JP5300477B2 - Pharmaceutical composition with improved absorption of pharmacologically active substances - Google Patents

Abstract

Disclosed is an orally administrable pharmaceutical composition which is improved in absorption of a pharmacologically active substance and is thus capable of efficiently exerting a pharmacological effect in a living body. Specifically, an orally administrable pharmaceutical composition is prepared by blending a pharmacologically active substance (A) with a drug absorption enhancer (B) and a wax (C) which is dissolved in a living body.

Description

  The present invention relates to an oral pharmaceutical composition having improved absorbability of a pharmacologically active substance and capable of efficiently expressing a pharmacological action in a living body.

  Some pharmacologically active substances are destabilized in the stomach even after oral administration, and the desired pharmacological action cannot be obtained. In addition, certain pharmacologically active substances may cause gastric damage during residence in the stomach. Therefore, today, pharmacologically active substances that are required to be absorbed in the gastrointestinal tract are devised on the formulation so that they can be absorbed by reaching the lower part of the gastrointestinal tract without dissolving in the stomach. It has become.

  Conventionally, pH-dependent ones 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 fluid and the lower gastrointestinal tract solution. In other words, pH-dependent enteric preparations are coated with a neutral polymer that is not decomposed when acidic (for example, cellulose derivatives, Eudragit, etc.), and dissolve in the stomach because the pH is acidic. However, since the pH is neutral at the lower part of the digestive tract, it can be dissolved (for example, see Non-Patent Documents 1 and 2). However, it is well recognized that conventional pH-dependent enteric preparations actually lead to a decrease in dispersibility of pharmacologically active substances when they pass through the stomach, resulting in reduced bioavailability. It has been.

  Moreover, in order to increase the bioavailability of a pharmacologically active substance, it is important that the pharmacologically active substance is sufficiently absorbed in the lower digestive tract in addition to being dissolved in the stomach and delivered to the digestive tract. Because the lower gastrointestinal tract is low in water, it may not be fully absorbed even if the pharmacologically active substance is delivered to the lower gastrointestinal tract. In particular, this tendency appears remarkably in the case of a poorly soluble pharmacologically active substance.

  Conventionally, the following methods have been reported as methods for improving the absorbability of pharmacologically active substances. It has been reported that the absorbability of pharmacologically active substances can be improved by blending lipophilic substances such as higher alcohols and fatty acids together with pharmacologically active substances that are difficult to be absorbed by oral administration (for example, see Patent Document 1). . It has also been reported that the absorbability of a pharmacologically active substance can be improved by blending a hydrophilic pharmacologically active substance in combination with at least two surfactants (see, for example, Patent Document 2). However, simply blending a lipophilic substance with a pharmacologically active substance, or combining a specific surfactant in combination, is still not satisfactory in terms of absorbability of the pharmacologically active substance. Then, further improvement is required.

Against the background of such conventional technology, it has been desired to develop a pharmaceutical composition that can sufficiently absorb a pharmacologically active substance in the lower part of the digestive tract and efficiently express a pharmacological action in vivo.
I. Mharaj et al., J. Pharm. Sci. 73, p.59 (1988) SY Lin et al., Pharm. Res., 4, p70 (1987) Isabel Gomez-Orellana and Duncan R. Parton, Advances in the oral delivery of proteins.Exptl. Opin. Ther. Patents, 9, 247-253, 1999. Rakhi B. Shar, Fukhrul Ahsan & Mansoor A. Khan, Oral delivery of proteins; Progress and prognostication. Crit. Rev. Ther. Drug Carrier Systems, 19, 135-169, 2002. J. Gordon Still, Development of oral insulin; Progress and current status.Diabetes Metab. Res. Rev., 18, suppl. 1, S29-S37, 2002. YH Lee, BA Perry, JP Sutyak, W. Stern and PJ Sinko, Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin in dogs. Pharm. Res., 17, 284-290, 2000. PJ Sinko, YH Lee, V. Makhey, GD Leesman, JP Gilligan and W. Stern, Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems; in vitro permeability and in vivo oral absorption of salmon calcitonin (sTC). Res., 16, 527-533, 1999. JP-A-10-231254 Japanese translation of PCT publication No. 2003-506476

  The object of the present invention is to solve the above-mentioned 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 intensive studies to solve the above problems, and when combined with (A) a pharmacologically active substance, (B) a drug absorption promoter, and (C) a wax that dissolves in vivo, It has been found that the absorbability of the pharmacologically active substance in the lower part of the digestive 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.

