MXPA01003731A - Sustained release pharmaceutical composition and method of releasing pharmaceutically active agent - Google Patents
Sustained release pharmaceutical composition and method of releasing pharmaceutically active agentInfo
- Publication number
- MXPA01003731A MXPA01003731A MXPA/A/2001/003731A MXPA01003731A MXPA01003731A MX PA01003731 A MXPA01003731 A MX PA01003731A MX PA01003731 A MXPA01003731 A MX PA01003731A MX PA01003731 A MXPA01003731 A MX PA01003731A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- average molecular
- weight
- molecular weight
- composition
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
- 230000002459 sustained Effects 0.000 title abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 53
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 36
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 35
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 35
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 23
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 21
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 21
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 20
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 12
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 11
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 56
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 19
- FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 claims description 15
- 229960003765 fluvastatin Drugs 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000005977 Ethylene Substances 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- -1 sustained release Substances 0.000 abstract description 27
- 230000001225 therapeutic Effects 0.000 abstract description 4
- 239000006186 oral dosage form Substances 0.000 abstract description 3
- 239000007787 solid Substances 0.000 abstract description 2
- LFSAPCRASZRSKS-UHFFFAOYSA-N 2-methylcyclohexan-1-one Chemical compound CC1CCCCC1=O LFSAPCRASZRSKS-UHFFFAOYSA-N 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 16
- 239000002552 dosage form Substances 0.000 description 16
- 230000037406 food intake Effects 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 9
- 230000002028 premature Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000499 gel Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229940096701 plain lipid modifying drugs HMG CoA reductase inhibitors Drugs 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 229920003091 Methocel™ Polymers 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 210000000056 organs Anatomy 0.000 description 4
- 210000003169 Central Nervous System Anatomy 0.000 description 3
- 229940107161 Cholesterol Drugs 0.000 description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N Lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940083542 Sodium Drugs 0.000 description 3
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 3
- 239000008351 acetate buffer Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004880 explosion Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229960004844 lovastatin Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940094025 potassium bicarbonate Drugs 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940075564 ANHYDROUS DIBASIC SODIUM PHOSPHATE Drugs 0.000 description 2
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N Carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N Cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N Codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N Ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 229960000868 Fluvastatin sodium Drugs 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
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- 229940045641 Monobasic Sodium Phosphate Drugs 0.000 description 2
- 229940069328 Povidone Drugs 0.000 description 2
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- LOUPRKONTZGTKE-LHHVKLHASA-N Quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N Simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 229960000278 Theophylline Drugs 0.000 description 2
- 230000003288 anthiarrhythmic Effects 0.000 description 2
- 230000001396 anti-anti-diuretic Effects 0.000 description 2
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- 230000001088 anti-asthma Effects 0.000 description 2
- 230000002429 anti-coagulation Effects 0.000 description 2
- 230000001773 anti-convulsant Effects 0.000 description 2
- 230000001430 anti-depressive Effects 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
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- 229960000623 carbamazepine Drugs 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
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- 239000011248 coating agent Substances 0.000 description 2
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- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000002218 hypoglycaemic Effects 0.000 description 2
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
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- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
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- NZHGWWWHIYHZNX-CSKARUKUSA-N 2-[[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino]benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940054556 metaproterenol Drugs 0.000 description 1
- 229950006804 methylclothiazide Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960002817 metolazone Drugs 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229960000993 norethisterone Drugs 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 229940005943 ophthalmologic Antivirals Drugs 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
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- 229960002702 piroxicam Drugs 0.000 description 1
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
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- 229960003111 prochlorperazine Drugs 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
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- 229960003471 retinol Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
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Abstract
The present invention is directed to solid, sustained-release, oral dosage form pharmaceutical compositions which contain therapeutic amounts of a pharmaceutically active agent, hydroxypropyl methyl cellulose and anon-ionic, hydrophilic polymer selected from the group consisting of hydroxyethyl cellulose having a number average molecular weight ranging from 90,000 to 1,300,000, hydroxypropyl cellulose having a number average molecular weight of 370,000 to 1,500,000, and poly(ethylene oxide) having a number average molecular weight ranging from 100,000 to 500,000.
