the component (B) is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms.
  • Item 15 The use according to Item 11, wherein component (C) is an ester of a higher fatty acid.
  • Item 16 The use according to Item 11, wherein the component (C) is a glycerin fatty acid ester.
  • Item 17 The use according to Item 11, wherein component (B) is a medium chain fatty acid salt and component (C) is an ester of a higher fatty acid.
  • Item 18 The use according to Item 11, wherein the component (B) is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms and the component (C) is a glycerin fatty acid ester.
  • the oral pharmaceutical composition comprises: (A) component of 0.000;! To 90% by weight; (B) component of 0.01 to 90% by weight; and (C) component;! To 95% by weight.
  • Item 20 The use according to Item 11, wherein the component (C) is used in a ratio of 1 to 10,000 parts by weight per 100 parts by weight of the component (B).
  • the oral pharmaceutical composition of the present invention contains (A) a pharmacologically active substance, (B) a drug absorption promoter, and (C) a wax that dissolves in vivo.
  • A a pharmacologically active substance
  • B a drug absorption promoter
  • C a wax that dissolves in vivo.
  • an oral pharmaceutical composition may be simply abbreviated as a pharmaceutical composition.
  • A Pharmacologically active substance
  • the pharmaceutical composition of the present invention contains a pharmacologically active substance (hereinafter sometimes simply referred to as “component (A)”).
  • component (A) a pharmacologically active substance
  • the pharmacologically active substance used in the present invention is pharmaceutically acceptable and is not particularly limited as long as it exhibits a pharmacological action, and is water-soluble, fat-soluble, or poorly water-soluble. May be used.
  • examples of such pharmacologically active substances include angiotensin 2 receptor antagonist (AR B), gastrointestinal drugs, nutrients, nutrient oils, opioid analgesics, calcium antagonists, overactive bladder drugs, keratolytic drugs , Cardiotonic, muscle relaxant, antineoplastic, antiviral, anti-inflammatory, antibacterial, antianginal, anthelmintic, antiepileptic, schizophrenia, antiepileptic, antiarrhythmic Drug, Analgesic, Antifungal, Anticoagulant, Antidiabetic, Antigout, Antihypertensive, Antiurinary Incontinence, Antimalarial, Antimigraine, Antimuscarinic, Antiparkinson, Anti Histamine, anti-obesity, anti-anxiety, antiarrhythmic, anti
  • pharmacologically active substance used in the present invention include acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atonolevastine, atbatawon, azithromycin, noclofen , Beclomethasone, benezeprinole, benzonate, betamethasone, bicanoletanide, budesonide, bupropion, busulfan, butenafine, calciphediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotene, cerivacerepine Colecanore Ferronore, cilostazol, cimetidine, cinnarizine, ciprofloxa Down, Shisapuri de, clarithromycin, clemastine, clomiphene, Ku
  • Cephalexin cefapirin sodium, cholera vaccine, cidofovir, cisplatin, cladribine, clidiyubromide, clindamycin and clindamycin derivatives, ciprofloxacin, clodronate, colistin metasodium, colistin sulfate, corticotropin, cosintropin, cromolyn sodium, Cytarabine, sodium dalteparin, danaparoid, deferoxamine, denileukin diftitox, desmopressin, diatrizoate medalmin and diatrizoate sodium, dicyclomine, didanosine, dirithromycin, dopamine hydrochloride, deoxyribonuclease ⁇ , doxatalium chloride, doxorubicin Disodium acid, enalabrilate, enkephalin, enoxa , Enoxaparin sodium, ephedrine, epin
  • a pharmacologically active substance used in the present invention in addition to the above compounds, peptides, and Tan Roh click proteins also can be force s mentioned.
  • interferon interferon-1 alpha, beta, interleukin 1-11
  • tumor necrosis factor TNF- alpha, beta
  • malignant leukocyte inhibitory factor LIF
  • erythropoietin granulocyte colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • M-CFS macrophage colony stimulating factor
  • thrombopoietin platelet growth stimulating factor, megakaryocyte growth stimulating factor, insulin, growth hormone , Luteinizing hormone releasing hormone (LH-RH), adrenocorticotropic hormone (ACTH), amylin, oxytocin, luteinizing hormone, nerve growth factor (NG F, NGF-2 / NT-3), epidermal growth factor ( EGF),
  • these pharmacologically active substances may be used alone or in any combination of two or more.