That is, the present invention provides the following inventions:
Item 1. An oral pharmaceutical composition comprising (A) a pharmacologically active substance, (B) a drug absorption promoter, and (C) a wax that dissolves in vivo.
Item 2. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (A) is a hardly soluble pharmacologically active substance.
Item 3. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (B) is a medium chain fatty acid salt.
Item 4. Item 2. 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. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (C) is an ester of a higher fatty acid.
Item 6. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (C) is a glycerin fatty acid ester.
Item 7. Item 2. 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. Item 2. 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. The total amount of the oral pharmaceutical composition contains 0.0001 to 90% by weight of component (A), 0.01 to 90% by weight of component (B), and 1 to 95% by weight of component (C). Item 2. The oral pharmaceutical composition according to Item 1.
Item 10. Item 2. The oral pharmaceutical composition according to Item 1, wherein the component (C) is contained at a ratio of 1 to 10,000 parts by weight with respect to 100 parts by weight of the component (B).
Item 11. Use of (B) a drug absorption promoter and (C) a wax that dissolves in vivo for the production of an oral pharmaceutical composition containing (A) a pharmacologically active substance.
Item 12. Item 12. The oral pharmaceutical composition according to Item 11, wherein the component (A) is a poorly soluble pharmacologically active substance.
Item 13. Item 12. The use according to Item 11, wherein the component (B) is a medium chain fatty acid salt.
Item 14. Item 12. 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. Item 12. The use according to Item 11, wherein the component (C) is an ester of a higher fatty acid.
Item 16. Item 12. The use according to Item 11, wherein the component (C) is a glycerin fatty acid ester.
Item 17. Item 12. The use according to Item 11, wherein the component (B) is a medium chain fatty acid salt, and the component (C) is an ester of a higher fatty acid.
Item 18. Item 12. 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.
Item 19. Item 11. The oral pharmaceutical composition contains 0.0001 to 90% by weight of the component (A), 0.01 to 90% by weight of the component (B), and 1 to 95% by weight of the component (C). Use as described in.
Item 20. Item 12. The use according to Item 11, wherein the component (C) is used at 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, in addition to (A) a pharmacologically active substance, (B) a drug absorption enhancer and (C) a wax that dissolves in vivo. By adopting it, it is possible to efficiently absorb orally administered pharmacologically active substances in the lower part of the digestive tract and effectively exert their pharmacological action in vivo. In the prior art, a hardly soluble pharmacologically active substance was difficult to be absorbed in the lower digestive tract. However, according to the pharmaceutical composition of the present invention, even a hardly soluble pharmacologically active substance can be absorbed in the lower digestive tract. It is sufficiently absorbed and can effectively exert its pharmacological action in vivo.

Hereinafter, the oral pharmaceutical composition of the present invention will be described in detail. Hereinafter, 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)”).

  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 any of water-soluble, fat-soluble, or poorly water-soluble can be used. Good. Examples of such pharmacologically active substances include angiotensin 2 receptor antagonist (ARB), gastrointestinal drugs, nutrients, nutrient oils, opioid analgesics, calcium antagonists, overactive bladder drugs, keratolytic drugs, cardiotonic drugs, Muscle relaxant, antineoplastic, antiviral, anti-inflammatory, antibacterial, antianginal, anthelmintic, antiepileptic, schizophrenia, antiepileptic, antiarrhythmic, analgesic, Antifungal, anticoagulant, antidiabetic, antigout, antihypertensive, antiurinary incontinence, antimalarial, antimigraine, antimuscarinic, antiparkinson, antihistamine, antiobesity , Anti-anxiety drugs, antiarrhythmic drugs, anti-benign prostatic hypertrophy drugs, stimulants, osteoporosis drugs, corticosteroids, CCR5 receptor antagonists (HIV entry inhibitors), lipid regulators, antispasmodics, erectile dysfunction improvement Drugs, immunosuppressants, antiprotozoal drugs, antithyroid drugs, Cox-2 inhibitors Hypnotics, muscle relaxants, sex hormones, sedatives, recognition enhancers, dysuria, beta blockers, essential fatty acids, non-essential fatty acids, protease inhibitors, macrolide antibiotics, diuretics, leukotriene antagonists, etc. Listed are ordinary drugs that are blended in various preparations. In the present invention, drugs may be used alone or in any combination of two or more.

