Compositions comprising lipophilic active compounds and method for their preparation

Abstract

Compositions are provided comprising a lipophilic active compound, e.g., a human or veterinary drug or a nutraceutical, interwoven with a polymeric matrix formed by two or more polymers, wherein one of the polymers is an amphiphilic polymer and the other polymer is either an amphiphilic polymer with a different hydrophobic-hydrophilic balance or a hydrophilic polymer, and the active lipophilic compound has modified physicochemical properties. The composition forms colloidal nanodispersion upon contact with aqueous media.

1 . A solid composition that forms a colloidal nanodispersion upon contact with aqueous media, said composition comprising at least one lipophilic active compound and two or more polymers, in which the at least one lipophilic active compound is interwoven with a polymeric matrix formed by the two or more polymers, at least one of the two or more polymers is an amphiphilic polymer and at least another of the two or more polymers is either a hydrophilic polymer or an amphiphilic polymer with a hydrophobic-hydrophilic balance different from the first amphiphilic polymer, and each of the at least one lipophilic active compound has modified physico-chemical properties as compared to the same lipophilic active compound used as the starting product for the preparation of the composition, wherein
 i. each of the at least one lipophilic active compound has modified physico-chemical properties represented either by decreased enthalpy of melting or by both decreased enthalpy and decreased temperature of melting as compared to the same bulk starting crystalline lipophilic active compound;   ii. said polymeric matrix is not crosslinked and no covalent interaction occurs between the two or more polymers and between the polymers and the at least one lipophilic active compound; and   said lipophilic active compound or a salt, isomer, ester, ether or other derivative thereof is selected from acetylcholinesterase inhibitors, analgesics and nonsteroidal antiinflammatory agents, anthelminthics, antiacne agents, antianginal agents, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticancer agents and immunosuppressants, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antiinflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, antiobesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, hypnotics, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opiod analgesics, protease inhibitors, sedatives, sex hormones, stimulants, vasodilators, essential fatty acids, non-essential fatty acids, proteins, peptides, sugars, vitamins, nutraceuticals, natural agents, or mixtures thereof.   
     
     
         2 - 4 . (canceled). 
     
