CN1905859A - Composition and method for enhancing bioavailability - Google Patents
Composition and method for enhancing bioavailability Download PDFInfo
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- CN1905859A CN1905859A CN 200480040436 CN200480040436A CN1905859A CN 1905859 A CN1905859 A CN 1905859A CN 200480040436 CN200480040436 CN 200480040436 CN 200480040436 A CN200480040436 A CN 200480040436A CN 1905859 A CN1905859 A CN 1905859A
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Abstract
The present invention relates to compositions and methods for enhancing the bioavailability of beneficial agents with low water solubility.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
The Application No. that the application requires to submit on November 19th, 2003 U.S. Provisional Application is submitted to number on November 9th, 60/523,421 and 2004 _ _ _ _ rights and interests.
Invention field
The present invention relates to improve the compositions and the method for low aqueous solubility beneficial agent bioavailability.
Background of invention
The dissolution and the bioavailability that improve the low aqueous solubility beneficial agent are significant in the art.This compounds comprises that all can be classified as 2 compounds of U.S. food and drug administration (FDA) division, the guide that FDA promulgation one cover is summarized bio-pharmaceutical categorizing system (BCS).BCS is according to its water solublity and the intestinal permeability science criterion with the medical substance classification.When combining with the dissolution of medicine, BCS considers three principal elements of decision IR solid oral dosage form Chinese medicine absorption rate and degree: dissolution, dissolubility and intestinal permeability.According to BCS, medical substance is classified as follows: 1 class: high-dissolvability-high osmosis; 2 classes: low solubility-high osmosis; 3 classes: high-dissolvability-hypotonicity; With 4 classes: low solubility-hypotonicity.In 2 class beneficial agents, the dissolving molecule is the conditioning step that absorbs in gastrointestinal dissolution and/or dissolving and chamber transhipment, and therefore improving dissolution rate is important purpose.2 class beneficial agents are a challenge aspect administration always, because exist and the problem of assembling, precipitation is relevant with preparation compositions (assemblies) difficulty.
Past, use the preparation that increases by 2 class beneficial agent dissolubility, comprise U.S. Patent number 6,419,952,6,342,249 and 6, make described in 174,547 beneficial agent easier by the patient gastrointestinal membranes and enter the self emulsifying liquid-carrier preparation of blood absorption, obtained good result.Each aforementioned document disclosure integral body by reference is attached to herein.
But, need to develop new raising low water-soluble compound, for example method of the bioavailability of 2 class beneficial agents all the time.Have now found that new being used to of available some compositions and method exploitation improves the compositions of 2 class beneficial agent bioavailability.
Summary of the invention
Description is used to discharge the compositions of low aqueous solubility beneficial agent.Said composition comprises the porous particle carrier that contacts with the mixture that contains beneficial agent and water-soluble polymer.
Also describe the method for compositions that preparation is used to discharge the low aqueous solubility beneficial agent, this method comprises provides the porous particle carrier; The solution that contains solvent, beneficial agent and water-soluble polymer is provided and these solution are used into carrier.
Similarly, the method that discharges to patient's low aqueous solubility beneficial agent is described.These class methods comprise provides the porous particle carrier; The solution that contains solvent, beneficial agent and water-soluble polymer is provided; These solution are applied on the carrier; With give the patient load carriers.
The accompanying drawing summary
Fig. 1 be one embodiment of the invention pass the medicine sketch map.
Detailed Description Of The Invention
The present invention relates to improve composition and the method for low aqueous solubility beneficial agent bioavilability. As Shown in Figure 1, in this embodiment, make beneficial agent (medicine) and mixed with polymers form medicine/ Polymer complex 12. Porous carrier 14 is contacted, preparation with medicine/polymer complex 12 Composition 16. Such as needs, such composition easily can be added conventional beneficial agent and discharge platform (not shown). When composition 16 is placed aqueous medium, when for example giving the patient, medicine/polymerization Thing compound 12 separates with carrier 14. Similarly, medicine/polymer complex 12 itself with Its component medicine 12a partly separates with polymer 12b, can be for the medicine that absorbs thereby produce.
In one embodiment, the present invention includes the composition that discharges the low aqueous solubility beneficial agent, Said composition comprises the porous particle that contacts with the mixture that contains beneficial agent and water-soluble polymer and carries Body.
Effectively porous particle is characterised in that high compression rate or hot strength, high porosity and hangs down crisp The property. Porous granulated carrier is selected from Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, microcrystalline cellulose, crosslinked Sodium carboxymethylcellulose, soybean skin fiber and sintering silica.
Fuji Chemical Industry Co., Ltd, Japan sells Magnesiumaluminumsilicate (Al
2O
3.MgO.1.7SiO
2.xH
2O), commodity NEUSILIN by name.Magnesiumaluminumsilicate can be used general formula Al
2O
3.MgO.xSiO
2.nH
2O representative, wherein x is about 1.5 to about 2, and n meets and concerns 0≤n≤10.