  Specific examples of the pharmacologically active substance used in the present invention include acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastein, atovaquan, azithromycin, baclofen, beclomethasone, benezepril, Benzonate, betamethasone, bicaltanide, budesonide, bupropion, busulfan, butenafine, calciferdiol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotene, celecoxib, cerivastatin, cetirizine, chlorphenirole, chlorphenirole , Cimetidine, cinnarizine, ciprofloxacin, cisapride, clari Romycin, clemastatin, clomiphene, clomipramine, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexcyclopheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotaxosterol, Dirithromycin, donezepil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid source, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, foss Phenytoin, frovatriptan, furazolidone, gabapentin, gemfibro , Glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, itotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosoprazole, peprirolomidol , Lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxalene, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitozantrone, montelukast, nabumetone, nalbuphine, nelfinavir Nifedipine, nilsoldipine, nirtanide, di Trofurantoin, nizatidine, omeprazole, oprequin, estradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetine, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pridestigmine, rabeprozol Rifapentine, rimexolone, ritanovir, lisatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatryptophan, tacrine, tacrolimus, tamoxifen, tamsuloten, targretin, tazarotene, Niposide, terbinaphene, terazosin, tetrahydrocanabinol, tiagabine, ticlovidin, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecalnone, valsatan, venlafaxine, verteporfin, vitamin A , Vitamin D, vitamin E, vitamin K, zafirlukast, diluton, zolmitriptan, zolpidem, zopiclone, acarbose, acyclovir, acetylcysteine, acetylcholine chloride, alatrofloxacin, alendronate, arglucerase, amantadine hydrochloride, ambenonium, amifostine, Amiloride hydrochloride, aminocaproic acid, amphotericin B, aprotinin, Sparaginase, atenolol, atracurium besylate, atropine, azithromycin, aztreonam, BCG vaccine, bacitracin, bekalermin, veradona, bepridil hydrochloride, bleomycin sulfate, human calcitonin, salmon calcitonin, carboplatin, capecitabine, capreomycin dodecafertoferto, cefamandazoline sulfate Sodium, cefepime hydrochloride, cefixime, cefoniside sodium, cefoperazone, cefotetan disodium, cefotaxime, cefoxitin sodium, ceftizoxime, ceftriaxone, cefuroxime axetil, cephalexin, cefapirin sodium, cholera vaccine, cidofovir, cisplatin, Cladribine, clidinium bromide, clindamycin and Clindamycin derivatives, ciprofloxacin, clodronate, colistin metasodium, colistin sulfate, corticotropin, cosintropin, cromolyn sodium, cytarabine, dalteparin sodium, danaparoid, deferoxamine, denileukin diftitox, desmopressin, diatrizoate meglumine And diatrizoate sodium, dicyclomine, didanosine, dirithromycin, dopamine hydrochloride, deoxyribonuclease α, doxacurium chloride, doxorubicin, disodium etidronate, enalaprilate, enkephalin, enoxacin, enoxaparin sodium, ephedrine, epinephrine, erythromycin hydrochloride, esmolol hydrochloride, Famciclovir, fludarabine, fluoxetine, ho Canet sodium, ganciclovir, gentamicin, glucagon, glycopyrrolate, gonadorelin, indinavir sulfate, influenza virus vaccine, ipratropium bromide, ifosfamide, lamivudine, leucovorin calcium, leuprolide, levofloxacin, lincomycin and lincomycin derivatives, lobucavir, lomefloxacin, loracarbef , Mepenzolate bromide, mesalamine, methenamine, methotrexate, metoscopolamine, metformin hydrochloride, metoprolol, mesocillin sodium, mibacurium chloride, nedocromil sodium, neostigmine bromide, neostigmine methyl sulfate, neurontin, norfloxacin, octreotide acetate, ofloxacin Olpadronate Oxytocin, disodium pamidronate, pancuronium bromide, paroxetine, perfloxacin, pentamidine isethionate, pentostatin, pentoxyphyllin, pericyclovir, pentagastrin, phentolamine mesylate, phenylalanine, physostigmine salicylate, plague vaccine, sodium piperacillin sulfate polymyxin B , Pralidoxime chloride, pramlintide, pregabalin, propaphenone, bromide propantheline, pyridostigmine bromide, rabies vaccine, residronate, ribavarine, rimantadine hydrochloride, salmeterol xinafoate, cincaride, solatol, somatostatin, sparfloxacin, spectinomycin, Stavudine, streptokinase, streptozocin, sukisametoniu Chloride, tacrine hydrochloride, terbutaline sulfate, thiopeta, ticarcillin, tiludronate, timolol, trandolapril, trimethrexate gluconate, trospectinomycin, trovafloxacin, tubocurarine chloride, urea, urokinase, vancomycin, valaciclovir, valsartan, vasopressin And vasopressin derivatives, vecuronium bromide, vinblastine, vincristine, vinorelbine, vitamin B12, warfarin sodium, zalcitabine, zanamivir, zolandronate, zidovudine, theophylline, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, tolvaptan, acetaminophen Ketoprofen, naproxen, piroxicam, phenytoin, verapa , Maprotiline hydrochloride, papaverine hydrochloride, norepinephrine, berberine chloride, sulfamethoxazole, diazepam, bromhexine hydrochloride, diphenidol hydrochloride, caffeine, perapamil hydrochloride, kitasamycin, josamycin, roxithromycin, midecamycin Salts, isomers and derivatives thereof, and the like.

