MX2007013912A - Low dose administration of a topical composition. - Google Patents

Abstract

Unexpectedly, the therapeutically required amount of active ingredient in a topical drug delivery product may be significantly reduced by applying the product in a delivery vehicle containing a SEPA?? penetration enhancer to the upper arms and shoulders of an individual in need of the active ingredient rather than to the abdomen of the individual.

Description

ADMINISTRATION OF LOW DOSE OF A TOPICAL COMPOSITION Cross Reference to Related Request This application claims benefit of the Request Provisional of E.U.A. No. 60 / 679,673 filed May 11, 12005. This application in its entirety is incorporated herein by reference.

Field of the Invention This invention relates to the field of topical drug delivery and more specifically to the field for improving topical delivery of physiologically active compounds by applying them to the skin of the shoulders and / or upper arms.

Background of the Invention The administration of drugs and other biological materials to the bloodstream via a transdermal route of administration has received much attention in recent years. The skin of an average adult covers more than two square meters of surface area and receives about one third of all the blood that circulates through the body. If it is elastic, rough and generally it is self-regenerating. Human skin consists of two layers: the epidermis (which is a mixed material of multiple layers including the stratum corneum), and the dermis. The stratum corneum (E.C.) represents the limiting step of the regime in the diffusion of the chemical through the skin. The E.C. it is composed of dead, keratinized, metabolically inactive cells that are tightly packed together, and embedded in an amorphous matrix primarily of lipid and non-fibrous protein within which the keratin filaments are distributed. The cells of E.C. they generally contain 20% water, while the following cells, in the germinative stratum, contain 70% water. The E.C. it does not rehydrate easily. Therefore, the transdermal permeation is mainly controlled by diffusion through the E.C. There are several main reasons of interest in transdermal drug delivery: 1) the elimination of uncertainties of absorption of, and irritation to, the gastrointestinal tract that may arise when the drugs are administered orally; 2) deriving the portal circulation, thus eliminating the first-pass metabolism in the liver; this is extremely important for drugs with short half-lives or with unwanted potential actions in the liver; 3) localized supply of medication to the intended target site; 4) drug delivery directly into the systemic circulation at a constant rate (similar to intravenous infusion); 5) infrequent dosage (daily, weekly or more) for certain drugs; 6) Ease of use and according to the patient of interest. The transdermal supply is generally restricted to small molecule drugs that require delivery regimens of less than 10 mg / day, in order to obtain higher blood levels, the drug delivery regimen should be increased. There have been many proposals to achieve the superior drug delivery regimen via the use of absorption promoters and the development of prodrugs that can be absorbed more easily. Examples of existing absorption enhancers include dimethyl sulfoxide (DMSO), ethylene glycol, hexanol, fatty acid and esters, alkyl-2- (N-N-disubstituted amino) -alkanoate, an (N, N-disubstituted amino) alkanoate. -alkanol, or a mixture thereof, cyclopentadecalacetones, sunscreens of ester and pyrrolidone derivatives, among others. One of said improving compounds that has received a lot of attention is Azona (N-dodecyl azacycloheptan-2-one).

The use of such penetration enhancers has been made for a variety of small molecule drugs as demonstrated. The prior art patents of relevance for penetration enhancers of physiologically active agents include the Patents of E.U.A. Nos. 3,551,554, which discloses dimethyl sulfoxide, US Pat. No. 3,989,816 describes 1-substituted azacycloheptane-2-one; The Patent of E.U.A. No. 4,132,781 discloses an antibiotic plus 2-pyrrolidone or a n-lower alkyl-2-pyrrolidone, The Patent of E.U.A. No. 4,017,641, also describes 2-pyrrolidone but with propylene glycol; others of interest are the Patents of E.U.A. Nos. 3,903,256, 4,343,798, 4,046,886, 3,934,013; 4,070,462; 4,1390,643, 4,130,667, 4,289,764; 4, 07 ', 462; 3,527,864, 3,535,422, 3,598,123, 3,952,099, 4,373,4354, 4,286,592; 4,299,826; 4,314,557; 4,343,798; 4,335,115; 3,598,122; 4,405,616, 3,896,238, 3,472,931 and 4,557,934. Applicants have previously requested a new class of compounds which are derivatives of 1,3-dioxanes and 1,3-dioxolanes to be used as skin penetration enhancing compounds. These compounds, which are commercially available under the trade name SEPA®, were described in detail in the U.S. Patent. No. 4,861,764. Work with dioxolane improvers has been described in several literature and patent publications.