     
         5 . The composition according to  claim 1 , wherein said lipophilic active compound or a salt, isomer, ester, ether or other derivative thereof is selected from the group consisting of:
 (i) acetylcholinesterase inhibitors selected from the group consisting of donepezil, tacrine, and pyridostigmine;   (ii) analgesics and nonsteroidal antiinflammatory agents (NSAIA) selected from the group consisting of aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine,   (iii) anthelminthics selected from the group consisting of albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, fenbendazole, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate and thiabendazole;   (iv) antiacne agents selected from the group consisting of isotretinoin and tretinoin;   (iv) antianginal agents selected from the group consisting of amyl nitrate, glyceryl trinitrate (nitroglycerin), isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate, and ubidecarenone (coenzyme Q10);   (v) antiarrhythmic agents selected from the group consisting of amiodarone HCl, digoxin, disopyramide, flecainide acetate and quinidine sulfate;   (vi) anti-asthma agents selected from the group consisting of zileuton, zafirlukast, terbutaline sulfate, montelukast, and albuterol;   (vii) antibacterial agents, including antibiotics, selected from the group consisting of alatrofloxacin, azithromycin, aztreonum, baclofen, benzathine penicillin, cefixime, cefuraxime axetil, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, phenoxymethyl penicillin, rifabutin, rifampicin, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulpha-methoxazole, sulphapyridine, tetracycline, trimethoprim, trovafloxacin, and vancomycin;   (vii) anti-benign prostate hypertrophy (BPH) agents selected from the group consisting of alfuzosin, doxazosin, phenoxybenzamine, prazosin, terazosin and tamulosin;   (viii) anticancer agents and immunosuppressants selected from the group consisting of abarelix, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide, amsacrine, anastrozole, arsenic trioxide, asparaginase, azacitidine, azathioprine, BCG Live, bevacuzimab (avastin), bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin HCl, dromostanolone propionate, ellipticine, enlimomab, estramustine, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide, exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, mofetil mycophenolate, nandrolone, nelarabine, nilutamide, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sirolimus, sorafenib, streptozocin, sunitinib maleate, tacrolimus, tamoxifen citrate, temozolomide, teniposide, testolactone, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, and zoledronic acid;   (ix) anticoagulants selected from the group consisting of cilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, and tirofiban;   (x) antidepressants selected from the group consisting of amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxine HCl;   (xi) antidiabetics selected from the group consisting of acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glyburide, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide and troglitazone;   (xii) antiepileptics selected from the group consisting of beclamide, carbamazepine, clonazepam, thotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;   (xiii) antifungal agents selected from the group consisting of amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl, terconazole, tioconazole and undecenoic acid;   (xiv) antigout agents selected from the group consisting of allopurinol, probenecid and sulphinpyrazone;   (xv) antihypertensive agents selected from the group consisting of amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan;   (xvi) antimalarial agents selected from the group consisting of amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine and quinine sulfate;   (xvii) antimigraine agents selected from the group consisting of dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;   (xviii) antimuscarinic agents selected from the group consisting of atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl, and tropicamide   (xix) antiparkinsonian agents selected from the group consisting of bromocriptine mesylate, lysuride maleate, pramipexole, ropinirole HCl, and tolcapone;   (xx) antiprotozoal agents selected from the group consisting of atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole and tinidazole;   (xxi) antithyroid agents selected from the group consisting of carbimazole and propylthiouracil;   (xxii) antitussive agent such as benzonatate;   (xxiii) antiviral agents selected from the group consisting of abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, and stavudine;   (xxiv) anxiolytics, sedatives, hypnotics and neuroleptics selected from the group consisting of alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, triflupromazine, flupenthixol decanoate, fluphenthixol decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, propofol, pseudoephedrine, quetiapine, risperidone, sertindole, sulpiride, temazepam, thioridazine, triazolam, zolpidem, and zopiclone;   (xxv) beta.-blockers selected from the group consisting of acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol and propranolol;   (xxvi) cardiac inotropic agents selected from the group consisting of anrinone, digitoxin, digoxin, enoximone, lanatoside C and medigoxin;   (xxvii) corticosteroids selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;   (xxviii) diuretics selected from the group consisting of acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone and triamterene;   (xxix) gastrointestinal agents selected from the group consisting of bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, pantoprazole, rabeprazole sodium, ranitidine HCl, and sulphasalazine;   (xxx) histamine H 1 - and H 2 -receptor antagonists selected from the group consisting of acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide, and terfenadine;   (xxxi) keratolytic agents selected from the group consisting of acetretin, calciprotriene, calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin, and tazarotene;   (xxxii) lipid regulating/hypolipidemic agents selected from the group consisting of atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, hesperetin, lovastatin, pravastatin, probucol, and simvastatin;   (xxxiv) muscle relaxants selected from the group consisting of cyclobenzaprine, dantrolene sodium and tizanidine HCl;   (xxxv) opioid analgesics selected from the group consisting of codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;   (xxxvi) sex hormones selected from the group consisting of clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, mifepristone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone and tibolone;   (xxxvii) stimulants selected from the group consisting of amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;   (xxxviii) nutraceutical agents selected from the group consisting of calcitriol, carotenes, chrysin, dihydrotachysterol, flavonoids, hesperetin resveratrol, jasmonates, -lipoic acid, lutein, lycopene, essential fatty acids, non-essential fatty acids, naringenin, phytonadiol, quercetin, vitamins including vitamin A, vitamin B 2 , vitamin D and derivatives, vitamin E, and vitamin K, coenzyme Q10 (ubiquinone), plant extracts, and minerals.   
     