Fuji Chemical Industry Co., Ltd, Japan sells calcium phosphate dibasic anhydrous (CaHPO
4), commodity are called FUJICALIN.Especially the example of Shi Yi porous particle has U.S. Patent number 5,486, and the specific form of calcium hydrogen phosphate described in 365, the document integral body by reference are attached to herein.By wherein said, prepare calcium hydrogen phosphate by the method that produces the squamous calcium hydrogen phosphate, this calcium hydrogen phosphate can be by formula CaHPO
4MH
2The O representative, wherein m meets expression formula 0≤m≤2.0.
FMC BioPolymer, Philadelphia, PA, USA and Degussa AG, Germany sells microcrystalline Cellulose, and trade name is respectively AVICEL and ELCEMA.
FMC BioPolymer, Philadelphia, PA, USA sells cross-linking sodium carboxymethyl cellulose, and commodity are called AC-DI-SOL.
Fibred Group, Cumberland, Maryland, USA sells the soybean cover fiber, and commodity are called FL-1 SOY FIBER.
Cabot Corporation, Boston, MA, USA and Degussa AG, Germany sells fused silica, and trade name is respectively CAB-O-SIL and AEROSIL.
Preferably, the porous particle carrier is Magnesiumaluminumsilicate or calcium phosphate dibasic anhydrous, and more preferably the porous particle carrier is a Magnesiumaluminumsilicate.
Preferably, the amount of porous particle carrier existence accounts for compositions about 20% to about 99% weight.More preferably, the amount of porous particle carrier existence accounts for compositions about 40% to about 99% weight.In one embodiment, the amount of porous particle carrier existence accounts for compositions about 40% to about 60% weight.In another embodiment, the amount of porous particle carrier existence accounts for compositions about 50% to about 99% weight.In going back another embodiment, the amount that the porous particle carrier exists accounts for compositions about 60% to about 80% weight.
Be used for beneficial agent of the present invention comprise known to the human or animal effectively and have all chemical compounds of low aqueous solubility.This compounds comprises that all that can classify as 2 compounds under the bio-pharmaceutical categorizing system (BCS) that U.S. food and drug administration (FDA) propose.Only need to determine BCS classification under the following medicine with normal experiment well known to those skilled in the art.
Can comprise the ethionic acid prochlorperazine by the exemplary beneficial agent that osmosis system of the present invention discharges, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procamide, amfetamine sulfate, benzfetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, inclined to one side choline chloride (metacholine chloride), pilocarpine hydrochloride, atropine sulfate, scopolamine methobromide (methascopolaminebromide), isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, spectinomycin hydrochloride, cimetidine hydrochloride, diphenidol, meclozine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine dimaleate, anisindone, diphenadione, erythrityl tetranitrate, digoxin, isoflurophate, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminium aspirin, methotrexate, the different azoles of vinegar sulfanilamide, erythromycin, Progesterone, estrogenicprogrestational, corticosteroid, hydrocortisone, the acetic acid hydrocortisone, cortisone acetate, triamcinolone, methyltestosterone, 17 beta estradiols, ethinylestradiol, ethinylestradiol 3-methyl ether, prednisolone, 17, the nor-Progesterone of 19-, norgestrel, orethindone, norethiderone, Progesterone, norgesterone (norgestrone), Norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, nitroglycerin, Propranolol, metoprolol (metroprolol), sodium valproate, valproic acid, taxanes is paclitaxel for example, camptothecin is 9-aminocamptothecin for example, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropropmazine, reserpine (resperine), methyldopa, dihydroxyphenylalanine, hydrochloric acid alpha-methyldopa new pentane acyloxy ethyl ester, theophylline, the calcium gluconate ferrous lactate, ketoprofen, ibuprofen, cefalexin, haloperiodol, zomepirac, vincamine, stable, phenoxybenzamine, nifedipine, diltiazem , verapamil, lisinopril, captopril, ramipril, fosinopril, benazepril, libenzapril, cilazapril, cilazaprilat, perindopril, zofenopril, enalapril, delapril (indalapril), quinapril (qumapril), megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride (fluoexetine), sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
For example the low aqueous solubility beneficial agent less than 50 μ g/ml can be used for the present invention.Beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin, verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
Preferably, beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil.More preferably, this compounds comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide and budesonide.
Preferably, the amount that beneficial agent exists accounts for compositions about 1% to about 60% weight, and more preferably, the amount that beneficial agent exists accounts for compositions about 40% to about 60% weight.
Be not subjected to aforementioned limitations, preferred, existing beneficial agent is extremely about 500mg of about 0.1mg, and more preferably existing beneficial agent is that about 20mg is to about 250mg.
Also add Pharmaceutical Sciences, the 14th edition, 1979, Mack PublishingCo., Easton, Pa.; The Beneficial agent, The Nurse, The Patient, IncludingCurrent Beneficial agent Handbook, 1976, Saunder Company, Philadelphia, Pa.; Medical Chemistry, the 3rd edition, the 1st and 2 volumes, Wiley-Interscience, New York; And Physician ' s Desk Reference, the 55th edition, 1998, Medical Economics Co., other known beneficial agent in this area described in the New Jersey.Should understand beneficial agent can be various forms, for example molecule original shape, molecular complex, the last acceptable salt of pharmacology, for example hydrochlorate, hydrobromate, sulfate, laruate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, Salicylate etc.For acid beneficial agent, can use metal, amine or organic cations salt, for example quaternary ammonium salt.Can use the derivant of beneficial agent, for example alkali, ester, ether and amide.