  • a poorly absorbable pharmacologically active substance means a pharmacological component that has low absorbability into the body and is inactivated or hardly exerts a pharmacological action when administered orally.
  • examples of such poorly absorbable pharmacologically active substances include peptides, proteins, and poorly soluble pharmacologically active substances.
  • the poorly soluble pharmacologically active substance means the term “slightly insoluble”, “hardly soluble”, “very insoluble” and “almost insoluble” in the 14th revision Japanese Pharmacopoeia. It is a pharmacologically active substance that shows solubility.
  • the solubility of a pharmacologically active substance in the Japanese Pharmacopoeia means that if the pharmacologically active substance is a solid, powder it, put it in a solvent, and shake vigorously for 30 seconds every 5 minutes at 20 ⁇ 5 ° C. Degree of solubility within 30 minutes.
  • “slightly insoluble” means that the amount of water required to dissolve lg or ImL of pharmacologically active substance is 30 mL or more and less than lOOmL; The amount of water required to dissolve lg or ImL is greater than or equal to lOOmL and less than lOOOmL; “extremely insoluble” means that the amount of water required to dissolve lg or ImL is 1000 mL or more but less than lOOOOmL; “Insoluble” means that the amount of water required to dissolve lg or lmL of the pharmacologically active substance is at least lOOOOmL.
  • ком ⁇ онентs include rebamipide, maprotiline hydrochloride, papaverine hydrochloride, norpinephrine hydrochloride, berberine chloride, cetraxate hydrochloride, sulfamethoxazol, metronidazole, diazepam, cimetidine, famotidine, Examples include bromhexine hydrochloride, difenidol hydrochloride, caffeine, digoxin, perapamil hydrochloride, erythromycin, clarithromycin, kitasamycin, josamycin, roxithromycin, midecamycin and the like.
  • the pharmaceutical composition of the present invention can also have a sustained release, so that the pharmacologically active substance used in the present invention is a sustained release.
  • Compounds that are required to have properties are preferred.
  • the pharmacologically active substance used in the present invention is preferably rebamipide, theophylline, cilostazol, ketoprofen, naproxen, diclofenac, itraconazolone, piroxicam, phenyloin, verapamil, probucol, tolvaptan;
  • Preferable examples include theophylline, cilostazo mononole, probuconole, and tonole paptan.
  • the daily dose of the component (A) in the pharmaceutical composition of the present invention varies depending on the type of the component (A), the age and sex of the patient, etc., but generally 0. ! ⁇ 200 Omg, preferably 0.5 ⁇ ;! OOOmg should be set as a guideline.
  • component (A) in the pharmaceutical composition of the present invention the gender and age of the patient, the dosage form, the shape and dosage form of the preparation, the type of (A) component used, the daily dose, etc. It may be set appropriately according to the situation.
  • (A) component 0.000;! ⁇ 9 0 weight 0/0, preferably (or 0.005 to 94 weight 0/0, more preferably (or 0.0; ! is to 90 weight 0/0 force Retsu ⁇ .
  • the pharmaceutical composition of the present invention further contains a drug absorption promoter (hereinafter sometimes simply referred to as “component (B)”).
  • the drug absorption promoter is not particularly limited as long as it is a compound that promotes the absorption of the pharmacologically active substance, and a wide variety of known ones can be used.
  • Examples of drug absorption promoters include medium chain fatty acid salts, long chain fatty acid salts, bile salts, surfactants, Examples include rhodextrin, alkyl saccharide, chelating agent, alkyl strength rubamate, sorbitan fatty acid ester and the like.
  • Examples of the medium chain fatty acid salts include salts of fatty acids having 6 to 13 carbon atoms (especially alkali metal salts), and specific examples thereof include caproic acid, strong prillic acid, lauric acid, lauryl sulfate, and the like. Potassium metal salts (sodium salt, potassium salt, etc.) are included.
  • Examples of long-chain fatty acid salts include salts of fatty acids having 14 to 20 carbon atoms (especially alkali metal salts).
  • alkali metal salts such as myristic acid, normitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, etc. .
  • bile salts include alkali metal salts of bile acids such as cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, taurodeoxycholic acid, and the like. These include sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate and the like.
  • Examples of the surfactant include a cation surfactant, nonionic surfactant and the like S.