Description
PHARMACEUTICAL COMPOSITION OF SUSTAINED RELEASE, AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT
Field of the Invention The present invention relates to sustained release oral dosage forms of pharmaceutical compositions.
BACKGROUND OF THE INVENTION Sustained-release oral dosage forms of conventional pharmaceutical compositions are used for a number of reasons. These compositions provide for the delivery of a pharmaceutically active agent for a prolonged period of time, against the non-sustained release or immediate release compositions, wherein all the pharmaceutically active agent is supplied for a short period of time immediately after ingestion. the composition. Because this immediate release results in the peak concentration of the active agent in the patient's system followed by reduced concentrations below the therapeutically effective levels, the non-sustained release compositions are usually administered in several separate dosages throughout. the day. Accordingly, conventional sustained release compositions provide advantages over compositions that are not sustained release, by providing the ability to reduce the number of doses required in a given period of time, for example a single dosage against multiple dosages, improving the compliance of the patient, and providing a concentration of the most constant active agent in the blood for prolonged periods of time. Although sustained release compositions typically allow for a single administration of the required dosage of the active agent during a desired delivery period, eg, a single daily dosage, however, these compositions may exhibit a premature release of significant amounts of the active agent. For a number of reasons, this premature release, or "explosion", of the pharmaceutically active agent can decrease the overall therapeutic efficiency of the active agent that is being delivered. A problem arises when the organ to which the active agent is delivered processes the active agent at a constant rate. Accordingly, the premature release results in an amount of the active agent in excess of the amount that the organ can process in a given time, i.e., the organ is "flooded" with the active agent. Accordingly, much of the active agent can pass through the organ without being processed, and essentially is lost in the user's system, where it does not provide any therapeutic effect.
U.S. Patent No. 5,376,383 teaches, in Example 8, a matrix delivery system containing the therapeutic agent lovastatin, a hydroxypropylcellulose (KLUCEL®LF), and a hydroxypropylmethylcellulose (METHOCEL® E5 and METHOCEL® K15M) . KLUCEL® LF, according to the manufacturer's literature, has a molecular weight range of approximately 95,000. At this low molecular weight, it is not known that KLUCEL® LF has any effect on the release profile of the matrix delivery system. The '383 patent remains silent with respect to the release profile soon after administration. It is desirable to develop a composition that provides all the advantages of conventional sustained release compositions and yet which minimizes the premature release of significant amounts of the active agent. Brief Description of the Figures Figure 1 is a graph illustrating the dissolution against time of a composition in water, wherein the amount of hydroxypropylmethylcellulose in the composition has varied. Figure 2 is a graph illustrating the dissolution against time of compositions in acetate buffer, pH of Figure 3 is a graph illustrating the dissolution
6. 8. Figure 4 is a graph illustrating the dissolution against time of compositions in water. Figure 5 is a graph illustrating the dissolution against time of a composition containing both hydroxypropylmethylcellulose and hydroxypropylcellulose, wherein the dissolution medium is a phosphate buffer, pH of 6.8. Figure 6 is a graph illustrating the dissolution against time of a composition containing hydroxypropylmethylcellulose, but not hydroxypropylcellulose, wherein the dissolution medium is a phosphate buffer, pH 6.8.
SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition containing a pharmaceutically active agent, hydroxypropylmethylcellulose, and a nonionic hydrophilic polymer selected from the group consisting of hydroxyethylcellulose having a number average molecular weight of from 90,000 to 1,300,000, hydroxypropylcellulose having a number average molecular weight of 370,000 to 1,500,000, and poly (ethylene oxide) having a number average molecular weight of 100,000 to 500,000.
The present invention also relates to a method for releasing a pharmaceutically active agent in a mammal, wherein the method includes orally administering the pharmaceutically active agent to the mammal as part of a pharmaceutical composition which includes the pharmaceutically active agent, hydroxypropylmethylcellulose; and a nonionic hydrophilic polymer selected from the group consisting of hydroxyethylcellulose having a number average molecular weight of 90,000 to 1,300,000, hydroxypropylcellulose having a number average molecular weight of 370,000 to 1,500,000, and ethylene) having a number average molecular weight of 370,000 to 500,000.