  Examples of the pharmacologically active substance used in the present invention include peptides and proteins in addition to the above compounds. Specifically, interferon (interferon-α, β, γ), interleukin (interleukin-1 to 11), tumor necrosis factor (TNF-α, β), malignant leukocyte inhibitory factor (LIF), erythropoietin, granulocyte Colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CFS), 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 (NGF, NGF-2 / NT-3), epidermal growth factor ( EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming growth factor (TGF), platelet-derived cell growth factor (PDGF), hepatocyte growth factor (HGF), endothelin, endothelin inhibitor, endothelin antagonist, endothelin synthase inhibitor, vasopressin, renin, angiotensin I, angiotensin II, angiotensin III, angiotensin I inhibitor, angiotensin II receptor antagonist, atrial natriuretic peptide (ANP), anti Arrhythmic peptide, Enkephalin, Endorphin, Kyotorphin, Neurotrophic factor (NTF), Calcitonin gene related peptide (CGRP), Adenylate cyclase activating peptide (PACAP), Thyroid hormone releasing hormone (TRH), Neurotensin, Calcitonin, Apoprotein E, thyroid hormone, secretin, gastrin and the like are exemplified.

  In the present invention, these pharmacologically active substances may be used alone or in any combination of two or more.

  According to the pharmaceutical composition of the present invention, even a pharmacologically active substance, which is usually poorly absorbed by oral administration, can enhance the absorbability and efficiently express the pharmacological action. In view of such an effect, a non-absorbable pharmacologically active substance is mentioned as a suitable example of the pharmacologically active substance blended in the pharmaceutical composition of the present invention. Here, the hardly absorbable pharmacologically active substance is a pharmacological component having low absorbability into the body and means a substance which is inactivated or hardly exerts a pharmacological action when orally administered. Examples of such poorly absorbable pharmacologically active substances include peptides, proteins, and poorly soluble pharmacologically active substances.

  Among such poorly absorbable pharmacologically active substances, those which are hardly soluble include pharmacologically active substances. In the present invention, the hardly soluble pharmacologically active substance means the term “slightly insoluble”, “hardly soluble”, “extremely insoluble” and “almost insoluble” in the 14th revised Japanese Pharmacopoeia. It is a pharmacologically active substance exhibiting any one of the solubility. The solubility of a pharmacologically active substance in the Japanese Pharmacopoeia means that when the pharmacologically active substance is solid, it is powdered and then placed in a solvent. When it is shaken vigorously for 30 seconds every 5 minutes at 20 ± 5 ° C, 30 minutes Specifically, “slightly insoluble” means that the amount of water required to dissolve 1 g or 1 mL of the pharmacologically active substance is 30 mL or more and less than 100 mL; “difficult to dissolve” means 1 g or 1 mL of the pharmacologically active substance The amount of water required to dissolve 100 mL or more and less than 1000 mL; “very difficult to dissolve” means 1 g of pharmacologically active substance or 1 mL of water required to dissolve 1 mL; “almost insoluble” means 1 g of pharmacologically active substance Or it shows that the quantity of the water required to melt | dissolve 1 mL is 10,000 mL or more.