Polymer is Berol Nobel, ethyl (ethoxy) cellulose, TheDow Chemical Company that Sweden sells, and the hydroxypropyl emthylcellulose that USA sells, commodity are called METHOCEL; With the hydroxyethyl-cellulose of hydrophobic group modification, The DowChemical Company for example, the CELLULOSE HEC SPLATTERGUARD 100 that USA sells; Anionic copolymer based on methacrylic acid and methyl methacrylate, Degussa AG for example, the ratio with mean molecule quantity 135000, free carboxy and methyl-esterified carboxyl that Germany (R hm subsidiary) sells is the copolymer of 1:＞3 (promptly about 1: 1 or about 1: 2), commodity are called EUDRAGIT, or any enteric polymer.
Preferred polymer comprises more hydrophobic hydroxypropyl emthylcellulose, The DowChemical Company for example, the hydroxypropyl emthylcellulose of the commodity that USA sells METHOCEL E, METHOCELJ by name and METHOCEL HB; And methacrylic acid copolymer, Degussa AG for example, the copolymer of the commodity that Germany sells EUDRAGIT L by name and EUDRAGITS.Most preferred polymer is a hydroxypropyl emthylcellulose.
Preferably, the amount that water-soluble polymer exists accounts for compositions about 1% to about 50% weight, and more preferably, the amount that water-soluble polymer exists accounts for compositions about 10% to about 30% weight.
In another embodiment of the invention, the method for compositions that preparation is used to discharge the low aqueous solubility beneficial agent has been described, this method comprises provides the porous particle carrier; The solution that contains solvent, beneficial agent and water-soluble polymer is provided; With these solution are applied to carrier.
Can carrier be contacted with solution, thereby use solution by comprising any conventional method of spraying.
Solvent is water, acetone, ethanol, methanol, dimethyl sulfoxide (" DMSO "), dichloromethane and composition thereof.In one embodiment, solvent is the second alcohol and water.In another embodiment, solvent is ethanol and DMSO.In going back another embodiment, solvent is DMSO.
Effectively porous particle is characterised in that high compression rate or hot strength, high porosity and low fragility.The porous particle carrier is selected from Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, soybean cover fiber and fused silica.
Fuji Chemical Industry Co., Ltd, Japan sells Magnesiumaluminumsilicate (Al
2O
3.MgO.1.7SiO
2.xH
2O), commodity NEUSILIN by name.Magnesiumaluminumsilicate can be used general formula Al
2O
3.MgO.xSiO
2.nH
2O representative, wherein x is about 1.5 to about 2, and n meets and concerns 0≤n≤10.
Fuji Chemical Industry Co., Ltd, Japan sells calcium phosphate dibasic anhydrous (CaHPO
4), commodity are called FUJICALIN.Especially the example of Shi Yi porous particle has U.S. Patent number 5,486, and the specific form of calcium hydrogen phosphate described in 365, the document integral body by reference are attached to herein.By wherein said, prepare calcium hydrogen phosphate by the method that produces the squamous calcium hydrogen phosphate, this calcium hydrogen phosphate can be by formula CaHPO
4MH
2The O representative, wherein m meets expression formula 0≤m≤2.0.
FMC BioPolymer, Philadelphia, PA, USA and Degussa AG, Germany sells microcrystalline Cellulose, and trade name is respectively AVICEL and ELCEMA.
FMC BioPolymer, Philadelphia, PA, USA sells cross-linking sodium carboxymethyl cellulose, and commodity are called AC-DI-SOL.
Fibred Group, Cumberland, Maryland, USA sells the soybean cover fiber, and commodity are called FL-1 SOY FIBER.
Cabot Corporation, Boston, MA, USA and Degussa AG, Germany sells fused silica, and trade name is respectively CAB-O-SIL and AEROSIL.
Preferably, the porous particle carrier is Magnesiumaluminumsilicate or calcium phosphate dibasic anhydrous, and more preferably the porous particle carrier is a Magnesiumaluminumsilicate.
Preferably, the amount of porous particle carrier existence accounts for compositions about 20% to about 99% weight.More preferably, the amount of porous particle carrier existence accounts for compositions about 40% to about 99% weight.In one embodiment, the amount of porous particle carrier existence accounts for compositions about 40% to about 60% weight.In another embodiment, the amount of porous particle carrier existence accounts for compositions about 50% to about 99% weight.In going back another embodiment, the amount that the porous particle carrier exists accounts for compositions about 60% to about 80% weight.
Be used for beneficial agent of the present invention comprise known to the human or animal effectively and have all chemical compounds of low aqueous solubility.This compounds comprises that all that can classify as 2 compounds under the bio-pharmaceutical categorizing system (BCS) that U.S. food and drug administration (FDA) propose.Only need to determine BCS classification under the following medicine with normal experiment well known to those skilled in the art.