Detailed Description of the Invention In a surprising manner, it has been discovered that the compositions containing, in addition to hydroxypropylmethylcellulose (hereinafter "HPMC"), at least one nonionic hydrophilic polymer, prevent the premature release of the pharmaceutically active agent. from the
composition. As used herein, "premature release" means that a substantial amount of the pharmaceutically active agent is released in a short period of time after ingestion of the composition, for example in an explosion, such that the amount of agent active
converted to a bioavailable form, is in excess of the
Y ^ tiSÉÉM. *, ^^ ^. ^, ^ Quantity of the active agent that can be processed in an efficient way in the directed active site. Accordingly, the prematurely released active agent can be derived from the directed active site without being processed. As a result, the therapeutic efficacy of the pharmaceutical composition can be reduced. The nonionic hydrophilic polymers used in the pharmaceutical composition are selected from the group consisting of hydroxyethylcellulose (hereinafter "HEC"), which has a number average molecular weight of from 90,000 to 1,300,000, preferably from about 1,000,000 to about 1,300,000, hydroxypropylcellulose (hereinafter "HPC"), which has a number average molecular weight of from 370,000 to 1,500,000, preferably from 850,000 to 1,500,000, more preferably from 1,000,000 to 1,200,000, and poly (ethylene oxide) (subsequently in the present "PEO") having a number average molecular weight of from 100,000 to 500,000, preferably from 150,000 to 300,000, and more preferably from 200,000. Examples of hydroxyethylcellulose polymers are commercially available from Hercules Incorporated, Aqualon Division, under the tradename NATROSOL®250H or NATROSOL®250L. Examples of the hydroxypropyl cellulose polymers are also available from Hercules Incorporation, Aqualon Division under the tradename KLUCEL® or KLUCEL® HXF, and examples of the poly (ethylene oxide) polymers are available from Union Carbide Corporatífa, under the trade name POLYOX®. Methods for making the nonionic hydrophilic polymers for use in the compositions described herein are known to those skilled in the art. The nonionic hydrophilic polymer may be present in the pharmaceutical composition in an amount of from about 1 to about 20 weight percent, preferably from about 3 to about 12 weight percent, more preferably from about 4 to about about 7 percent by weight. The nonionic hydrophilic polymer is present in an amount sufficient to prevent premature release of the pharmaceutically active agent. As mentioned, the pharmaceutical compositions described herein also contain hydroxypropylmethylcellulose in an amount effective to provide sustained release of the pharmaceutically active agent after its ingestion. As used herein, "sustained release" means that the pharmaceutically active agent is released from the dosage form over a prolonged period of time, for example greater than about 6 hours. Preferably, the pharmaceutical compositions release less than about 80 weight percent of the active agent in the first 8 hours after ingestion of the composition, the remainder of the pharmaceutically active agent being released thereafter. In the preferred compositions, less than about 15 weight percent of the pharmaceutically active agent is released in the first half hour after ingestion, about 10 to about 50 weight percent of the pharmaceutically active agent is released within 10 hours. about 2 hours after ingestion, and about 40 to about 60 weight percent of the pharmaceutically active agent is released within about 6 hours after ingestion. The pharmaceutical compositions comprise from about 15 to about 50 weight percent of hydroxypropylmethylcellulose, preferably from about 20 to about 40 weight percent of hydroxypropylmethylcellulose, based on the total weight of the composition. The hydroxypropylmethylcellulose and the nonionic hydrophilic polymer are preferably present in a weight ratio of the hydroxypropylmethylcellulose to the nonionic