For example, Samour, and others, Proc. Int. Symp. Control. I laughed Bioact. Mater. 16: 183-184 (1989); Marty, and others, Proc. Int. Symp. Control. I laughed Biocat. Mater. 16: 179-180 (1989); Marty et al., Proc. Int. Symp. Control. I laughed Bioact. Mater. 17: 415-416 (1990); Michniak, et al., Drug Delivery 2: 117-122 (1995); Marty, et al., Abstract of Paper Presented at the American Association of Pharmaceutical Scientists, Washington, C.C. Mar. 26-28, 1990. Specific examples of SEPA® improvers can be found in the patents of E.U.A. 5,976,566 and 5,968,919 where the topical delivery of non-steroidal anti-inflammatory drugs and hormones has been demonstrated. Even with improved penetration, it may be difficult to supply sufficient quantities of some small molecule drugs to achieve therapeutic blood levels. An example of this problem can be found in the difficulty associated with the supply of the hormone testosterone. Due to the high serum concentrations required for testosterone, the extremely large amounts of topical testosterone formulations, on the order of 5-10 g / day, are required to be applied in order to achieve therapeutic serum levels of testosterone. Methods are required to reduce the amount of active ingredient required when topical administration is used, even with existing penetration improvers. The applicants have discovered a method for treatment that allows a significant reduction in the required dose of active ingredient when applied topically.

Summary of the Invention The present invention has a main object to provide an improved method of topical delivery of physiologically active compounds or ingredients by the administration to the skin of the upper arms and / or shoulders. In one embodiment, the improved method allows a significant reduction in the dose of active ingredient required to achieve the same therapeutic effect. In one embodiment, a method for raising the total serum testosterone concentration in an individual deficient in testosterone includes applying to the upper arm and / or shoulders the individual a low dose amount of a testosterone composition that includes an improving amount of penetration of the skin of a 1, 3-dioxalano substituted with hydrocarbyl from C7 to C? , 1,3-dioxane or acetal thereof. In another embodiment, a method for delivering an active ingredient and a 1,3-dioxane substituted with C7 to Ci4, 1,3-dioxane or acetal thereof to the shoulders and / or upper arms of an individual.

Detailed description of the invention The compositions used in the invention are intended for topical non-invasive application to the skin, providing improved systemic delivery of the active ingredient and any other coactive ingredient. The low dose administration of a composition may be applied as required to the skin of the upper arms and / or shoulders of an individual seeking the therapeutic effect. Examples of the active ingredients that are advantageously administered by the topical formulations of this invention include any locally or systemically active agents that are compatible with the dermal penetration enhancers of the present invention and that can be delivered through the skin with the aid of the enhancer. of skin penetration to achieve a desired effect. The amount of the active ingredient used will depend on the ability of the active to be incorporated into a delivery vehicle and the therapeutic amount required. In part, this amount may depend on the solubility of the active in specific solvents used in the delivery vehicle. The active agents (grouped by therapeutic class) include: Food system: Antidiarrheals such as diphenoxylate, loperamide and hyoscyamine. Cardiovascular System: Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, ganetidine, methyldopa, reserpine, trimetafan. Calcium channel blockers such as dithiazem, felodopine, amiodipine, nitrendipine, nifedipine and verapamil. Antiarrhythmics such as amidarona, flecainide, isopyramide, procainamide, mexiletene and quinidine. Antianginal agents such as glyceryl trinirate, erythritol tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexylene, isosorbide dinitroate and nicorandil. Beta-adrenergic blocking agents such as alprenolol, atenol, buprnolo, carteolol, labetalol, metoprolol, nadolol, nadoxolo, oxprenolol, pindolo, propanolol, sotalol, timolol and timolol maleate. Cardiotonic glycosides such as diogoxin and other cardiac glycosides and theophylline derivatives. Adrenergic stimulants such as adenaline, ephedrine, fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamonl, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine.