  Specific examples of such poorly soluble drugs include rebamipide, maprotiline hydrochloride, papaverine hydrochloride, norepinephrine, berberine chloride, cetraxate, sulfamethoxazole, metronidazole, diazepam, cimetidine, famotidine, bromhexine hydrochloride, difenidol hydrochloride, cafe In, digoxin, perapamil hydrochloride, erythromycin, clarithromycin, kitasamycin, josamycin, roxithromycin, midecamycin and the like are exemplified.

  In addition to the excellent absorbability in the lower digestive tract, the pharmaceutical composition of the present invention can also have sustained release, so that the pharmacologically active substance used in the present invention has sustained release. Compounds that are required to be From such a viewpoint, the pharmacologically active substance used in the present invention is preferably rebamipide, theophylline, cilostazol, ketoprofen, naproxen, diclofenac, itraconazole, piroxicam, phenytoin, verapamil, probucol, tolvaptan; more preferably theophylline, cilostazol , Probucol, and tolvaptan.

  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 usually 0.1 to 2000 mg per day for an adult, preferably May be set with 0.5 to 1000 mg as a guide.

  About the mixing ratio of the component (A) in the pharmaceutical composition of the present invention, depending on the sex and age of the patient, the dosage form, the shape and dosage form of the preparation, the type of the component (A) used, the daily dose, etc. What is necessary is just to set suitably. For example, (A) component is 0.0001-90 weight% with respect to the total amount of a pharmaceutical composition, Preferably 0.005-94 weight%, More preferably, 0.01-90 weight% is illustrated.

(B) Drug absorption enhancer The pharmaceutical composition of the present invention further contains a drug absorption enhancer (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 absorption of the pharmacologically active substance, and a wide variety of known drugs can be used. Examples of drug absorption promoters include medium chain fatty acid salts, long chain fatty acid salts, bile salts, surfactants, cyclodextrins, alkyl saccharides, chelating agents, alkyl carbamates, sorbitan fatty acid esters, and the like.

  Examples of the medium chain fatty acid salt include salts of fatty acids having 6 to 13 carbon atoms (particularly alkali metal salts). Specifically, alkali metal salts (sodium salts) such as caproic acid, caprylic acid, lauric acid, lauryl sulfuric acid, etc. , Potassium salts, etc.).

  Examples of the long-chain fatty acid salt include salts of fatty acids having 14 to 20 carbon atoms (particularly alkali metal salts). Specifically, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, Alkali metal salts such as arachidonic acid (sodium salt, potassium salt, etc.) and the like are included.

  Examples of bile salts include alkali metal salts of bile acids such as cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, taurodeoxycholic acid, specifically sodium cholate, glycochol. Sodium acid, sodium taurocholate, sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate and the like are included.

  Examples of the surfactant include an anionic surfactant and a nonionic surfactant. Nonionic surfactants include, for example, monostearic glyceride, tricapric glyceride, trilauric glyceride, glyceryl monoundecylenate, tetraglyceryl pentastearate, polysorbate 80, polyoxyethylene cured Castor oil, polyoxyethylene castor oil, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether and the like can be mentioned.

  Examples of the cyclodextrin include dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and the like.

  Examples of the alkyl saccharide include carboxyfluorescein and lauryl maltoside.

  Examples of the chelating agent include polyaminocarboxylic acids such as EDTA, oxycarboxylic acids such as citric acid, and oximes such as dimethylglyoxime.

Examples of the alkyl carbamate include C ₁ -C ₄ alkyl carbamate, specifically, methyl carbamate, ethyl carbamate, butyl carbamate and the like.

  Examples of the sorbitan fatty acid ester include sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquistearate, sorbitan sesquioleate, and the like.

  In the present invention, the drug absorption promoter is used singly or in combination of two or more.

  Among the above-mentioned drug absorption accelerators, preferably a medium chain fatty acid salt, more preferably an alkali metal salt of a fatty acid having 6 to 18 carbon atoms, particularly preferably an alkali metal salt of lauryl sulfate, capric acid and lauric acid, Preferably, an alkali metal salt of lauryl sulfate is exemplified.

  About the mixture ratio of (B) component in the pharmaceutical composition of this invention, for example, it is 0.01 to 90 weight% with respect to the total amount of this pharmaceutical composition, Preferably it is 0.1 to 80 weight%, More preferably, it is 1 -70 wt% is exemplified.