hydrophilic polymer of from about 10: 1 to about 3: 1, more preferably from about 7: 1 to about 5: 1, and still more preferably of about 6: 1. A hydroxypropylmethylcellulose polymer useful in the pharmaceutical composition described herein is commercially available from Dow Chemical under the tradename METHOCEL®. Preferably, the hydroxypropylmethylcellulose will have a degree of hydroxypropyl (HP) substitution of up to about 12, ie, or -hydroxypropylmethylcellulose will comprise up to about 12 percent hydroxypropyl functionality. Preferably, the hydroxypropylmethylcellulose will comprise from about 7 to about 12 percent hydroxypropyl functionality, and more preferably from about 7 to about 9 percent hydroxypropyl. The hydroxypropylmethylcellulose will preferably have a normal viscosity (2.0 percent hydroxypropylmethylcellulose in water) of about 100 to about 100,000 cps, and a number average molecular weight of about 20,000 to about 170,000. A particularly preferred hydroxypropylmethylcellulose is METHOCEL® K100LV, which has a number average molecular weight of from about 20,000 to about 30,000. The methods for making these hydroxypropylmethylcellulose polymers are well known to those skilled in the art. After ingestion, the nonionic hydrophilic polymer and the hydroxypropylmethylcellulose form a gel matrix in which the active agent is contained. The pharmaceutically active agent is then released from the gel matrix over time, thereby providing sustained release
The active agent can be expressed in such a way that a substantial amount of the active agent released can be processed efficiently in the targeted active site. Preferably, the gel matrix has sufficient strength to prevent premature substantial degradation of the matrix. The gel matrix must also be formed within a period of time that is effective to prevent premature release of the active agent prior to the formation of the gel matrix. For example, the gel matrix is preferably formed within about 5 minutes after ingestion of the composition, to prevent an explosion of the active agent prior to gel formation. It is believed that the nonionic hydrophilic polymer operates to decrease the rate of gel formation to an acceptable level. Typical pharmaceutically active agents that can be administered by the present invention include, but are not limited to: (a) agents for the central nervous system
(CNS), such as antipsychotics, anticonvulsants, including carbamazepine and oxacarbazepine, antidepressants, antiepileptics, anxiolytics, and hypnotics; (b) cardiovascular agents, such as antiarrhythmic, hypolipidemic, antianginal, anticoagulant, antihypertensive, antiplatelet, diuretic, and electrolyte (Ca, K, Mg); and (c) anti-inflammatory, anti-asthmatic, anti-arthritic, oral hypoglycemic, and aromatase inhibitors; to name
«^ --- iiMtmrH a few. The pharmaceutically active agents that can be delivered include inorganic and organic compounds without limitation, including drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular, smooth muscles, circulatory blood system, synaptic sites, neuroefector binding sites, endocrine and hormone systems, immune system, reproductive system, system
Skeletal, food and excretory systems, hormone and histamine inhibitor systems, those materials that act on the central nervous system, such as antidepressants, including amiflamin, amitriptyline, alaproclate, protriptyline, doxepin, imiprimine, trazodine, paprotiline,
zimelidine, fluvoxa ina, antipsychotic-neuroleptic agents, such as chlorpromazine, haloperidol, thioridazine, trifluoperazine, MK-0212, remoxipride; anticonvulsants, such as carbamazepine, oxacarbamazepine, phenytoin, phenobarbital; sedative-hypnotic agents, such as triazolam,
chlordiazepoxide, temazepam, clorazepate, alprazolam, diazepam, flurazepam, lorazepam, oxazepam, hydroxyzine, prazepam, meprobamate, butalbital, orfenadrine, chlorzoxazone, cyclobenzaprine, antiparkinson agents, such as benzotropin, carbidopa, levodopa, L 647,339; analgesics, such as
acetaminophen, oxycodone, hydrocodone, codeine, and propoxyphene.
