Solvent system of hardly soluble drug with improved dissolution rate

• US 20040157928A1
• Filed: 10/14/2003
• Published: 08/12/2004
• Est. Priority Date: 02/12/2003
• Status: Abandoned Application

• Current Assignee: R & P Korea Co., Ltd. (Daewoong Co., Ltd.)
• Original Assignee: R & P Korea Co., Ltd. (Daewoong Co., Ltd.)
• Inventors: Kim, Jae-Hwan, Lee, So-Ra, Yi, Jae-Hun, Shin, Woo-Choul, Lee, Kyung-Sik
• Application Number:
  US10/682,989
• Publication Number:
  US 20040157928A1
• Time in Patent Office: Days
• US Class Current: 514/570
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention relates to a solvent system with improved disintegration degree and dissolution ratio of a hardly soluble drug by highly concentrating the drug through partial ionization, and by establishing optimal conditions for enhancing bioavailability of the drug, such as the co-relation between the acid drug and the accompanied components, ionization degree of a solvent system, use of an appropriate cation acceptance, water content, selection of optimal mixing ratio of the respective components and use of specific surfactants, and to a pharmaceutical preparation comprising the same. The solvent system of the invention has advantages in that it can enhance bioavailability by improving the disintegration degree and dissolution ratio of a hardly soluble drug and also provide a capsule with a sufficiently small volume to permit easy swallowing.

Claims

1. A pharmaceutical preparation comprising a hardly soluble acidic drug and a solvent system therefor, in which the solvent system comprises a pharmaceutically acceptable cation acceptance, 10 to 90% by weight of polyethylene glycol, 0.1 to 15% by weight of water and 0.1 to 50% by weight of a surfactant having an HLB value of 3 to 40 to improve the dissolution rate of the drug, and the said pharmaceutically acceptable cation acceptance increases solubility of the drug by partially ionize the hardly soluble acidic drug so that the drug exists in both forms of a free acid and a cationic salt, and is contained in an amount of 0.1 to 2 mole equivalent per mole of acidic groups in the acidic drug.

2. The pharmaceutical preparation according to claim 1, wherein the hardly soluble acidic drug is selected from the group consisting of Naproxen (C₁₄H₁₄O₃, M.W 230.26), R,S-Ibuprofen (C₁₃H₁₈O₂, M.W 206.28), Dexibuprofen(S-Ibuprofen, C₁₃H₁₈O₂, M.W 206.28), Indomethacin (C₁₉H₁₆ClNO₄, M.W 357.79), Acetaminophen (M.W 151.17), Mefenamic acid (C₁₅H₁₅NO₂, M.W 241.29), Chlorocinnazine hydrochloride (C₂₆H₂₇N₂Cl.2HCl, MW:

475.88), Loxoprofen (C₁₅H₁₈O₃, MW;

246.31), Fenoprofen(C₁₅H₁₄O₃, MW;

242.27), Ketoprofen (C₁₆H₁₄O₃, MW;

254.29), Pranoprofen (C₁₅H₁₃NO₃, MW;

255.27), Meclofenamic acid (C₁₄H₁₁Cl₂NO₂, MW;

296.15) and salts thereof, Sulindac(C₂₀H₁₇FO₃S, MW;

356.42), Piroxicam (C₁₅H₁₃N₃O₄S, MW;

331.35), Meloxicam (C₁₄H₁₃N₃O₄S₂, MW;

351.41), Tenoxicam(C₁₃H₁₁N₃O₄S₂, MW;

337.38), Diclofenac (C₁₄H₁₁Cl₂NO₂, MW;

296.15), Aceclofenac(C₁₆H₁₃Cl₂NO₄, MW;

354.19), Rebamipide (C₁₉H₁₅ClN₂O₄, MW;

370.79), Enalapril maleate(C₂₀H₂₈N₂O₅, MW;

492.52), Captopril (C₉H₁₅NO₃S, MW;

217.29), Ramipril (C₂₃H₃₂N₂O₅ MW;

416.52), Fosinopril(C₃₀H₄₆NO₇P, MW;

563.67), Benazepril (C₂₄H₂₈N₂O₅, MW;

424.50), Quinapril hydrochloride (C₂₅H₃₀N₂O₅ HCl, MW;

474.99), Temocapril (C₂₃H₂₈N₂0₅S₂ MW;

476.62), Cilazapril (C₂₂H₃₁N₃O₅ MW;

417.51), Lisinopril (C₂₁H₃₁N₃O₅, MW;

405.50), Valsartan (C₂₄H₂₉N₅O₃, MW;

435.53), Losartan potassium (C₂₂H₂₂ClKN₆O MW;

461.01), Irbesartan (C₂₅H₂₈N₆O MW;

428.54), Cetirizine hydrochloride (C₂₁H₂₅ClN₂O₃, MW;

388.90), Diphenhydramine hydrochloride (C₁₇H₂₁NO. HCl, MW;

291.82), Fexofenadine (C₃₂H₃₉NO₄, MW;

501.67), Pseudoephedrine hydrochloride (C₁₀H₁₅NO HCl, MW;

201.70), Methylephedrine hydorchloride (C₁₁H₁₇NO.HCl, MW;