Can comprise the ethionic acid prochlorperazine by the exemplary beneficial agent that osmosis system of the present invention discharges, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procamide, amfetamine sulfate, benzfetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, inclined to one side choline chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine methobromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, spectinomycin hydrochloride, cimetidine hydrochloride, diphenidol, meclozine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine dimaleate, anisindone, diphenadione, erythrityl tetranitrate, digoxin, isoflurophate, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminium aspirin, methotrexate, the different azoles of vinegar sulfanilamide, erythromycin, Progesterone, estrogenic progrestational, corticosteroid, hydrocortisone, the acetic acid hydrocortisone, cortisone acetate, triamcinolone, methyltestosterone, 17 beta estradiols, ethinylestradiol, ethinylestradiol 3-methyl ether, prednisolone, 17, the nor-Progesterone of 19-, norgestrel, orethindone, norethiderone, Progesterone, norgesterone, Norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, nitroglycerin, Propranolol, metoprolol, sodium valproate, valproic acid, taxanes is paclitaxel for example, camptothecin is 9-aminocamptothecin for example, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropropmazine, reserpine, methyldopa, dihydroxyphenylalanine, hydrochloric acid alpha-methyldopa new pentane acyloxy ethyl ester, theophylline, the calcium gluconate ferrous lactate, ketoprofen, ibuprofen, cefalexin, haloperiodol, zomepirac, vincamine, stable, phenoxybenzamine, nifedipine, diltiazem , verapamil, lisinopril, captopril, ramipril, fosinopril, benazepril, libenzapril, cilazapril, cilazaprilat, perindopril, zofenopril, enalapril, delapril, quinapril, megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
For example the low aqueous solubility beneficial agent less than 50 μ g/ml can be used for the present invention.Beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin, verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
Preferably, beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil.More preferably, this compounds comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide and budesonide.
Preferably, the amount that beneficial agent exists accounts for compositions about 1% to about 60% weight, and more preferably, the amount that beneficial agent exists accounts for compositions about 40% to about 60% weight.
Be not subjected to aforementioned limitations, preferred, existing beneficial agent is extremely about 500mg of about 0.1mg, and more preferably existing beneficial agent is that about 20mg is to about 250mg.
Also add Pharmaceutical Sciences, the 14th edition, 1979, Mack PublishingCo., Easton, Pa.; The Beneficial agent, The Nurse, The Patient, IncludingCurrent Beneficial agent Handbook, 1976, Saunder Company, Philadelphia, Pa.; Medical Chemistry, the 3rd edition, the 1st and 2 volumes, Wiley-Interscience, New York; And Physician ' s Desk Reference, the 55th edition, 1998, Medical Economics Co., other known beneficial agent in this area described in the New Jersey.Should understand beneficial agent can be various forms, for example molecule original shape, molecular complex, the last acceptable salt of pharmacology, for example hydrochlorate, hydrobromate, sulfate, laruate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, Salicylate etc.For acid beneficial agent, can use metal, amine or organic cations salt, for example quaternary ammonium salt.Can use the derivant of beneficial agent, for example alkali, ester, ether and amide.
Polymer is Berol Nobel, ethyl (ethoxy) cellulose, TheDow Chemical Company that Sweden sells, and the hydroxypropyl emthylcellulose that USA sells, commodity are called METHOCEL; With the hydroxyethyl-cellulose of hydrophobic group modification, The DowChemical Company for example, the CELLULOSE HEC SPLATTERGUARD 100 that USA sells; Anionic copolymer based on methacrylic acid and methyl methacrylate, Degussa AG for example, the ratio with mean molecule quantity 135000, free carboxy and methyl-esterified carboxyl that Germany (R hm subsidiary) sells is the copolymer of 1:＞3 (promptly about 1: 1 or about 1: 2), commodity are called EUDRAGIT, or any enteric polymer.
Preferred polymer comprises more hydrophobic hydroxypropyl emthylcellulose, The DowChemical Company for example, the hydroxypropyl emthylcellulose of the commodity that USA sells METHOCEL E, METHOCELJ by name and METHOCEL HB; And methacrylic acid copolymer, Degussa AG for example, the copolymer of the commodity that Germany sells EUDRAGIT L by name and EUDRAGITS.Most preferred polymer is a hydroxypropyl emthylcellulose.
Preferably, the amount that water-soluble polymer exists accounts for compositions about 1% to about 50% weight, and more preferably, the amount that water-soluble polymer exists accounts for compositions about 10% to about 30% weight.
In also another embodiment of the present invention, the method that discharges to patient's low aqueous solubility beneficial agent is described, this method comprises provides the porous particle carrier; The solution that contains solvent, beneficial agent and water-soluble polymer is provided; Solution is applied to carrier; With give the patient this load carriers.
Can carrier be contacted with solution, thereby use solution.
Can be by comprising any conventional method administration through delivery system.As for the beneficial agent delivery system, with the OROS of ALZA
TMSystem obtains good result, this system use infiltration technology make beneficial agent easier by the patient gastrointestinal membranes and enter blood flow and absorb.Press U.S. Patent number 5,770, described in 227, beneficial agent layer and osmotic engine are packed in the semi-permeable membrane-enclosed hard capsule of controlled speed, this patent disclosure integral body by reference is attached to herein.In brief, the sealing coat of being made up of inert substance separates beneficial agent layer and osmotic engine, stops the reaction of beneficial agent and osmotic engine.On the relative terminal membrane of osmotic engine, bore release aperture by laser, provide outlet to beneficial agent.Preferred delivery system comprises the OROS of ALZA
TMPUSH-STICK
TMThe OROS of beneficial agent delivery system (be designed for the insoluble drugs that release needs high capacity, have optimal delay pattern or pulse release curve), ALZA
TMPUSH-PULL
TMBeneficial agent delivery system (be designed for and discharge low aqueous solubility) and matrix tablet beneficial agent delivery system to highly water soluble drugs.