Respiratory agents can also be used, including sympathomimetics, bronchodilators, antihistamines; and anti-asthmatics, such as diethylpropion, ephedrine, epinephrine, isoproterenol, metaproterenol, terbutaline, cyproheptadine, azatadine, diphenhydramine, promethazine, chlorpheniramine, brompheniramine, aminophylline, theophylline, albuterol, tranilast, enprophyllin, and budesonide. Cardiovascular and antihypertensive agents can also be used, including coronary vasodilators, cardiac glycosides, beta blockers, slow calcium channel blockers, antiarrhythmics, peripheral vasodilators such as isosorbide dinitrate, nitroglycerin, dipyridamole, digoxin, nadolol, propranolol, metaprolol, atenolol, timolol, disopyramide, procainamide, nifedipine, quinidine, lidocaine, diltiazam, verapamil, prazosin, clinidine, hydralazine, methyldopa, captopril, metiresin, enalapril, lisinopril, felodipine, tocainide. Diuretics can also be used, such as amiloride, spiranolactone, hydrochlorothiazide, chlorothiazide, acetazolamide, chlorthalidone, metolazone, furosemide, triamterene, methyclothiazide, ethacrynic acid, indacrinone; antiarteriosclerotic agents, such as conjugated estrogens, estradiol, ethinylestradiol, diethyl-lesbesterol; progestins, such as progesterone, hydroxyprogesterone, medroxyprogesterone, norethindrone; glucocorticoids and mineralocorticoids, such as hydrocortisone, beta-etasone, dexamethasone, methylprednisolone,
^ * ^^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Non-steroidal anti-inflammatory agents, antiarthritic and anti-rat agents, such as allopurinol, aspirin, fenprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, sulindac, tolmetin, diflunisol, piroxicam, meclofenamate, penicillamine, probenecid, and colchicine; gastrointestinal agents, including anticholinergic, antispasmodic, antidiarrheal; and histamine-H2 antiulcer antagonists, such as bethanechol, clidinium, dicyclomin, meclizine, prochlorperazine, trimethobenzamide, loperamide, cimetadma, ranitidine, diphenoxylate, famotidine, and omeprazole; oral hypoglycemics, such as chlorpropamide, tolazamide, and tolbutamide; anticoagulants, such as warfarin, phenindione, and anisindione; anti-infective agents, including antibiotics, antimicrobials, antivirals, antiparasitic agents; and antifungal agents, such as cefoxitin, thiabendazole, cephalexin, tetracycline, ampicillin, amoxicillin, sulfamethoxa-col, cefaclor, erythromycin, penicillin, nitrofurantoin, minocycline, doxycycline, cefadroxil, miconazole, phenazopyridine, norfloxacin, clorsulon, fludalanin, pentizidone, cilastine, phosphonomycin, ivermectin, imipenem, arprinocida, and foscarnet; nutritional supplements, including vitamins, such as isotretinion (Vitamin A), Vitamin D, tocopherols (Vitamin E), and phytonadione (Vitamin K); amino acids, such as L-tryptophan and L-lysine; and lipids, such as corn oil and medium chain triglycerides. Another class of pharmaceutical agents that can be used include those agents that help reduce cholesterol in humans. The above-mentioned pharmaceutically active agents may be present in the pharmaceutical composition in an amount of from about 0.1 to about 80 weight percent, preferably from about 10 to about 50 weight percent, more preferably from about 20 weight percent. at about 40 weight percent. A class of pharmaceutically active agents known as inhibitors of HMG-CoA reductase is known, for use in certain pharmaceutical compositions, in order to improve the decrease of plasma cholesterol level in humans. Methods for making the HMG-CoA reductase inhibitors are well known to those skilled in the art, and these agents include those commercially available as fluvastatin (available from Novartis Pharmaceuticals, Inc. under the tradename LESCOL®), simvastatin (available in Merck and Co., Inc. under the tradename ZOCOR®), atorvastatin (available from Warner-Lambert under the tradename LIPITOR®), pravastatin (available from Bristol-Myer Squibb, under the tradename PRAVACHOL®), cerivastatin ( available from BASF under the trade name LIPOBAY®), lovastatin (available from Merck &Co. Inc. under
commercial name MEVACOR®), and mevastatma. The HMG-CoA reductase inhibitors can be used in their free acid forms, in their ester forms, or as their pharmaceutically acceptable salts. These pharmaceutically acceptable salts include, for example, sodium salts, calcium salts, and ester salts. The HMG-CoA reductase inhibitors can be used as racemic mixtures, or as a more active stereoisomer, as appropriate. For example, a racemic mixture of 3-R-5-S-fluvastatma sodium and 3-S-5-R-fluvastatin sodium may be used, although it has been found that the 3-R-5-S-γ-luvastatin sodium stereoisomer It is the most active form. The HMG-CoA reductase inhibitors may be present in an amount effective to inhibit the biosynthesis of cholesterol in humans. In one embodiment, the pharmaceutical compositions comprise from about 5 to about 50 weight percent of the HMG-CoA reductase inhibitor, based on the total weight of the composition. In a more preferable way, the compositions comprise from about 20 to about 40 weight percent of the HMG-CoA reductase inhibitors, based on the total weight of the composition. Other ingredients that can be incorporated into the compositions to facilitate processing and / or provide improved properties of the composition include well-known tablet-forming binders (eg, gelatin, sugars, natural and synthetic gums, polyvinylpyrrolidone), disintegrants (e.g. croscarmellose, crospovidone, sodium starch glycolate), lubricants (eg, magnesium stearate, hydrogenated vegetable oil, carnauba wax); flow agents (eg, silicon dioxide), antiadhesives or brighteners (eg, talcum), as well as sweeteners, coloring agents (eg, iron oxide, aluminum flakes), fillers (eg, lactose and other carbohydrates, previously gelatinized starch, potassium bicarbonate), flavoring media, and antioxidants. The selection of a particular ingredient or combinations of ingredients, and the amounts used, may be readily determined by one skilled in the art, with reference to conventional procedures and practices for the preparation of dosage forms in tablets or encapsulated or other. The pharmaceutical compositions described herein may be administered to mammals, more particularly humans, as treatments associated with the particular pharmaceutically active agents included therein.