215.72), Dextromethorphan hydrobromide (C₁₈H₂₅NO HBr H₂O, MW;

370.33), Guaifenesin (C₁₀H₁₄O₄, MW;

198.22), Noscapine (C₂₂H₂₃NO₇, MW;

413.43), Tri-metoquinol hydrocloride (C₁₉H₂₃NO₅. HCl, MW;

399.87), Doxylamine succinate (C₁₇H₂₂N₂O, C₄H₆O₄, MW;

388.5), Ambroxol (C₁₃H₁₈Br₂N₂O, MW;

378.11), Letosteine (C₁₀H₁₇NO₄S₂, MW;

279.37), Sobrerol (C₁₀H₁₈O₂, MW;

170.25), Bromhexine hydrochloride (C₁₄H₂₀Br₂N₂ HCl, MW;

412.59), Chlorpheniramine Maleate (C₁₆H₁₉ClN₂. C₄H₄O₄, MW;

390.87) and optical isomers thereof.

3. The pharmaceutical preparation according to claim 1, wherein the cation acceptance is selected from the group consisting of pharmaceutically acceptable basic compounds, metallic salts of week acids, amines and mixtures thereof which can be dissociated into a cation and an anion or take hydrogen ion.

4. The Pharmaceutical preparation according to claim 1, wherein the cation acceptance is selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium acetate, potassium acetate, potassium citrate, sodium citrate, prolamine, diethanol amine, mono-ethanol amine, tri-ethanol amine, lysine, methylglucamine and mixtures thereof.

5. The pharmaceutical preparation according to claim 1, wherein water is contained in an amount of 50% or more based on the weight of the cation acceptance.

6. The pharmaceutical preparation according to claim 1, wherein the surfactant is one selected from the group consisting of reaction products of natural or hydrogenated vegetable oils and ethylene glycol, polyoxyethylene sorbitan fatty acid esters, transesterification products of natural vegetable oil tri-glycerides and polyalkylene polyols, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, propylene glycol mono- and di-fatty acid esters, pharmaceutically acceptable C_1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of low molecular mono- or poly-oxy-alkanediols, polyoxyethylene fatty acid ethers, polyoxyethylene-polyoxypropylene copolymers or a mixture of two or more thereof.

7. The pharmaceutical preparation according to claim 6, wherein the surfactant is one selected from the group consisting of Cremophor RH40 (Polyoxyl 40 hydrogenated castor oil), Cremophor EL (Polyoxyl 35 castor oil), Labrasol (polyethylene glycol caprylate/caprate), Transcutol (diethylene glycolmono-ethyl ether), Tween (polysorbate) 20, 21, 40, 61, 65, 80, 81, 85, 120, Poloxamer 124, 188, 237, 338, 407 (polyoxyethylene-polyoxypropylene), Nikkol HCO-40 (polyoxyethylene glycolated natural or hydrogenated castor oil), Myrj 45 (polyoxyethylene(8)stearate), Tagat L (polyoxyethylene(30) mono-laurate), Marlosol 1820 (polyoxyethylene(20) stearate), Marlosol OL 15 (polyoxyethylene(15) oleate), Brjj 96 (polyoxyethylene(10) oleyl ether), Volpo 015 (polyoxyethylene(15) oleyl ether), Marlowet OA30 (polyoxyethylene(30) oley ether), Marlowet LMA 20 (polyoxyethylene(20) oleyl ether), Syperonic PE L44 (polyoxyethylene-polyoxypropylene copolymer), Syperonic F127 (polyoxyethylene-polyoxypropylene copolymer, Labrafil M 2125 CS (linoleoyl macrogol glycerides), Labrafac PG (propylene glycol dicaprylocaprate), Imbitor (caprylic acid/capric acid mono- and di-glyceride), sorbitan mono-stearate, sorbitan tri-stearate, sorbitan mono-oleate, polyethylene glycol mono-oleate, MIGLYOL 840 (propylene glycol dicaprylate), Gelucir 44/14 (lauroyl polyoxyl-32 glyceride) and the mixtures thereof.

8. The pharmaceutical preparation according to claim 2, wherein the polyethylene glycol has an average molecular weight of 200 to 800.

9. The pharmaceutical preparation according to claim 2, wherein the polyethylene glycol is replaced by one selected from the group consisting of tetraglycol, polyethylene glycol ethers of alcohols and polyethylene glycol copolymers.

10. The pharmaceutical preparation according to claim 1, wherein pH of the solvent system is in the range of 2.0 to 8.0.

11. A soft capsule comprising the pharmaceutical preparation according to claim 1 and a shell composition comprising, based on the dry weight of the shell, 30 to 65% of gelatin, 10 to 40% of Esitol and sorbitans, 1 to 15% of water and, if necessary, a preservative, a coloring agent, a fragrance, an light blocking agent, a flavoring agent, a disintegration enhancer, succinated gelatin.

12. The soft capsule according to claim 11, which further comprises a subsidiary component selected from the group consisting of glycerin, propylene glycol, propyl carbonate, polyvinylpyrrolidone and an anti-oxidant.

13. A two-piece capsule or tablet comprising the solvent system of the pharmaceutical preparation according to claim 1.