(C) Wax that dissolves in vivo In addition to the above components (A) and (B), the pharmaceutical composition of the present invention is a wax that dissolves in vivo (hereinafter simply referred to as “component (C)”) Is also included. Here, the wax that dissolves in a living body refers to a wax that exhibits a semi-solid or solid state, preferably a solid state at room temperature (15 ° C.), and has a property of melting in the living body (lower part of the digestive tract). Specific examples of the wax that dissolves in vivo include a wax having a melting point of 40 ° C. or lower, preferably 31 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.

  Specific examples of the wax used in the present invention include higher fatty acids, higher fatty acid esters, higher alcohols, higher alcohol esters, and the like.

  Examples of higher fatty acids include higher fatty acids having 12 to 28 carbon atoms, and specifically include lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, and arachidic acid. , Behenic acid, lignoceric acid, serotic acid, montanic acid and the like.

  Examples of higher fatty acid esters include 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.); obtained from animals or plants Examples thereof include glycerides of saturated fatty acids, mixtures thereof, and hardened fats and oils of these glycerides; glycerides of unsaturated fatty acids such as oleic acid, linoleic acid, and ricinoleic acid, and mixtures thereof. Specific examples of the glycerin fatty acid ester include mono-, di- or triglycerides of higher saturated fatty acids; preferably mono-, di- or triglycerides of saturated fatty acids having 12 to 18 carbon atoms; more preferably triglycerides of saturated fatty acids having 12 to 18 carbon atoms. Is exemplified.

  Examples of higher alcohols include pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosadecanol, and wool alcohol.

  Examples of the esters of higher alcohols include cholesteryl palmitate and plant sterol palmitate.

  In the present invention, the above waxes may be used alone or in any combination of two or more.

  Among the waxes, esters of higher fatty acids are preferable, glycerol fatty acid esters are more preferable, triglycerides of higher saturated fatty acids are particularly preferable, and triglycerides of saturated fatty acids having 12 to 18 carbon atoms are more preferable.

  The blending ratio of the component (C) in the pharmaceutical composition of the present invention is, for example, 1 to 95% by weight, preferably 5 to 95% by weight, more preferably 10 to 90% by weight, based on the total amount of the pharmaceutical composition. Is exemplified.

Combination Modes of Components (A) to (C) As long as the pharmaceutical composition of the present invention includes the above components (A) to (C), the combination mode of each component is not particularly limited, but the following specific examples By adopting the combination mode, the absorbability of the pharmacologically active substance can be further improved:
A combination in which the component (B) is a medium chain fatty acid salt and the component (C) is an ester of a higher fatty acid; preferably the component (B) is an alkali metal salt of a fatty acid having 6 to 18 carbon atoms and (C ) Component is a glycerin fatty acid ester; more preferably, component (B) is an alkali metal salt of lauryl sulfate, capric acid or lauric acid, and component (C) is a mono-, di- or triglyceride of a higher saturated fatty acid More preferably, the combination (B) is an alkali metal salt of lauryl sulfate and the (C) component is a triglyceride of a saturated fatty acid having 12 to 18 carbon atoms.

  Further, from the viewpoint of making the improvement in absorbability of a pharmacologically active substance more remarkable, it is desirable that the above components (B) and (C) in the pharmaceutical composition of the present invention further satisfy the following ratio: The component (C) is 1 to 10000 parts by weight, preferably 10 to 5000 parts by weight, more preferably 100 to 5000 parts by weight with respect to 100 parts by weight of the component B).

Other optional additives In addition to the above components (A) to (C), the pharmaceutical composition of the present invention may optionally include a water-soluble polymer, a water-insoluble polymer, an enteric polymer, and a gastric polymer. It is also possible to mix an appropriate amount of a polymer material such as As such a polymer substance, specifically, hydroxycellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, Carmellose, carmellose sodium, hydroxyethyl cellulose, cyclodextrin, cyclodextrin derivative, aminoalkyl methacrylate copolymer E, alkyl methacrylate copolymer RS, methacrylate copolymer L, methacrylate copolymer S, carboxyvinyl polymer, polyvinyl acetal diethylaminiacetate, polyvinyla Call, sodium alginate, propylene glycol alginate, gelatin, shellac, and the like.