  • nonionic surfactants include monostearic glyceride, tricapric glyceride, trilauric glyceride, glyceryl monoundecylenate, tetraglyceryl pentastearate, polysorbate 80, polyoxyethylene hardened castor Oil, polyoxyethylene castor oil, polyoxyethylene lanolin
  • polyoxyethylene lanolin alcohol polyoxyethylene lauryl ether
  • polyoxyethylene cetyl ether polyoxyethylene cetyl ether
  • cyclodextrins include dimethyl 1- ⁇ -cyclodextrin, hydroxypropyl 1-cyclodextrin, sulfobutyl ether 1-cyclodextrin, and the like.
  • alkyl saccharide examples include carboxyfluorescein and lauryl maltoside.
  • Examples of the chelating agent include polyaminocarboxylic acids such as EDTA, oxycarboxylic acids such as citrate, and oximes such as dimethyl daroxime.
  • Examples of alkyl strength rubamates include C 1 -C alkyl carbamates, specifically
  • Methyl carbamate, ethyl carbamate, butyl carbamate and the like Methyl carbamate, ethyl carbamate, butyl carbamate and the like.
  • sorbitan fatty acid ester examples include sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquistearate, sorbitan sesquioleate, and the like.
  • the drug absorption promoter is used singly or in combination of two or more.
  • a medium chain fatty acid salt preferably an alkali metal salt of a fatty acid having 6 to 18 carbon atoms, particularly preferably lauryl sulfate, strong puric acid, and lauric acid.
  • alkali metal salts of lauryl sulfate are more preferable.
  • the blending ratio of the component (B) in the pharmaceutical composition of the present invention is, for example, 0.0;! To 90% by weight, preferably 0 .;! To 80, based on the total amount of the pharmaceutical composition. % By weight, more preferably;! -70% by weight.
  • the pharmaceutical composition of the present invention contains a cocoon that dissolves in the living body (hereinafter sometimes simply referred to as “component (C)”).
  • component (C) a cocoon that dissolves in the living body
  • the wax that dissolves in a living body refers to a wax that exhibits a semi-solid state or a solid state, preferably a solid state at room temperature (15 ° C), and has a property of melting in the living body (lower digestive tract).
  • Specific examples of the wax that dissolves in vivo include a wax having a melting point of 40 ° C. or lower, preferably 3;! To 40 ° C. The melting point is measured in accordance with “14th Revised Japanese Pharmacopoeia General Test Method 14. Freezing Point Measurement Method”.
  • the wax used in the present invention is not particularly limited in its origin, and may be animal-derived, plant-derived, synthetic, or semi-synthetic.
  • wax used in the present invention include higher fatty acids, esters of higher fatty acids, higher alcohols, esters of higher alcohols, and the like.
  • Examples of higher fatty acids include higher fatty acids having 12 to 28 carbon atoms, and specific examples include lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, normitic acid, marga. Examples include phosphoric acid, stearic acid, nonadecanoic acid, araquinic acid, behenic acid, lignoceric acid, serotic acid, and montanic acid.
  • higher fatty acid esters include, for example, esters of the above higher fatty acids (specifically, glycerin fatty acid esters, ethylene glycol fatty acid esters, propylene glycol fatty acid esters, sorbitol fatty acid esters, polyethylene glycol fatty acid esters, etc.);
  • Illustrative examples include glycerides of saturated fatty acids obtained from animals or plants, mixtures thereof, and hardened fats and oils of these glycerides; dalycerides of unsaturated fatty acids such as oleic acid, linoleic acid, ricinoleic acid, and mixtures thereof.
  • glycerin fatty acid ester examples include higher saturated fatty acid models or triglycerides; preferably 12 to 18 carbon atoms; saturated fatty acid models or tridalylides having 18 carbon atoms; more preferably 12 to 18 carbon atoms; Illustrative is the fatty acid tridalylide.
  • Examples of the higher alcohols include pentadecanol, hexade diol, heptade diol, octadecanol, nonade diol, eicosadecanol, wool alcohol and the like.
  • esters of higher alcohols include cholesteryl palmitate, plant sterol palmitate, and the like.
  • the above wax may be used alone or in any combination of two or more.
  • esters of higher fatty acids preferred are glycerin fatty acid esters, particularly preferred are tridalylides of higher saturated fatty acids, more preferably 12 to 18 carbon atoms; Is done.
