Methods and systems for the delivery of a therapeutic agent

Abstract

The present invention provides a liquid pharmaceutical composition comprising a therapeutic agent and an alkoxy-polyethylene glycol, for example, methoxy-polyethylene glycol, for administration of the therapeutic agent to the mammal. The compositions can be applied to a membrane, for example, a nasal membrane during intranasal administration. The invention also provides methods of administering such compositions to a mammal.

1 - 40 . (canceled) 
     
     
         41 . A liquid pharmaceutical composition formulated for administration to a mucosal membrane comprising:
 a) a therapeutically effective amount of a therapeutic agent, a pharmaceutically acceptable salt thereof or combinations thereof; and   b) a methoxy-polyethylene glycol of Formula I
   H3C—O—(CH2CH2O) n -H
 
   
       wherein n is a number in the range of from about 1 to about 25. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the composition is formulated for administration to a rectal membrane. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the therapeutic agent is selected from the group consisting of an analgesic agent, an anti-inflammatory agent, an anti-arrhythmic agent, an anti-asthma agent, an anti-bacterial agent, an anti-viral agent, an anti-coagulant, an anti-depressant, an anti-diabetic, an anti-epileptic, an anti-fungal agent, an anti-hypertensive agent, an anti-malarial, an anti-migraine agent, an anti-muscarinic agent, an anti-neoplastic agent, an immunosuppressant, an anti-protozoal agent, an anti-thyroid agent, an anxiolytic agent, a sedative, a hypnotic agent, a neuroleptic agent, a beta-Blocker, a cardiac inotropic agent, a corticosteroid, a diuretic agent, an anti-Parkinsonian agent, a gastrointestinal agent, an anti-histamine, a histamine-receptor antagonist, a lipid regulating agent, a muscle relaxant, nitrate and other anti-anginal agent, a nutritional agent, an opioid analgesic, sex hormone, stimulant, cytokine, peptidomimetic, peptide, protein, toxoid, sera, antibody, vaccine, nucleoside, nucleotide, nucleic acid and a peptidyl-nucleic acid. 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of analgesic and anti-inflammatory agents 
     
     
         45 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of opiod analgesics. 
     
     
         46 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory agents. 
     
     
         47 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is 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, refocoxib, sulindac, tetrahydrocannabinol, tramadol, tromethamine, amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate, zileuton, zafirlukast, montelukast, albuterol, baclofen, benzathine penicillin, cinoxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim, trovafloxacin, abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, citostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, and tirofiban, amoxapine, bupropion, citalopram, clomipramine, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate, venlafaxine HCl, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide and troglitazone, beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, vigabatrin, amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl, terconazole, tioconazole, undecenoic acid, amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril, 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, valsartan, amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulfate, dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotyline malate, rizatriptan benzoate, sumatriptan succinate, zolmitriptan, atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, oxyphencyclimine HCl, tropicamide, aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene, busulfan, camptothecin, chlorambucil, cyclosporin, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, mitomycin, mitotane, mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl, toremifene citrate, atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole, carbimazole, paracalcitol, propylthiouracil, benzonatate, alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, trifluoromazine, fluphenthixol decanoate, fluphenazine decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine, rispiridone, sertindole, sulpiride, temazepam, thioridazine, triazolam, Zolpidem, and zopiclone, acebutolol, alprenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin, beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene, bromocriptine mesylate, lysuride maleate, pramipexole, ropinirole HCl, and tolcapone, bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lansoprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium, ranitidine HCl and sulphasalazine, acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide, and terfenadine, atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, simvastatin, dantrolene sodium, tizanidine HCl, amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate and pentaerythritol tetranitrate, calcitriol, carotenes, dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonadiol, vitamin A, vitamin B2, vitamin D, vitamin E and vitamin K, codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, hydromorphone, nalbuphine and pentazocine, clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone, tibolone, amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol, becaplermin, donepezil HCl, L-thryroxine, methoxsalen, verteporfrin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine HCl, sildenafil citrate, tacrine, tamsulosin HCl, tolterodine, and their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         48 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is 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, refocoxib, sulindac, tetrahydrocannabinol, tramadol, tromethamine, and their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         49 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is ketorolac and its pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         50 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratidine, meclizine HCl, oxatomide, terfenadine, and their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         51 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of loratadine and its pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         52 . The pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of sildenafil citrate, amlodipine, tramadol, celecoxib, rofecoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, alprazolam, bromazepam, chlorpromazine, clonazepam, diazepam, flunitrazepam, flurazepam, haloperidol, lorazepam, lormetazepam, nitrazepam, oxazepam, pseudoephedrine, temazepam, triazolam, Zolpidem, zopiclone, tetrahydrocannabinol, testosterone, megestrol acetate, repaglinide, progesterone, rimexolone, cyclosporin, tacrolimus, sirolimus, teniposide, paclitaxel, pseudoephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, and pharmaceutically acceptable salts, isomers and derivatives thereof. 
     
     
         53 . The liquid pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of lorazepam, clonazepam, alprazolam, and pharmaceutically acceptable salts, isomers and derivatives thereof. 
     
     
         54 . The liquid pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; aminocaproic acid; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deferoxamine, denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; esmol hydrochloride; Factor IX; famciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor, granulocyte-macrophage stimulating factor; growth hormones (human or bovine); gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human; insulin-porcine; insulin NPH; insulin aspart; insulin glargine; insulin detemir, interferon-α; interferon-β; ipratropium bromide; isofosfamide; Japanese encephalitis virus vaccine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir, lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate; methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; poliovirus vaccine (live or inactivated); polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosis factor, typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir, varicella virus vaccine live; vasopressin and vasopessin derivatives; vecoronium bromide; vinblastin; vincristine; vinorelbine; warfarin-sodium; yellow fever vaccine; zalcitabine; zanamavir, zolandtronate; zidovudine, and pharmaceutically acceptable salts, isomers and derivatives thereof. 
     