The vasodilators such as cycllandelate, isoxsuprine, papaverine, dipyrimadol, isosorbide dinitrate, phentolamine, nicotinic alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and zantanol. Antimigraine preparations such as esroglamin, dihydroergolamina, metilsergido, pizotifeno and sumatriptan. Drugs Affecting Blood and Hematopoietic Tissues: Anticoagulants and thrombolytic agents such as warfarin, dicumerol, low molecular weight heparins such as enoxaparin; Streptokinase and its active derivatives. Hemostatic agents such as aprotinin, tranexamic acid and prolamine. Central Nervous System: Analgesics, antipyretics including opioid analgesics, such as buprenorphine, dextromoramide, dextropropoxyphenop, fetanyl, alfentanil, sufentanil, hydroforphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine. Others include acetylsalicylic acid (aspirin), paracetamol and phenazone. Hypnotics and sedatives such as barbiturates, amylobarbitone, butobarbitone and pentobarbitone and others hypnotics and sedatives such as coral hydrate, chlormethiazole, hydroxyzine and meprobamate. Antianxiety agents such as benzodiazapihas, alprasolam, bromazepan, chlordiazapoxide, clobazan, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, termazepam and triazolam.

Neuroleptic and antipsychotic drugs - such as phenotriazines, chlorpromazine, fluphenazine, periciazine, perphenazine, promazine, thiopropazate, thioridazine and trifluoperazine and the butyrophenones, roperidol and haloperidol and the other antipsychotic drugs such as pimozido, thiothizole and lithium. Antidepressants such as the tricyclic antidepressants amitriptyline, clomipramine, desipramine, dotiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine and tetracyclic antidepressants such as mlanserin, and monoamine oxidase inhibitors such as isocarbozazide, phenelizine, tranylcypromine and moclobemine and inhibitors of selective serotonin reuptake such as fluoxetine ,. paroxetine, citalopram, fluvoxamine and sertraline. CNS Stimulants such as Caffeine Anti-Alzheimer Agents such as Tacrine Anti-Parkinson Agents such as amentadine, benserazide, carbidopa, levodopa, benzylptopine, biperiden, benzexol, procyclidine and dopamine agonists 2 such as S (-) -2- (N-propyl-N-2-thienylethylamino) -5-hydroxytetrali-n (N-0923). Aticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and caraamaepine, ethosuximide, metosuximide, phenosuximide, sultiame and clonazepam. Skeletal Muscle System: Non-steroidal anti-inflammatory agents including their racemic mixtures or individual enantiomers where applicable, such as ibuprofen, flubiprofen, ketoprofen, aclofenac, diclofenac, aloxiprine, acetone, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindaco, deoxysulinaco, tenoxicam, tramadol and quetoralaco. Additional nonsteroidal anti-inflammatory agents that can be formulated in combination with dermal penetration enhancers include salicylamide, salicylic acid, flufenisal, salsalate, tritanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, cintazone, flufenamicin, clonixeril, clonixin, acid meclofenamico, flunixina, colchicina, demecolcina, allopurinol, oxipurinol, bencidamina hydrochloride, dimefadano, indoxol, intrazol, hydrochloride of Mimbium, paranylene hydrochloride, tetridamine, benzindopyrine hydrochloride, fluoprofen, ibufenac, naproxol, fenbufen, cinchofen, sodium difluumidone, fenaomol, flutiazine, metazamide, letimide hydrochloride, nexeridine hydrochloride, oxtazamide, molinazole, neocincofen, nimazole, prozaxol citrate, tesicam, tesimide, tolmetin, and triflumidate. Antireumatoid agents such as penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate and auranofin. Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, ofenadrine and quinine. Agents used in gout and hyperuricemia such as alupurinol such as alupurinol, colchicine, probenecid and sulfiniprazone. Hormones and Steroids: Estrogens such as estradiol, estriol, estrone, ethylestradiol, mestranol stilboestrl, dienoestrol, epiostriol, estropipate and zeranol. Progesterone and other progestogens such as allystestrenol, dihydrogesterone, linoestrenol, norgestrel, norethindrine, norethisterone, neretiesterone acetate, geslodene, levonorgestrel, medroxyprogesterone, and megestrol.