  • the blending ratio of the component (C) in the pharmaceutical composition of the present invention is, for example, from! To 95% by weight, preferably 5 to 95% by weight, more preferably, relative to the total amount of the pharmaceutical composition 10-9
  • the combination mode of each component is not particularly limited, but by adopting the following specific combination mode, pharmacological activity
  • the substance absorbability can be further improved:
  • Combination (B) component is a medium chain fatty acid salt, and (C) component is an ester of a higher fatty acid; preferably (B) component is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms;
  • (C) component is a glycerin fatty acid ester; more preferably, (B) component is laurinosulfuric acid, strong purine acid or alkali metal salt of lauric acid, and (C) component is a higher saturated fatty acid compound.
  • a combination of di- or tri-dalylide more preferably a combination of (B) component being an alkali metal salt of lauryl sulfate and (C) component being tri-arylide of saturated fatty acid having 12 to 18 carbon atoms.
  • the components (B) and (C) may further satisfy the following ratios. Desirable: (B) Component 1 to 100 parts by weight (C) Component 1 to; 10,000 parts by weight, preferably 10 to 5000 parts by weight, more preferably ⁇ 100 to 5000 parts by weight.
  • the pharmaceutical composition of the present invention may contain a polymer such as a water-soluble polymer, a water-insoluble polymer, an enteric polymer, a gastric polymer, as necessary.
  • a polymer such as a water-soluble polymer, a water-insoluble polymer, an enteric polymer, a gastric polymer, as necessary.
  • Appropriate amounts of substances can be added to the raw materials.
  • Specific examples of such a high molecular weight substance include hydroxy cetate succinate, cenololose acetate phthalate, ethinoresenololose, cenorose acetate, polyvinylinolepyrrolidone, hydroxy ethinoresenololose, methinoresenoles.
  • the pharmaceutical composition of the present invention includes ion exchange resins, solubilizers, plasticizers, diluents, sweeteners, lubricants, excipients or fillers, enzyme inhibitors, Anti-adhesive, anti-coagulant, antifoam, binder, pH adjuster or buffer, chelating agent, coagulant, binder, fragrance desensitizer, taste-masking agent, preservative, antioxidant, antifreeze, Colorant, opacifier, coolant, solvent, Additives such as thickeners and disintegrants may be added in appropriate amounts.
  • additives include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, phosphorus, PVP- Phosphatidinorethananolamine, Macrogonore 400, Macrogonore 4000, Macrogol 600, Macrogol 10000, Macrogol 6000, Lactose, Sucrose, Mannitol, Sodium chloride, Glucose, Calcium carbonate, Kaolin, Crystalline cellulose, Key salt, Water , Ethanol, simple syrup, dextrose solution, starch solution, gelatin solution, dextrin, pullulan, citrate, anhydrous citrate, sodium citrate, sodium citrate Dihydrate, anhydrous sodium monohydrogen
  • the mixing ratio of these additives is determined by the force S, which is appropriately set according to the use of the pharmaceutical composition and the preparation form.
  • the pharmaceutical composition of the present invention is not limited as long as it can be administered orally, and examples thereof include tablets, granules, powders, solutions, suspensions and the like.
  • the pharmaceutical composition of the present invention can be filled into microcapsules, soft capsules, hard capsules and the like to take the form of capsules. In the case of capsules, enteric capsules may be used!
  • the pharmaceutical composition of the present invention can be produced according to a known production method. That is, by adding a predetermined amount of the above components (A) to (C) and, if necessary, other additives and mixing them by heating, the resulting mixture is used to form the desired preparation form.
  • the pharmaceutical group of the present invention A composition is prepared.
  • Rebamipide 20g Sodium Laurate (Tokyo Kasei Kogyo Co., Ltd.) 20g, Witepsol H_15 (carbon number 12 ⁇ ; 18 saturated fatty acid triglyceride, melting point 33.5-35.5 ° C, Dynamil Nobel (Germany)) 100g , Cornstarch (Nippon Shokuhin Kako Co., Ltd.) 100g, and Crystal Cellulos Sua (made by Asahi Kasei Co., Ltd.) lOOg was mixed, and 0.5 g of stearic acid Mg (made by Taihei Chemical Co., Ltd.) was added, and this was tableted with a mortar with a diameter of 8.5 mm, and tablets (weight per tablet) : 34.5 mg).
