Controlled-release nanoparticulate compositions
View Patent ↗Described are controlled release nanoparticulate formulations comprising a nanoparticulate agent to be administered and a rate-controlling polymer which functions to prolong the release of the agent following administration. The novel compositions release the agent following administration for a time period ranging from about 2 to about 24 hours or longer.
1. A solid dose controlled release nanoparticulate composition consisting of:
(a) a poorly soluble nanoparticulate drug and at least one surface stabilizer associated with the surface of the nanoparticulate drug, wherein at least 50% of the drug particles have an average particle size of less than about 1000 nm when measured by light scattering techniques, and
(b) a rate controlling matrix consists of at least one pharmaceutically acceptable high molecular weight rate-controlling polymer, wherein:
(i) the nanoparticulate drug and the surface stabilizer associated with the surface thereof are dispersed in the high molecular weight rate-controlling polymer throughout the rate controlling matrix,
(ii) the controlled release nanoparticulate composition provides controlled release of the nanoparticulate drug for a time period ranging from about 2 to about 24 hours,
(iii) the concentration of the high molecular weight rate controlling polymer is from about 5 to about 95% (w/w),
(iv) the surface stabilizer is selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, poloxamine 908, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), SA9OHCO, decanoyl-N-methylglucamide, n-decyl -D-glucopyranoside, n-decyl -D-maltopyranoside, n-dodecyl -D-glucopyranoside, n-dodecyl -D-maltoside, heptanoyl-N-methylglucamide, n-heptyl—D-glucopyranoside, n-heptyl -D-thioglucoside, n-hexyl -D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl -D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl—D-glucopyranoside, and octyl -D-thioglucopyranoside, and
(v) the high molecular weight rate-controlling polymer is selected from the group consisting of polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetaldiethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters.
2. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the effective average particle size of the nanoparticulate drug is selected from the group consisting of less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm, wherein at least 50% of the drug particles have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques.
3. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the concentration of the high molecular weight rate controlling polymer is from about 10 to about 65% (w/w).
4. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the solid dose formulation is made by wet granulation.
5. The solid dose controlled release nanoparticulate composition of claim 1 formed by wet granulation, wherein water is added to the nanoparticulate drug, surface stabilizer, and polymer to form granules prior to forming the solid dose of the controlled release formulation.
6. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the high molecular weight rate-controlling polymer is hydroxypropylmethyl cellulose (HPMC).
7. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the poorly water soluble nanoparticulate drug is present in an amount of from about 1 μg to about 800 mg.
8. A solid dosage form consisting of the controlled release nanoparticulate composition according to claim 1 and at least one auxiliary excipient, wherein the solid dosage form is in a tablet form, a multiparticulate form, or a powder form.
9. The solid dosage form of claim 8 , wherein the controlled release nanoparticulate composition and the at least one auxiliary excipient are compressed to form a tablet.
10. The solid dosage form of claim 8 , wherein the controlled release nanoparticulate composition and the at least one auxiliary excipient are compressed to form a multilayer tablet.
11. A method of preparing a solid dose controlled release nanoparticulate formulation comprising:
(a) combining a nanoparticulate composition of a nanoparticulate drug, at least one surface stabilizer associated with the surface of the nanoparticulate drug, wherein at least 50% of the drug particles have an average particle size of less than about 1000 nm when measured by light scattering techniques, and at least one pharmaceutically acceptable high molecular weight rate-controlling polymer at a concentration of from about 5% to about 95% (w/w);
(b) forming a solid dose formulation from the mixture of step (a); wherein the high molecular weight rate-controlling polymer forms a rate controlling matrix, and the nanoparticulate drug and the surface stabilizer associated with the surface thereof are dispersed throughout the rate controlling matrix, and
(c) selecting the solid dose formulation which has a controlled release of the nanoparticulate drug following administration for a time period ranging from about 2 to about 24 hours,
wherein the solid dose controlled release nanoparticulate composition consists of:
(1) the nanoparticulate drug and the surface stabilizer associated with the surface of the nanoparticulate drug, wherein at least 50% of the drug particles have an average particle size of less than about 1000 nm when measured by light scattering techniques, and
(2) a rate controlling matrix comprised of at least the high molecular weight rate-controlling polymer, wherein:
(i) the nanoparticulate drug and the surface stabilizer associated with the surface thereof are dispersed in the high molecular weight rate-controlling polymer throughout the rate controlling matrix,
(ii) the concentration of the high molecular weight rate controlling polymer is from about 5 to about 95% (w/w),
(iii) the surface stabilizer is selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, poloxamine 908, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), SA9OHCO, decanoyl-N-methylglucamide, n-decyl -D-glucopyranoside, n-decyl -D-maltopyranoside, n-dodecyl -D-glucopyranoside, n-dodecyl -D-maltoside, heptanoyl-N-methylglucamide, n-heptyl—D-glucopyranoside, n-heptyl -D-thioglucoside, n-hexyl -D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl -D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl—D-glucopyranoside, and octyl -D-thioglucopyranoside,
wherein the nanoparticulate drug is in a crystalline phase, an amorphous phase, or a mixture thereof, and
(iv) wherein the high molecular weight rate-controlling polymer is selected from the group consisting of polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetaldiethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters.