Example 1 A portion of fluvastatin is calculated and weighed
a ** *** »*** **» *** ^. ^.,. ^ -, ...
sodium Potassium bicarbonate, microcrystalline cellulose, povidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose are weighed and placed in individual containers labeled separately. Then an excess of 20 percent by weight of the lot amount of OPADRY® Yellow, YS-1-6347-G, is placed in a labeled container. Microcrystalline cellulose, fluvastatm sodium, povidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose are transferred, in that order, to a Collette Gral and mixed
for 5 minutes with the rake at low speed and the chopper off. The resulting mixture is passed through a 0.8382 millimeter mesh using a tornado mill with blades forward, and at a slow speed. Then the sieved material is mixed again in a Collette Gral with
the rake at slow speed and the chopper off. Potassium bicarbonate is dissolved in purified water until a clear homogenous solution is obtained. The solution of potassium bicarbonate is then combined with the sifted material, and the resulting mixture is granulated in a Collette Gral
with the rake at high speed and the chopper at slow speed. After adding the above solution, granulation should continue for 30 seconds with the rake at high speed and the chopper at low speed, and for another 30 seconds with the rake at high speed and the
mincer at fast speed. Then the granulated mixture is dried
in a fluid bed dryer using a target inlet temperature of 50 ° C, until a drying loss of 2 percent to 3 percent is obtained. The dried granules are then passed through a 1.5875 millimeter mesh using a tornado mill with blades forward and at low speed. An amount of magnesium stearate is calculated and weighed based on the ratio of the actual yield from the screening step of 1.5875 millimeters to the theoretical yield from the same step. The heavy magnesium stearate is then passed through a 60 mesh screen, and mixed with the dry granules in a free-fall mixer, and the resulting granulation mixture is discharged into a labeled drum coated with plastic. The granulation mixture is then compressed into tablets, and the tablets are dedusted, passed through a metal tester, and stored in a labeled plastic drum. To coat the tablets, OPADRY® Yellow is mixed with a required amount of purified water, to obtain a 10 percent weight / weight suspension. The tablets are transferred to a coating tray and heated to a temperature of 40 ° C to 45 ° C. The OPADRY® Yellow suspension is then added to spray-coat the tablets until a solid weight gain of 3 percent per tablet is achieved. The coating spray is deactivated, and the tablets are cooled by deactivating the heat of the
é222Yes.
tray, and vibrating the tray for 5 minutes.
Example 2 84.24 milligrams of fluvastatm sodium were combined with the following excipients according to the method described in Example 1, to provide a single dosage form described in Table 1:
TABLE 1
EXAMPLE 3 84.25 milligrams of fluvastatin sodium were combined with the following excipients, by the method described in Example 1, to provide a single dosage form described in Table 2:
TABLE 2
EXAMPLE 4 168.48 milligrams of fluvastatin sodium were combined with the following excipients, according to the method described in Example 1, to provide a single dosage form described in Table 3:
TABLE 3
üHí ^ i ii IÉMitaüütfiíi tiill j§H || ^ ^ ^ ^ ^ ^ ^ ^^^ ^ ^ ^ ^? Example 5
weight percent up to 10 percent by weight in increments of 5 percent by weight. Then each dosage form was tested to determine its dissolution in water, while stirring at a paddle speed of 50 rpm, at a temperature of 37 ° C. The results of each experiment were plotted on a graph as the percentage of dissolution against time, as shown in Figure 1.