  In addition to the above, the pharmaceutical composition of the present invention includes ion exchange resins, solubilizers, plasticizers, diluents, sweeteners, lubricants, excipients or fillers, enzyme inhibitors, and anti-adhesives. , Anticoagulants, antifoaming agents, binders, pH adjusters or buffers, chelating agents, coagulants, binders, fragrance desensitizers, flavoring agents, preservatives antioxidants, antifreeze agents, colorants, An appropriate amount of additives such as an opacifier, a cooling agent, a solvent, a thickener, and a disintegrant may be blended. Specific examples of such additives include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, macrogol 400, macrogol 4000, macrogol 600, macrogol 10000, macrogol 6000, lactose, sucrose, mannitol, sodium chloride, glucose, calcium carbonate, kaolin, crystalline cellulose , Silicate, water, ethanol, simple syrup, glucose solution, starch solution, gelatin solution, dextrin, Pullulan, citric acid, anhydrous citric acid, sodium citrate, sodium citrate dihydrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate, polysorbate 80, quaternary ammonium base, purification Talc, stearate, polyethylene glycol, colloidal silicic acid, yellow iron oxide, yellow iron sesquioxide, iron sesquioxide, β-carotene, titanium oxide, food coloring (eg food blue No. 1 etc.), copper chlorophyll, riboflavin, Examples include ascorbic acid, aspartame, amateur, sodium chloride, fructose, saccharin, and powdered sugar.

  The blending ratio of these additives can be appropriately set according to the use of the pharmaceutical composition and the preparation form.

The form of the pharmaceutical composition 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, liquids, suspensions and the like. It is done. In addition, 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 a capsule form, enteric capsules may be employed.

Method for Producing Pharmaceutical Composition The pharmaceutical composition of the present invention can be produced according to a known production method. That is, after adding a predetermined amount of the above components (A) to (C) and, if necessary, other additives and mixing with heating, the resulting mixture is used to form the desired preparation form, thereby The pharmaceutical composition of the invention is prepared.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, a test example, etc., this invention is not limited by these.

Example 1 Enteric capsule 10 g of rebamipide, 5 g of sodium lauryl sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.), and Witepsol H-15 (triglyceride of saturated fatty acid having 12 to 18 carbon atoms, melting point 33.5 to 35.5 ° C., Dynamin After adding 55 g of Nobel (Germany) and using a heating stirrer (set temperature 80 ° C., IWAKI GLASS1) to make a mixed solution, 700 mg of the obtained mixed solution was enteric capsule (material: hydroxypropyl) Poured into methylcellulose acetate succinate (manufactured by Shionogi Qualicaps Co., Ltd.) to obtain an enteric capsule (rebamipide content per capsule: 100 mg).

Example 2 Enteric Capsule 20 g of rebamipide, 20 g of sodium lauryl sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) and Witepsol H-15 (triglyceride of saturated fatty acid having 12 to 18 carbon atoms, melting point 33.5 to 35.5 ° C., Dynamin After adding 100 g of Nobel (Germany) and using a heating stirrer (set temperature 80 ° C., manufactured by IWAKI GLASS1), 150 mg of the resulting mixture was enteric capsule (material: hydroxypropyl) Methyl cellulose acetate succinate, manufactured by Shionogi Qualicaps Co., Ltd.) to obtain an enteric capsule.

Example 3 Soft capsule 20 g of rebamipide, 20 g of sodium lauryl sulfate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and 100 g of Witepsol (Mitsuba Trading Co., Ltd.) were added and mixed using a heating stirrer (set temperature 80 ° C., manufactured by IWAKI GLASS1). After that, 150 mg of the obtained mixed solution was poured into soft capsules to obtain soft capsules.

Example 4 Tablet 20 g of rebamipide, 20 g of sodium laurate (manufactured by Tokyo Chemical Industry Co., Ltd.), Witepsol H-15 (triglyceride of saturated fatty acid having 12 to 18 carbon atoms, melting point 33.5 to 35.5 ° C., manufactured by Dynanami Nobel ( Germany)) 100 g, corn starch (Nihon Shokuhin Kako Co., Ltd.) 100 g, and crystalline cellulose (Asahi Kasei Co., Ltd.) 100 g are mixed. Tableting was performed with a 5 mm mortar to obtain tablets (weight per tablet: 340.5 mg).

Example 5 Tablet 20 g of rebamipide, 20 g of sodium laurate (manufactured by Tokyo Chemical Industry Co., Ltd.), Witepsol H-15 (triglyceride of saturated fatty acid having 12 to 18 carbon atoms, melting point 33.5 to 35.5 ° C., manufactured by Dynanami Nobel ( Germany)) 100 g, corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) 100 g, and crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) 100 g are mixed. Tableting was performed with a 0 mm mortar to obtain tablets (weight per tablet: 340.5 mg).