Usually, the beneficial agent dosage that can give the patient by any known method is about 0.001 to about 1.0mmol/kg body weight (and dosage range and wherein all combinations and the subgroup of concrete dosage are closed).Effective dose that gives and concrete mode of administration will change according to this type of factor, for example age, body weight and the disease of being treated and the specifically beneficial agent of use, and this is apparent to those skilled in the art.Usually, the dosage level is low during beginning, increases the diagnostic result that needs until reaching then.
Solvent is water, acetone, ethanol, methanol, dimethyl sulfoxide (" DMSO "), dichloromethane and composition thereof.In one embodiment, solvent is the second alcohol and water.In another embodiment, solvent is ethanol and DMSO.In going back another embodiment, solvent is DMSO.
Effectively porous particle is characterised in that high compression rate or hot strength, high porosity and low fragility.The porous particle carrier is selected from Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, soybean cover fiber and fused silica.
Fuji Chemical Industry Co., Ltd, Japan sells Magnesiumaluminumsilicate (Al
2O
3.MgO.1.7SiO
2.xH
2O), commodity NEUSILIN by name.Magnesiumaluminumsilicate can be used general formula Al
2O
3.MgO.xSiO
2.nH
2O representative, wherein x is about 1.5 to about 2, and n meets and concerns 0≤n≤10.
Fuji Chemical Industry Co., Ltd, Japan sells calcium phosphate dibasic anhydrous (CaHPO
4), commodity are called FUJICALIN.Especially the example of Shi Yi porous particle has U.S. Patent number 5,486, and the specific form of calcium hydrogen phosphate described in 365, the document integral body by reference are attached to herein.By wherein said, prepare calcium hydrogen phosphate by the method that produces the squamous calcium hydrogen phosphate, this calcium hydrogen phosphate can be by formula CaHPO
4MH
2The O representative, wherein m meets expression formula 0≤m≤2.0.
FMC BioPolymer, Philadelphia, PA, USA and Degussa AG, Germany sells microcrystalline Cellulose, and trade name is respectively AVICEL and ELCEMA.
FMC BioPolymer, Philadelphia, PA, USA sells cross-linking sodium carboxymethyl cellulose, and commodity are called AC-DI-SOL.
Fibred Group, Cumberland, Maryland, USA sells the soybean cover fiber, and commodity are called FL-1 SOY FIBER.
Cabot Corporation, Boston, MA, USA and Degussa AG, Germany sells fused silica, and trade name is respectively CAB-O-SIL and AEROSIL.
Preferably, the porous particle carrier is Magnesiumaluminumsilicate or calcium phosphate dibasic anhydrous, and more preferably the porous particle carrier is a Magnesiumaluminumsilicate.
Preferably, the amount of porous particle carrier existence accounts for compositions about 20% to about 99% weight.More preferably, the amount of porous particle carrier existence accounts for compositions about 40% to about 99% weight.In one embodiment, the amount of porous particle carrier existence accounts for compositions about 40% to about 60% weight.In another embodiment, the amount of porous particle carrier existence accounts for compositions about 50% to about 99% weight.In going back another embodiment, the amount that the porous particle carrier exists accounts for compositions about 60% to about 80% weight.
Be used for beneficial agent of the present invention comprise known to the human or animal effectively and have all chemical compounds of low aqueous solubility.This compounds comprises that all that can classify as 2 compounds under the bio-pharmaceutical categorizing system (BCS) that U.S. food and drug administration (FDA) propose.Only need to determine BCS classification under the following medicine with normal experiment well known to those skilled in the art.
Can comprise the ethionic acid prochlorperazine by the exemplary beneficial agent that osmosis system of the present invention discharges, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procamide, amfetamine sulfate, benzfetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, inclined to one side choline chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine methobromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, spectinomycin hydrochloride, cimetidine hydrochloride, diphenidol, meclozine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine dimaleate, anisindone, diphenadione, erythrityl tetranitrate, digoxin, isoflurophate, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminium aspirin, methotrexate, the different azoles of vinegar sulfanilamide, erythromycin, Progesterone, estrogenic progrestational, corticosteroid, hydrocortisone, the acetic acid hydrocortisone, cortisone acetate, triamcinolone, methyltestosterone, 17 beta estradiols, ethinylestradiol, ethinylestradiol 3-methyl ether, prednisolone, 17, the nor-Progesterone of 19-, norgestrel, orethindone, norethiderone, Progesterone, norgesterone, Norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, nitroglycerin, Propranolol, metoprolol, sodium valproate, valproic acid, taxanes is paclitaxel for example, camptothecin is 9-aminocamptothecin for example, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropropmazine, reserpine, methyldopa, dihydroxyphenylalanine, hydrochloric acid alpha-methyldopa new pentane acyloxy ethyl ester, theophylline, the calcium gluconate ferrous lactate, ketoprofen, ibuprofen, cefalexin, haloperiodol, zomepirac, vincamine, stable, phenoxybenzamine, nifedipine, diltiazem , verapamil, lisinopril, captopril, ramipril, fosinopril, benazepril, libenzapril, cilazapril, cilazaprilat, perindopril, zofenopril, enalapril, delapril, quinapril, megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
For example the low aqueous solubility beneficial agent less than 50 μ g/ml can be used for the present invention.Beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin, verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
Preferably, beneficial agent comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin and verapamil.More preferably, this compounds comprises megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide and budesonide.