     
         55 . The liquid pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of ACTH and analogs thereof, teracosactrin, alsactide, cortisone, hydrocortisone alcohol, hydrocortisone acetate, hydrocortisone hemisuccinate, prednisolone terbutate, 9-alpha-fluoroprednisolone, triamcinolone acetonide, dexamethasone phosphate, flurisolide, toxicorol pivalate; benzphetamine HCl chlorphentermine HCl, tetracycline HCl, tyrothricin, cephalosporine, aminoglycosides, streptomycin, gentamycin, leucomycin, penicillin and derivatives, monoclonal or polyclonal antibodies, amitriptyline HCl, imipramine HCl, neuroleptica, metopimazin, domperidon, diphenhydramin HCl, chloropheniramine maleate, histamine, prophenpyridamine maleate, chlorprophenpyridamine maleate, disodium cromoglycate, meclizine, clonidine HCl, chymotrypsin, bromelain seratiopeptidase, acetaminophen, aspirin, aminopyrine, phenylbutazone, colchicine, probenocid, fluticasone, predonisolone, triaxncinolone acetonide, actinomycin C, chlorhexidine HCl, hexylresorcinol, dequalinuim cloride, ethacridine, sodium cromoglycate, isoprotereol HCl; interferons, phenyl-p-guanidino benzoate, enviroxime, propranolol HCl, blood factor VII, blood factor VIII, vitamin D3, clenbuterol HCl, bitolterol mesylate, digitalis, bradykin antagonists, hydrailsazine, angiotensin II antagonist, nitroglycerin, propranolol, clofilium rosylate, sulphathiazole, nitrofurazone, lidocaine, cocaine, lacicortone, hydrocorticeone, fluocinolone acetonide, triamcinolone acetonide, lysozyme chloride, dextranase, secretin, substance P, LHRH, naferelin, buserelin, zolidex, thyrotropin releasing hormone, benzocaine, dihydroergot amine, ergometrine, ergotamine, pizotizin, insulin (hexameric/dimeric/monomeric forms), nicotine, methacholine, scopolamine, attopine, ipratropium, apomorphin, growth hormone (e.g. human), vasopressin and analogues (DDAVP, Lypressin), PGA and derivatives thereof, PGE1 and derivatives thereof, PGE2 and derivatives thereof, PGF1 and derivatives thereof, dinoprost trometamol, citrate, or α1-antitrypsin, ethinyloestradiol, levonorgestrel, FSH, LH, LTH, estradiol-17-beta, norethindrone, phenylephrine, xylometazoline, tramazoline, dopamine, dobutamine, granistron, ramelteon, brotizolam, camazepam, chlorazepic acid, cloxazolam, delorazepam, estazolam, ethyl loflazepate, fludiazepam, flutazolam, halazepam, haloxazolam, ketazolam, loprazolam, lormetazepam, nimetazepam, nitrazepam, nordiazepam, oxazepam, pinazepam, prazepam, temazepam, tetrazepam, tofisopam, AIDS-vaccines, parainfluenza virus, polio, rhinovirus type 13, respiratory syncytial virus, phenylephrine HCl, tetrahydrozoline HCl, naphazoline nitrate, oxymetazoline HCl, tramazoline HCl, papaverine HCl, Substance P, vasoactive intestinal peptide (VIP), and pharmaceutically acceptable salts, isomers and derivatives thereof. 
     
     
         56 . The liquid pharmaceutical composition of  claim 41 , wherein the therapeutic agent is selected from the group consisting of oxytocin, vasopression (desmopresin), insulin, calcitonin, elcatonin, cyanocobalmin B12, glucagon-like protein-1 (GLP-1), dinoprostone, misoprostol, apomorphine, fentanyl, metoclopramide, butorphanol, and their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. 
     
     
         57 . A method of administering a therapeutic agent to a mammal, the method comprising administering to a mucosal membrane of the mammal a liquid pharmaceutical composition comprising:
 a) a therapeutically effective amount of a therapeutic agent, a pharmaceutically acceptable salt thereof or combinations thereof; and   b) a methoxy-polyethylene glycol of Formula I
   H3C—O—(CH2CH2O) n -H
 
   
       wherein n is a number in the range of from about 1 to about 25. 
     
     
         58 . The method of  claim 57 , wherein the mucosal membrane is a rectal membrane. 
     
     
         59 . The method of  claim 57 , wherein the mucosal membrane is an intranasal mucosal membrane. 
     
     
         60 . A system for mucosal delivery of a liquid pharmaceutical composition formulated for mucosal administration comprising:
 a) a mucosal membrane administration device; and   b) a liquid pharmaceutical composition formulated for mucosal administration disposed in the mucosal membrane administration device, the liquid pharmaceutical composition comprising:
 i) a therapeutically effective amount of a therapeutic agent, a pharmaceutically acceptable salt thereof or combinations thereof; and 
 ii) a methoxy-polyethylene glycol of Formula I
   H3C—O—(CH2CH2O) n -H
 
 
   
       wherein n is a number in the range of from about 1 to about 25. 
     
     
         61 . The system of  claim 60 , wherein the mucosal membrane is a rectal membrane. 
     
     
         62 . The system of  claim 60 , wherein the mucosal membrane administration device is a nasal spray device, and the mucosal membrane is an intranasal mucosal membrane.