  • Rebamipide 20g Sodium Laurate (Tokyo Kasei Kogyo Co., Ltd.) 20g, Witepsol H_15 (carbon number 12 ⁇ ; 18 saturated fatty acid triglyceride, melting point 33.5-35.5 ° C, Dynamil Nobel (Germany)) 100g , Corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) 100 g and crystal cellulose (manufactured by Asahi Kasei Co., Ltd.) lOOg, and further mixed with 0.5 g of stearic acid Mg (manufactured by Taihei Chemical Co., Ltd.) Tableting was performed with a mortar to obtain tablets (weight per tablet: 340.5 mg).
  • Rebamipide 20g Sodium Laurate (Tokyo Kasei Kogyo Co., Ltd.) 20g, Witepsol H_15 (carbon number 12 ⁇ ; 18 saturated fatty acid triglyceride, melting point 33.5-35.5 ° C, Dynamil Nobel (Germany)) 100g , 100 g of cornstarch (Nippon Shokuhin Kako Co., Ltd.) and 100 g of crystal cellulose (Asahi Kasei Co., Ltd.) are put into a kneader (NSK-150 by Seika Okada Co., Ltd.), mixed, and then mixed with an appropriate amount of aqueous solution. Get things.
  • the resulting kneaded product was subjected to extrusion granulation with an extrusion granulator equipped with a 0.8 mm hole dome die (Fuji Baudal Dome Gran DG-L1), and then a spherical granulator (Fuji Baudal) Spherical sizing with Malmerizer QJ-400).
  • the obtained granules are dried to obtain granules.
  • Example 6 the granules of Example 6 are sprayed with a coating solution containing 6% by weight hydroxypropylmethylcellulose, 2% by weight polyethylene glycol, 1% by weight talc and 1% by weight titanium oxide to obtain coated granules.
  • Rebamipide lOOmg was placed in an enteric capsule (material: hydroxypropyl methylcellulose sulfate succinate, manufactured by Shionogi Qualicabus Co., Ltd.) to obtain an enteric capsule.
  • Comparative Example 2 Enteric Capsule Rebamipide lOOmg and sodium laurate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) 50 mg were accommodated in enteric strength Psell (material: hydroxypropylmethylcellulose acetate succinate, Shionogi Oribusu Bus Co., Ltd.) to obtain an enteric capsule.
  • enteric strength Psell material: hydroxypropylmethylcellulose acetate succinate, Shionogi Oribusu Bus Co., Ltd.
  • the enteric capsule of Example 1 was orally administered to four Beagle dogs on an empty stomach, blood was collected over time, and blood drug concentration (rebamipide blood concentration) was measured. For comparison, the same tests were performed using the enteric capsules of Comparative Examples 1 and 2.
  • Fig. 1 shows the changes in blood drug concentration and Table 1 shows the average values of pharmacokinetic parameters. From these results, it was found that the preparation with rebamipide and sodium laurate showed almost no improvement in rebamipide absorption (see the results of Comparative Example 2). In contrast, rebamipide, sodium laurate and a higher saturated fatty acid triglyceride compound significantly improved renopide absorbability. In particular, at 3 hours after administration, the concentration of rebamipide in the blood reached 4 times or more in the preparation of Example 1 compared to the preparation of Comparative Example 2 (see FIG. 1).
  • FIG. 1 In Test Example 1, the time course of the average concentration of pharmacologically active substance (rebamipide) in blood when the enteric capsules of Example 1, Comparative Example 1 or 2 were orally administered to beagle dogs, respectively.
  • FIG. 1 In Test Example 1, the time course of the average concentration of pharmacologically active substance (rebamipide) in blood when the enteric capsules of Example 1, Comparative Example 1 or 2 were orally administered to beagle dogs, respectively.

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Abstract

La présente invention concerne une composition pharmaceutique pouvant être administrée oralement et permettant une meilleure absorption d'une substance pharmacologiquement active et qui est donc capable d'exercer efficacement un effet pharmacologique dans un organisme vivant. L'invention concerne spécifiquement une composition pharmaceutique pouvant être administrée oralement qui est préparée en mélangeant une substance pharmacologiquement active (A) avec un amplificateur de l'absorption d'un médicament (B) et une cire (C) qui est dissoute dans un organisme vivant.