Preferably, the amount that beneficial agent exists accounts for compositions about 1% to about 60% weight, and more preferably, the amount that beneficial agent exists accounts for compositions about 40% to about 60% weight.
Be not subjected to aforementioned limitations, preferred, existing beneficial agent is extremely about 500mg of about 0.1mg, and more preferably existing beneficial agent is that about 20mg is to about 250mg.
Also add Pharmaceutical Sciences, the 14th edition, 1979, Mack PublishingCo., Easton, Pa.; The Beneficial agent, The Nurse, The Patient, IncludingCurrent Beneficial Agent Handbook, 1976, Saunder Company, Philadelphia, Pa.; Medical Chemistry, the 3rd edition, the 1st and 2 volumes, Wiley-Interscience, New York; And Physician ' s Desk Reference, the 55th edition, 1998, Medical Economics Co., other known beneficial agent in this area described in the New Jersey.Should understand beneficial agent can be various forms, for example molecule original shape, molecular complex, the last acceptable salt of pharmacology, for example hydrochlorate, hydrobromate, sulfate, laruate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, Salicylate etc.For acid beneficial agent, can use metal, amine or organic cations salt, for example quaternary ammonium salt.Can use the derivant of beneficial agent, for example alkali, ester, ether and amide.
Polymer is Berol Nobel, ethyl (ethoxy) cellulose, TheDow Chemical Company that Sweden sells, and the hydroxypropyl emthylcellulose that USA sells, commodity are called METHOCEL; With the hydroxyethyl-cellulose of hydrophobic group modification, The DowChemical Company for example, the CELLULOSE HEC SPLATTERGUARD 100 that USA sells; Anionic copolymer based on methacrylic acid and methyl methacrylate, Degussa AG for example, the ratio with mean molecule quantity 135000, free carboxy and methyl-esterified carboxyl that Germany (R hm subsidiary) sells is the copolymer of 1:＞3 (promptly about 1: 1 or about 1: 2), commodity are called EUDRAGIT, or any enteric polymer.
Preferred polymer comprises more hydrophobic hydroxypropyl emthylcellulose, The DowChemical Company for example, the hydroxypropyl emthylcellulose of the commodity that USA sells METHOCEL E, METHOCELJ by name and METHOCEL HB; And methacrylic acid copolymer, Degussa AG for example, the copolymer of the commodity that Germany sells EUDRAGIT L by name and EUDRAGITS.Most preferred polymer is a hydroxypropyl emthylcellulose.
Preferably, the amount that water-soluble polymer exists accounts for compositions about 1% to about 50% weight, and more preferably, the amount that water-soluble polymer exists accounts for compositions about 10% to about 30% weight.
Further describe the present invention with following embodiment.
Embodiment
Embodiment 1
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 50/50% weight itraconazole and hydroxypropyl emthylcellulose (" HPMC ") (obtaining) with trade name METHOCEL E5.Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 14: 14, in percentage rate.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 11.8: 11.8: 15: 0.5, and in percentage rate.1 this final composition of gram is compressed to immediate release dosage form, and this dosage form contains the 118mg itraconazole.
Embodiment 2
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 50/50% weight itraconazole and METHOCEL E5 HPMC.Rapidly with solution spray to the fluidisation porous particle, only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 14: 14, in percentage rate.
(derive from Carbomer Inc., MA USA) granulates, with dry blended with magnesium stearate with said composition and ACDISOL cross-linking sodium carboxymethyl cellulose and CARBOMER 71G and CARBOMER 934 blends then.Be carrier/drug/polymer/CARBOMER 71G/CARBOMER 934/ excipient/lubricant final the composition, and ratio is about 55.4: 10.8: 10.8: 5.0: 2.5: 15.0: 0.5.Granule is pressed into controlled release matrix tablet.By changing the ratio (from 7.5/0 to 0/7.5 (weight)) of CARBOMER 71G/CARBOMER 934, can obtain various release lasting effects (from 2h to 20h).
Embodiment 3
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 75/25% weight itraconazole and METHOCEL E5 board HPMC.Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 21: 7, in weight percent.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 17.7: 5.9: 15: 0.5, and in weight percent.1 this final composition of gram is compressed to immediate release dosage form, and this dosage form contains the 177mg itraconazole.
Embodiment 4
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 95/5% weight itraconazole and METHOCEL E5 HPMC.Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 26.6: 1.4, in weight percent.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 22.4: 1.2: 15: 0.5, and in weight percent.1 this final composition of gram is compressed to immediate release dosage form, and this dosage form contains the 224mg itraconazole.