Comparative Example 1 A dosage form having the composition described below was prepared in Table 4, according to the method described in Example 1: TABLE 4
Comparative Example 2 A dosage form having the composition shown plus Table 5 was prepared, according to the method described in
TABLE 5
Comparative Example 3 The dosage forms of Example 2, Example
Comparative 1, and Comparative Example 2, were tested to determine their dissolution at a temperature of 37 C, placing each dosage form in a 100 mM acetate buffer, and stirring at a paddle speed of 50 rpm. The acetate buffer contained 4.0 grams of sodium hydroxide dissolved in approximately 450 milliliters of water. The pH was adjusted to 4.0 by the addition of acetic acid, and the solution was diluted to one liter with distilled water.
The dissolution data were plotted on a graph as the percentage of dissolution against time, as shown in Figure 2. As you can see in the graph, the composition of fluvastatin The Comparative Example 1, which contained hydroxypropylcellulose but did not contain hydroxypropylmethylcellulose, showed an undesirably high dissolution rate, compared to the composition of Example 2.
Comparative Example 4 The dosage forms of Example 3 2, of Comparative Example 1, and Comparative Example 2, were tested for their dissolution at a temperature of 37 C, by placing each dosage form in a 50 mM phosphate buffer, pH of 6.8, and stirring at paddle speeds of 50 rpm and 100 rpm. The phosphate buffer contained 3,312 grams of monobasic sodium phosphate monohydrate, and 3,692 grams of anhydrous dibasic sodium phosphate dissolved in approximately 500 milliliters of water. The resulting solution was diluted to one liter with distilled water. The dissolution data were plotted on a graph as the percentage of dissolution against time, as shown in Figure 3. As can be seen in the graph, the fluvastatin composition of Example 2 showed a profile of
release comparable to a stirring speed of 50 rpm, to the compositions of fluvastatin having only one of hydroxypropylmethylcellulose or hydroxypropylcellulose. Comparative Example 5 The dosage forms of Example 2, of Comparative Example 1, and of Comparative Example 2, were tested for their dissolution at a temperature of 37 C, by placing each dosage form in distilled water, and stirring at a rate of the blades of 50 rpm. The results of each experiment were plotted on a graph as the percentage of dissolution against time, as shown in Figure 4. As can be seen in the graph, the fluvastatin composition of Example 2 showed a dissolution profile comparable to that of the fluvastatin compositions having only one of hydroxypropylmethylcellulose or hydroxypropylcellulose.
Comparative Example 6 The dosage forms of Example 2 and Example
Comparative 2, were repeatedly tested to determine their dissolution at a temperature of 37 ° C, by placing each dosage form in a 50 mM phosphate buffer, pH 6.8, and stirring at a paddle speed of 50 rpm. The phosphate buffer contained 3,312 grams of monobasic sodium phosphate monohydrate, and 3,692 grams of anhydrous dibasic sodium phosphate, dissolved in approximately 500 milliliters of water. The resulting solution was diluted to 1 liter with distilled water. 5 The dissolution data for Example 2 and for the
Comparative Example 2, were plotted on a graph as the percentage of dissolution against time, as shown in Figures 5 and 6, respectively. A comparison of Figures 5 and 6 shows that the composition of Example 2, which contained both hydroxypropylmethylcellulose and hydroxypropylcellulose, showed better reproducibility in its dissolution profile than the composition of Comparative Example 2, which only contained hydroxypropylmethylcellulose.