Example 6 Granules 20 g of rebamipide, 20 g of sodium laurate (manufactured by Tokyo Chemical Industry Co., Ltd.), Witepsol H-15 (triglyceride of saturated fatty acid having 12 to 18 carbon atoms, melting point 33.5 to 35.5 ° C., manufactured by Dynanami Nobel) (Germany)) 100 g, 100 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.), and 100 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) are added to a kneader (NSK-150 manufactured by Okada Seiko Co., Ltd.) and mixed. Get a kneaded product. The resulting kneaded product was subjected to extrusion granulation with an extrusion granulator equipped with a dome die with a 0.8 mm hole (Dome Gran DG-L1 manufactured by Fuji Powder Co.), and then a spherical granulator (Fuji Powder Co., Ltd.). Spherical sizing with Malmerizer QJ-400). The obtained granules are dried to obtain granules.

Example 7 Granule Further, the granule of Example 6 was 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 form a coating granule. Get.

Comparative Example 1 Enteric Capsule 100 mg of rebamipide was placed in an enteric capsule (material: hydroxypropylmethylcellulose acetate succinate, manufactured by Shionogi Qualicaps Co., Ltd.) to obtain an enteric capsule.

Comparative Example 2 Enteric Capsule 100 mg of rebamipide and 50 mg of sodium laurate (Tokyo Chemical Industry Co., Ltd.) are contained in an enteric capsule (material: hydroxypropyl methylcellulose acetate succinate, manufactured by Shionogi Qualicaps Co., Ltd.) Got.

Test example 1
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.

  The resulting blood drug concentration transition is shown in FIG. 1, and the average pharmacokinetic parameters are shown in Table 1. From this result, in the preparation in which rebamipide and sodium laurate were mixed, the effect of improving rebamipide absorbability was hardly observed (see the result of Comparative Example 2). On the other hand, the rebamipide absorbability was remarkably improved in a preparation containing rebamipide, sodium laurate and triglycerides of higher saturated fatty acids. 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).

  From the above results, by combining a pharmacologically active substance, a drug absorption promoter, and a wax that dissolves in vivo, the absorbability of the pharmacologically active substance in the lower gastrointestinal tract is improved. It was confirmed that the action can be effectively exhibited.

  In addition, from the above results, even when other hardly soluble pharmacologically active substances (for example, theophylline, cilostazol, probucol, tolvaptan, etc.) are used as the pharmacologically active substance instead of rebamipide, absorption of the pharmacologically active substance in the lower digestive tract It is understood that the pharmacological action of the pharmacologically active substance can be effectively exhibited.

In Test Example 1, it is a figure which shows a time-dependent change of the average density | concentration of the pharmacologically active substance (rebamipide) in the blood when the enteric capsule of Example 1, the comparative example 1 or 2 is orally administered to a beagle dog, respectively.

Claims (7)

(A) rebamipide, (B) an alkali metal salt of a fatty acid having 6 to 18 carbon atoms , and (C) a glycerin fatty acid ester which is an ester of a higher fatty acid having 12 to 28 carbon atoms is mixed and contained. An oral pharmaceutical composition. The oral pharmaceutical composition according to claim 1, wherein component (B) is at least one selected from the group consisting of lauryl sulfate, capric acid, and alkali metal salts of lauric acid . The oral pharmaceutical composition according to claim 1, wherein the component (C) is a mono-, di- or triglyceride of a saturated fatty acid having 12 to 18 carbon atoms . Component (B) is at least one selected from the group consisting of lauryl sulfate, capric acid, and alkali metal salts of lauric acid , and component (C) is a mono-, di- or di-saturated fatty acid having 12 to 18 carbon atoms. The oral pharmaceutical composition according to claim 1, which is triglyceride . The total amount of the oral pharmaceutical composition contains 0.0001 to 90% by weight of component (A), 0.01 to 90% by weight of component (B), and 1 to 95% by weight of component (C). The oral pharmaceutical composition in any one of 1-4. The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the component (C) is contained at a ratio of 1 to 10,000 parts by weight with respect to 100 parts by weight of the component (B). For the production of an oral pharmaceutical composition containing (A) rebamipide of (B) an alkali metal salt of a fatty acid having 6 to 18 carbon atoms and (C) a glycerin fatty acid ester which is an ester of a higher fatty acid having 12 to 28 carbon atoms Use of.

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