PCT/JP2007/064685 2006-08-01 2007-07-26 Composition pharmaceutique permettant une meilleure absorption d'une substance pharmacologiquement active WO2008015959A1 (fr)

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JP2008527720A JP5300477B2 (ja) 2006-08-01 2007-07-26 薬理活性物質の吸収性が改善された医薬組成物
KR1020097004307A KR101390695B1 (ko) 2006-08-01 2007-07-26 약리 활성 물질의 흡수성이 개선된 의약 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015500330A (ja) * 2011-12-14 2015-01-05 エルテーエス ローマン テラピー−ジステーメ アーゲー フェノフィブラートのための強化された溶解速度を備えたウェーハ及びカプセル製剤

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102139115B (zh) * 2011-03-30 2012-12-05 天津红日药业股份有限公司 阿托伐他汀的环糊精包合物及其口服固体制剂的制备方法
WO2013103668A1 (fr) * 2012-01-05 2013-07-11 Ala Wai Pharma Inc. Formulations pour une biodisponibilité augmentée de zanamivir
CN105012267A (zh) * 2015-08-19 2015-11-04 海南科进生物制药有限公司 一种瑞巴派特片及其制备方法
CN105617353A (zh) * 2016-01-04 2016-06-01 李志海 一种黏菌素口服给药组合物

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5372814A (en) * 1976-12-03 1978-06-28 Scherer Ltd R P Pharmaceutical composition
JPH06502143A (ja) * 1990-10-19 1994-03-10 プロヴァリス　ユーケー　リミテッド 親油性薬剤用の２相放出配合物
JPH07196483A (ja) * 1993-11-25 1995-08-01 Taisho Pharmaceut Co Ltd 経口吸収性を改善した製剤組成物
JPH07507565A (ja) * 1992-10-02 1995-08-24 ファイザー・インク． 非イオン性表面活性剤を含有する医薬組成物
JPH10503750A (ja) * 1994-03-16 1998-04-07 アール． ピー． シェーラー リミテッド 疎水性薬剤の投与システム
JPH10231254A (ja) * 1996-12-19 1998-09-02 Dai Ichi Seiyaku Co Ltd 経口吸収改善医薬用組成物
JP2002532539A (ja) * 1998-12-18 2002-10-02 アボット・ラボラトリーズ 脂質調節剤を含む新規な製剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1240363A (zh) * 1996-12-19 2000-01-05 第一制药株式会社 口服给药的药物组合物
JP4570725B2 (ja) 2000-04-05 2010-10-27 大塚製薬株式会社 医薬製剤用組成物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5372814A (en) * 1976-12-03 1978-06-28 Scherer Ltd R P Pharmaceutical composition
JPH06502143A (ja) * 1990-10-19 1994-03-10 プロヴァリス　ユーケー　リミテッド 親油性薬剤用の２相放出配合物
JPH07507565A (ja) * 1992-10-02 1995-08-24 ファイザー・インク． 非イオン性表面活性剤を含有する医薬組成物
JPH07196483A (ja) * 1993-11-25 1995-08-01 Taisho Pharmaceut Co Ltd 経口吸収性を改善した製剤組成物
JPH10503750A (ja) * 1994-03-16 1998-04-07 アール． ピー． シェーラー リミテッド 疎水性薬剤の投与システム
JPH10231254A (ja) * 1996-12-19 1998-09-02 Dai Ichi Seiyaku Co Ltd 経口吸収改善医薬用組成物
JP2002532539A (ja) * 1998-12-18 2002-10-02 アボット・ラボラトリーズ 脂質調節剤を含む新規な製剤

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015500330A (ja) * 2011-12-14 2015-01-05 エルテーエス ローマン テラピー−ジステーメ アーゲー フェノフィブラートのための強化された溶解速度を備えたウェーハ及びカプセル製剤
JP2017114885A (ja) * 2011-12-14 2017-06-29 エルテーエス ローマン テラピー−ジステーメ アーゲー フェノフィブラートのための強化された溶解速度を備えたウェーハ及びカプセル製剤
JP2017122099A (ja) * 2011-12-14 2017-07-13 エルテーエス ローマン テラピー−ジステーメ アーゲー フェノフィブラートのための強化された溶解速度を備えたウェーハ及びカプセル製剤
US9849184B2 (en) 2011-12-14 2017-12-26 Lts Lohmann Therapie-Systeme Ag Wafer and capsule formulations with enhanced dissolution rates for fenofibrate
US11497811B2 (en) 2011-12-14 2022-11-15 Lts Lohmann Therapie-Systeme Ag Wafer and capsule formulations with enhanced dissolution rates for fenofibrate

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CN101495150B (zh) 2011-06-01
CN101495150A (zh) 2009-07-29

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