12. The method of claim 11 , wherein the effective average particle size of the nanoparticulate drug particles is selected from the group consisting of less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm , wherein at least 50% of the drug particles have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques.
13. The method of claim 11 , wherein the concentration of the high molecular weight rate-controlling polymer is from about 10 to about 65% (w/w).
14. The method of claim 12 , comprising adding water to the nanoparticulate drug, surface stabilizer, and high molecular weight rate-controlling polymer to form granules prior to step (b).
15. A method of treating a mammal comprising administering to the mammal an effective amount of a solid dose controlled release nanoparticulate formulation composition, wherein the composition consists of:
(a) the formulation consists of a poorly soluble nanoparticulate drug particles and at least one surface stabilizer associated with the surface of the nanoparticulate drug, wherein at least 50% of the drug particles have an average particle size of less than about 1000 nm when measured by light scattering techniques, and
(b) a rate controlling matrix consists of at least one pharmaceutically acceptable high molecular weight rate-controlling polymer, wherein:
(i) at a concentration of from about 5% to about 95% (w/w), wherein the nanoparticulate drug and the surface stabilizer associated with the surface thereof are dispersed in the high molecular weight rate-controlling polymer throughout the rate controlling matrix;
(ii) the formulation has a controlled release of the nanoparticulate drug following administration composition provides controlled release of the nanoparticulate drug for a time period ranging from about 2 to about 24 hours,
(iii) the concentration of the high molecular weight rate controlling polymer is from about 5 to about 95% (w/w),
(iv) wherein the surface stabilizer is selected from the group consisting of gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, poloxamine 908, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), SA9OHCO, decanoyl-N-methylglucamide, n-decyl -D-glucopyranoside, n-decyl -D-maltopyranoside, n-dodecyl -D-glucopyranoside, n-dodecyl -D-maltoside, heptanoyl-N-methylglucamide, n-heptyl—D-glucopyranoside, n-heptyl -D-thioglucoside, n-hexyl -D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl -D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl—D-glucopyranoside, and octyl -D-thioglucopyranoside,
wherein the nanoparticulate drug is in a crystalline phase, an amorphous phase, or a mixture thereof, and
(v) wherein the high molecular weight rate-controlling polymer is selected from the group consisting of polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetaldiethylamino acetate, poly(alkylmethacrylate), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters.
16. The method of claim 15 , wherein the effective average particle size of the nanoparticulate drug particles is selected from the group consisting of less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, and less than about 50 nm, wherein at least 50% of the drug particles have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques.
17. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the drug is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antiasthma agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antitussives, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, bronchodilators, cardiac inotropic agents, chemotherapeutics, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, proteins, polypeptides, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, hormones, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.
18. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the drug is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenytoin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem, and pharmaceutically acceptable salts thereof
19. The solid dose controlled release nanoparticulate composition of claim 1 , wherein the drug is selected from the group consisting of naproxen, glipizide, and nifedipine.
20. The solid dosage form of claim 8 , wherein the drug is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antiasthma agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antitussives, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, bronchodilators, cardiac inotropic agents, chemotherapeutics, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, proteins, polypeptides, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, hormones, sex hoimones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.
21. The solid dosage form of claim 8 , wherein the drug is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenytoin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem, and pharmaceutically acceptable salts thereof.
22. The solid dosage form of claim 8 , wherein the drug is selected from the group consisting of naproxen, glipizide, and nifedipine.
23. The method of claim 11 , wherein the drug is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antiasthma agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antitussives, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, bronchodilators, cardiac inotropic agents, chemotherapeutics, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, proteins, polypeptides, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, hormones, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.
24. The method of claim 11 , wherein the drug is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenytoin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem, and pharmaceutically acceptable salts thereof.
25. The method of claim 11 , wherein the drug is selected from the group consisting of naproxen, glipizide, and nifedipine.
26. The method of claim 15 , wherein the drug is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antiasthma agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antitussives, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, bronchodilators, cardiac inotropic agents, chemotherapeutics, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, proteins, polypeptides, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, hormones, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.
27. The method of claim 15 , wherein the drug is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenytoin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem, and pharmaceutically acceptable salts thereof.
28. The method of claim 15 , wherein the drug is selected from the group consisting of naproxen, glipizide, and nifedipine.