Embodiment 5
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 50/50% weight phenytoin and METHOCEL E5 HPMC.Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 14: 14, in percentage rate.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 11.8: 11.8: 15: 0.5, and in percentage rate.1 this final composition of gram is compressed to immediate release dosage form, and this dosage form contains the 118mg phenytoin.
Embodiment 6
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 50/50% weight itraconazole and methacrylic acid copolymer (EUDRAGITL100-55 obtains with trade name).Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 14: 14, in percentage rate.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 11.8: 11.8: 15: 0.5, and in percentage rate.1 this final composition of gram is compressed to immediate release dosage form, and this dosage form contains the 118mg itraconazole.
Embodiment 7
By repeating spraying/seasoning, in fluidised bed granulator, load Magnesiumaluminumsilicate with DMSO solution with 6% solid 50/50% weight phenytoin and METHOCEL E5 HPMC.Rapidly solution spray is arrived on the fluidisation porous particle (Magnesiumaluminumsilicate), only suitably load the adsorption capacity in 75% hole.Stop spraying then, continue heating and fluidisation simultaneously,, medicine/polymer solids is trapped in the hole solvent evaporation.Repeat this process, and remain that the percentile amount of filler opening is not proportional, each circulation reduces the solution amount of using in proportion.After 10 repetitions, the drug/polymer solid should fill up 75% hole.Suppose 50% porosity, the final composition of compositions is a carrier/drug/polymer, and ratio is about 72: 14: 14, in percentage rate.
Then with said composition and ACDISOL sodium croscannellose, and dry blended with magnesium stearate.Be carrier/drug/polymer/excipient/lubricant final the composition, and ratio is about 60.9: 11.8: 11.8: 15: 0.5, in percentage rate, form porous drug layer composition granule.
With said composition and OROS PUSH-STICK SYSTEM
TMUse OROSPUSH-STICK SYSTEM together
TMIt is the compositions that forms permeable formation; it contains 58.75% weight sodium carboxymethyl cellulose (7H4F), 30.0% weight sodium chloride, 5.0% weight hydroxypropyl emthylcellulose (METHOCEL E5), 1.0% weight iron oxide red; make them separately by 40 order stainless steel sifts; blend in the GALTT fluidised bed granulator is then sprayed until obtaining single-size with the purification of aqueous solutions of 5.0% hydroxypropyl cellulose (EF).Make these granules by 8 order stainless steel sifts, mix with 0.25% magnesium stearate then, form osmotic granulation.
Above 500mg porous drug layer composition granule and above 250mg osmotic granulation are pressed into double-layer circular-circular piece." these tablets of circle punching press system on CARVER tablet machine or D3B MANESTY tablet machine, with 17/64.Then, give these tablet coatings with clothing compositions at the bottom of containing the 18mg that 95% weight NATROSOL and 5% weight molecular weight are 3,350 Polyethylene Glycol.Then, the compositions of the cellulose acetate of the acetyl-containing content 39.8% of reuse formation semi-permeable wall and PLURONIC F68 copolymer is given the coating tablets of sub-coating.The compositions that forms wall is dissolved in acetone, prepares 4% solid solution.Spray forms the compositions of wall on the tablet in FREUD HI-COATER coating equipment.Can change the weight ratio of film weight/sheet and cellulose acetate and PLURONIC F68 copolymer, to obtain the targeting release duration.At last, machinery cuts portal (155mil) on the drug-layer side of system.By 30 ℃ and under ambient humidity with system's dried overnight, remove residual solvent.System contains the 59mg medicine.
Each patent of quoting in this document or describing, patent application and publication content, integral body is attached to herein by reference.
Each scope of enumerating comprises that all combinations and the subgroup of scope close and the concrete numeral that wherein comprises.
According to aforementioned specification, except that described those herein, various modifications of the present invention to those skilled in the art are conspicuous.This type of modification will fall in the scope of claims.
Claims (26)
1. compositions that discharges the low aqueous solubility beneficial agent, described compositions comprises:
The porous particle carrier that contacts with the mixture that comprises beneficial agent and water-soluble polymer.
2. the compositions of claim 1, wherein said porous particle carrier is selected from least a following carrier: Magnesiumaluminumsilicate, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, soybean cover fiber and fused silica.
3. the compositions of claim 1, wherein said porous particle carrier is Magnesiumaluminumsilicate or calcium phosphate dibasic anhydrous.
4. the compositions of claim 1, wherein said porous particle carrier is a Magnesiumaluminumsilicate.
5. the compositions of claim 1, wherein existing porous particle carrier accounts for said composition about 20% to about 99% weight.
6. the compositions of claim 1, wherein existing porous particle carrier accounts for said composition about 40% to about 99% weight.
7. the compositions of claim 1, wherein existing porous particle carrier accounts for said composition about 40% to about 60% weight.
8. the compositions of claim 1, wherein existing porous particle carrier accounts for said composition about 50% to about 99% weight.
9. the compositions of claim 1, wherein existing porous particle carrier accounts for said composition about 60% to about 80% weight.