     
         6 . The composition according to  claim 1 , wherein
 i. said amphiphilic polymer is selected from the group consisting of polyethylene oxide (PEO), PEO derivatives, poloxamers, poloxamines, polyvinylpyrrolidones, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylates, polymethacrylates, polyethylene glycol (PEG) copolymers, PEO/polypropylene glycol copolymers, PEG-modified starches, vinyl acetate-vinyl pyrrolidone copolymers, polyacrylic acid copolymers, polymethacrylic acid copolymers, plant proteins and protein hydrolysates; and   ii. said hydrophilic polymer is selected from starch, sodium carboxymethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, sodium alginate, chitosan, and carrageenan.   
     
     
         7 . (canceled) 
     
     
         8 . The composition according to  claim 1 , wherein;
 i. two polymers form the polymeric matrix, one of the polymers is an amphiphilic polymer selected from Poloxamer 407 or vinylpyrrolidone-vinyl acetate copolymer, and the other polymer is a hydrophilic polymer selected from sodium carboxymethylcellulose, sodium alginate or chitosan, or   ii. two amphiphilic polymers form the polymeric matrix, said two amphiphilic polymers are selected from polyvinylpyrrolidone and a plant protein such as corn zein, or hypromellose acetate succinate and protein hydrolysate.   
     
     
         9 - 11 . (canceled) 
     
     
         12 . The composition according to  claim 1 , wherein three polymers form the polymeric matrix, and either
 i. one of the three polymers is an amphiphilic polymer and the other two polymers are hydrophilic polymers; or,   ii. two of the three polymers are amphiphilic polymers with different hydrophobic-hydrophilic balance, selected from polyvinylpyrrolidone and a plant protein hydrolysate, or polyvinylpyrrolidone and Poloxamer 407, and the third polymer is a hydrophilic polymer, such as sodium carboxymethylcellulose.   
     
     
         13 - 14 . (canceled) 
     
     
         15 . The composition according to  claim 5 , wherein the composition is;
 i. a pharmaceutical composition comprising at least one lipophilic drug selected from fenofibrate, atorvastatin, clarithromycin, itraconazole, nifedipine, albendazole, or tacrolimus;   ii. a veterinary composition comprising at least one lipophilic drug selected from albendazole, fenbendazole or itraconazole; or   iii. a nutraceutical composition, comprising at least one nutraceutical selected from resveratrol or hesperetin.   
     
     
         16 . (canceled) 
     
     
         17 . The pharmaceutical composition according to claim  claim 15 , comprising fenofibrate as the sole lipophilic drug, and either:
 i. two polymers forming the polymeric matrix selected from an amphiphilic polymer, such as Poloxamer 407, and a hydrophilic polymer selected from sodium carboxymethylcellulose or sodium alginate, or   ii. three polymers forming the polymeric matrix.   
     
     
         18 - 38 . (canceled) 
     
     
         39 . The nutraceutical composition according to  claim 15 , comprising resveratrol as the lipophilic nutraceutical and two polymers forming the polymeric matrix, wherein one of the polymers is an amphiphilic polymer, preferably Poloxamer 407, and the other is a hydrophilic polymer, preferably sodium carboxymethylcellulose, sodium alginate or chitosan. 
     
     
         40 - 41 . (canceled) 
     
     
         42 . The pharmaceutical composition according to  claim 15 , comprising two lipophilic drugs selected from fenofibrate and atorvastatin. 
     
     
         43 - 46 . (canceled) 
     
     
         47 . The pharmaceutical composition according to  claim 15 , further comprising one or more pharmaceutically acceptable carriers, excipients or both wherein said composition is formulated for oral administration into a dosage form, selected from the group consisting of capsules, tablets, beads, grains, pills, granulates, granules, powder, pellets, sachets, troches, oral suspensions and aerosol, preferably tablets. 
     
     
         48 - 54 . (canceled) 
     
     
         55 . The nutraceutical composition according to  claim 39  further comprising one or more nutraceuticals, nutritional agents, acceptable carriers, excipients or a mixture thereof. 
     
     
         56 - 74 . (canceled)