Claims (17)
1. A pharmaceutical composition, which comprises: fluvastatin or a pharmaceutically acceptable salt thereof, 5 hydroxypropylmethylcellulose, and a nonionic hydrophilic polymer selected from the group consisting of hydroxyethyl cellulose having an average molecular weight of from 90,000 to 1,300,000, hydroxypropyl cellulose having an average molecular weight in 10 number from 370,000 to 1,500,000, and poly (oxide of ethylene) having a number average molecular weight of 100,000 to 500,000.
2. A pharmaceutical composition of claim 1, wherein the nonionic hydrophilic polymer is selected from the group consisting of hydroxyethylcellulose, which has A number average molecular weight of 1,000,000 to 1,300,000, hydroxypropylcellulose having a number average molecular weight of 850,000 to 1,500,000, and poly (ethylene oxide) having a number average molecular weight of 150,000 to 300,000.
3. A pharmaceutical composition of claim 20, wherein the nonionic hydrophilic polymer is hydroxypropylcellulose having a number average molecular weight of about 1,150,000.
4. A pharmaceutical composition of claim 1, which comprises from about 5 to about 25 50 percent by weight fluvastatin or one salt ^^^^^^^^^^^^^, ^^ -. "^ HJlttfciííi i itMmMprrr rf ná?" Pharmaceutically acceptably thereof, based on the total weight of the composition
5. A pharmaceutical composition of claim 1, which comprises from about 20 to about 40 weight percent of fluvastatin or a pharmaceutically acceptable salt thereof, based on the total weight of the composition
6. A pharmaceutical composition of claim 1, which comprises from about 15 to about 50 weight percent of the hydroxypropylmethylcellulose, based on the total weight of the composition
7. A pharmaceutical composition of claim 1, which comprises from about 20 to about 40 percent of the hydroxypropylmethylcellulose, based on the total weight of the composition
8. A pharmaceutical composition of claim 1, which comprises from about 3 to about 12 percent in weight of the nonionic hydrophilic polymer, based on the total weight of the composition.
9. A pharmaceutical composition of the claim 1, which comprises from about 4 to about 7 weight percent of the nonionic hydrophilic polymer, based on the total weight of the composition.
10. A pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxypropylmethylcellulose to the nonionic hydrophilic polymer is from about 10: 1 to about 3: 1.
11. A pharmaceutical composition of claim 1, wherein the weight ratio of the hydroxypropylmethylcellulose to the nonionic hydrophilic polymer is from about 7: 1 to about 5: 1.
12. A method for lsiberar a pharmaceutically active agent in a mammal, wherein the method comprises: orally administering the pharmaceutically active to the mammal as part of a pharmaceutical composition agent, comprising: fluvastatin or a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose and a nonionic selected from the group hydrophilic polymer is hydroxyethyl cellulose having an average molecular weight of from 90,000 to 1,300,000, hydroxypropyl cellulose having an average molecular weight of from 370,000 to 1,500,000, and poly (ethylene oxide) which has a number average molecular weight of 100,000 to 500,000.
13. A method of claim 12 wherein the nonionic hydrophilic polymer is selected from the group consisting of hydroxyethylcellulose having an average molecular weight of from 1,000,000 to 1,300,000, hydroxypropylcellulose ^ mlene a molecular weight average in number of 850, 000 to 1,500,000, and poly (ethylene oxide) having an average molecular weight n number of 150,000 to 300,000.
14. One method the nonionic hydrophilic polymer is hydroxypropylcellulose having a number average molecular weight of about 1,150,000.
15. A method of claim 12, wherein the pharmaceutical composition comprises from about 5 to about 50 percent by weight of fluvastatin or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
16. A method of claim 12, wherein the pharmaceutical composition comprises from about 15 to about 50 weight percent of the hydroxypropylmethylcellulose, based on the total weight of the composition.
17. A method of claim 12, wherein the pharmaceutical composition comprises from about 31 3 to about 12 weight percent of the nonionic hydrophilic polymer, based on the total weight of the composition. 2 ^ 2íí3E ja ^^ a ^^^ a ^ aa ^^^^^^ íÉ ^^ fej ^^^ feS £ a¿r r ^ ^ fei > . ,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/172,491 | 1998-10-14 |
Publications (1)
Publication Number | Publication Date |
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MXPA01003731A true MXPA01003731A (en) | 2001-12-04 |
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