10. the compositions of claim 1, wherein said beneficial agent is selected from least a following medicine: megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide, budesonide, Progesterone, megestrol acetate, topiramate, naproxen, flurbiprofen, ketoprofen, desipramine, diclofenac, itraconazole, piroxicam, carbamazepine, phenytoin, verapamil, indinavir sulfate, lamivudine, stavudine, nelfinavir mesilate, the combination of lamivudine and zidovudine, saquinavir mesilate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoxetine Hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, BUPROPIONE HCl, nefazodone hydrochloride, mirtazapine, auroix, mianserin hydrochloride, zanamivir, olanzapine, risperidone, quetiapine fumarate, buspirone hydrochloride, alprazolam, lorazepam, leotan, chlorine nitrogen dipotassium, clozapine, sulpiride, amisulpride, methylphenidate hydrochloride and pemoline.
11. the compositions of claim 1, wherein said beneficial agent is selected from megestrol acetate, ciprofloxan, itroconazole, lovastatin, simvastatin, omeprazole, phenytoin, ciprofloxacin, Cyclosporin A, ritonavir, carbamazepine, carvedilol, clarithromycin, diclofenac, etoposide and budesonide.
12. the compositions of claim 1, wherein existing beneficial agent account for said composition about 1% to about 60% weight.
13. the compositions of claim 1, wherein existing beneficial agent account for said composition about 40% to about 60% weight.
14. the compositions of claim 1, wherein existing beneficial agent are that about 0.1mg is to about 500mg.
15. the compositions of claim 1, wherein existing beneficial agent are that about 20mg is to about 250mg.
16. the compositions of claim 1, wherein said water-soluble polymer are selected from least a following polymer: ethyl (ethoxy) cellulose, hydroxypropyl emthylcellulose, by the hydroxyethyl-cellulose and the methacrylic acid copolymer of hydrophobic group modification.
17. the compositions of claim 1, wherein said water-soluble polymer is selected from hydroxypropyl emthylcellulose and methacrylic acid copolymer.
18. the compositions of claim 1, wherein said water-soluble polymer are hydroxypropyl emthylcellulose.
19. the compositions of claim 1, wherein existing water-soluble polymer account for said composition about 1% to about 50% weight.
20. the compositions of claim 1, wherein existing water-soluble polymer account for said composition about 10% to about 30% weight.
21. a method for compositions for preparing claim 1, described method comprises:
The porous particle carrier is provided;
The solution that comprises solvent, beneficial agent and water-soluble polymer is provided; With
Described solution is applied to described carrier.
22. the method for claim 21, wherein said solvent are selected from least a following solvent: water, acetone, ethanol, methanol, DMSO and dichloromethane.
23. the method for claim 21, wherein said solvent are the second alcohol and waters.
24. the method for claim 21, wherein said solvent are ethanol and DMSO.
25. the method for claim 21, wherein said solvent is DMSO.
26. one kind discharges method to the patient with the low aqueous solubility beneficial agent, described method comprises:
Give the compositions of described patient's claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52342103P | 2003-11-19 | 2003-11-19 | |
| US60/523,421 | 2003-11-19 | ||
| US10/984,401 | 2004-11-09 |
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| Publication Number | Publication Date |
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| CN1905859A true CN1905859A (en) | 2007-01-31 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103263396A (en) * | 2013-06-17 | 2013-08-28 | 南京正宽医药科技有限公司 | Meloxicam dispersible tablets and preparation method thereof |
| CN110325192A (en) * | 2017-06-30 | 2019-10-11 | 伊兹瓦里诺帕玛有限责任公司 | Pharmaceutical composition with HIV-resistant activity |
| CN111643463A (en) * | 2020-07-08 | 2020-09-11 | 西安远大德天药业股份有限公司 | Megestrol acetate dispersible tablet and preparation method thereof |
| CN114146061A (en) * | 2020-09-07 | 2022-03-08 | 歌礼生物科技（杭州）有限公司 | Protease inhibitor synergistic composition comprising a solid dispersion and process for preparing the same |
-
2004
- 2004-11-12 CN CN 200480040436 patent/CN1905859A/en active Pending
-
2006
- 2006-06-15 ZA ZA200604969A patent/ZA200604969B/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103263396A (en) * | 2013-06-17 | 2013-08-28 | 南京正宽医药科技有限公司 | Meloxicam dispersible tablets and preparation method thereof |
| CN110325192A (en) * | 2017-06-30 | 2019-10-11 | 伊兹瓦里诺帕玛有限责任公司 | Pharmaceutical composition with HIV-resistant activity |
| CN111643463A (en) * | 2020-07-08 | 2020-09-11 | 西安远大德天药业股份有限公司 | Megestrol acetate dispersible tablet and preparation method thereof |
| CN114146061A (en) * | 2020-09-07 | 2022-03-08 | 歌礼生物科技（杭州）有限公司 | Protease inhibitor synergistic composition comprising a solid dispersion and process for preparing the same |
| CN114146061B (en) * | 2020-09-07 | 2023-06-30 | 歌礼生物科技（杭州）有限公司 | Protease inhibitor synergistic composition containing solid dispersion and preparation method thereof |
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| Publication number | Publication date |
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| ZA200604969B (en) | 2007-11-28 |
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