Antiandrogens such as cyproterone acetate and danazol. Antiestrogens such as tamoxifen and epitiosestanol and aromatase inhibitors, exomestane and 4-hydroxy-androstenedione and their derivatives. Androgens and anabolic agents such as testosterone, methyltestosterone, clostebol acetate, drostanolone, furazabol, oxandroolone, nanofrolone, stanozolol, trenbolone acetate, dihydro-testosterone, 17-a-methyl-19-nortestosterone and fluoxymesterone. 5-alpha-reductase inhibitors such as finasteride, turoesteride, LY-191704 and MK-306. Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, flucinonide, flucinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate , hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, acetonide of tramcinolone. Additional examples of steroidal anti-inflammatory agents for use in the compositions herein include shortdoxone, phycocetone, fludrocortisone, difluorsone diacetate, fluranderenolone acetonide, medrisone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, chlorcoterlone, descinolone, desonide, dichlorixone, difluorednate, flucloronide, flumetasone, flunisolide, flucortolone, fluorometalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, parametasone, cortisone acetate, cyclopentipropionate Hydrocortisone, Chorodoxone, Flucetonide, Fludrocortisone Acetate, Flurandrenolone Acetonide, Medrisone, Amcinafal, Amcinafide, Betamethasone, Betamethasone Benzoate, Chloroprednisone Acetate, Chlorocortolone Acetate, Descinolone Acetonide, Deoximetasone, Dichlorisone Acetate, Diflupredonate, Flucloronide, Pivalate of flumetasone, flunisolide acetate, fluperolone acetate, fluperdnisolone valerate, parametasone acetate, prednisolamate, prednival, triamcinofona hexacetonide, cortivazol, formocortal and nivazole. Pituitary hormone and its analogous active derivatives such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and gonadotropin releasing hormone (GnRH). Hypoglycemic agents such as insulin, chlorpropanide, glibenclamide, gliclazide, glipzide, tolazamide, tolbutamide and metformin.

Thyroid hormones such as calcitonin, thyroxine and lithioronin and antithyroid agents such as carbimazole and propylthiouracil. Other diverse hormone agents such as cotreotide. Pituitary inhibitors such as bromocriptine. Ovulation inducers such as clomiphene. Genitourinary system: Diuretics such as thiazides, related diuretics and cycle diuretics, bendrofluazide, chlorothiazide, chlorothalidone, dopamine cyclopenthiazide, hydrochlorothiazide, idapamide, mefruside, methyclothiazide, metolazone, quinetrzone, bumetamide, ethacrynic acid and frusemide, and potassium-moderating diuretics, spironolactone, Amiloride and triamterene. Antidiuretics such as desmopressin, lyserin and vasopressin including their active derivatives or the like. Obstetric drugs including agents that act on the uterus such as ergo etrin, oxytocin and gemeprost. Prostaglandins such as alprostadil (PPGEl), prostacyclin (PGI2), dinoprost (prostaglandin F2-ala) and misoprostol. Antimicrobials: Antimicrobials including cephalosporins such as cephalexin, cefoxitin and cephalothin.

Penicillins such as amoxilcillin, amoxicillin with clavulanic acid, ampicillin, becampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenoxymethylpenicillin, flucloxacillin, meziocillin, piperacillin, ticarcillin, and azoicillin. Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, metacycline and oxytetracycline and other antibiotics of the tetracycline type. Aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, n-ethylmycin and tobramycin. Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacin and norfloacin. Sulfonamias such as phthalylsulfothiazole, sulfddoxin, sulfadiazine, sulfametizole, and sulfamethoxazole. Sulfones such as dapsone. Other various antibiotics such as chloranfernicol, clindamycin, erythromycin, erythromycin ethylcarbonate, erythromycin estolate, erythromycin glycetate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofuatoin, spectinomycin, vnacomycin, aztreonam, colistin IV, metronidazole, tidazol, fusidic acid and trimethoprim; 2-Thiopyridine N-oxide, compounds of halogen, particularly iodine and iodine compounds such as PVP complex of iodine and diiodohydroxyquinoline; hexachlorophene; chlorhexidine, chloramine compounds,; benzolyl peroxide. Antitubercular drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin and cyofazimine. Antimalarials such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine and halofantrine. Antiviral agents such as acyclovir and prodrugs of acyclovir, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantadine and yodoxuridine. l Antihelmintics such as mebendazole, thiabendazo, cyclosamide, praziquante, pyrantel embonate and diethylcarbamazine. Cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine, fluorouracil and their prodrugs [described, for example, in International Journal of Pharmaceutics 111, 223-233 (1994)], methotrexate, procarbazine, 6-mercaptopiopurine and mucophenolic acid. Metabolism: Anorexic agents and weight reducers including desfenfluraina, fenfluramina, dietilpropiona, mazindol and fenetermina. Agents used in hypercalcemia such as calcitriol, dihydrotaquiesterol and its active derivatives or the like. Respiratory System: Antitussives such as ethylmorphine, dextromethorphan and pholcodine. Expectorants such as acetylcysteine, bromhexine, emetine, guaifenesin, ipecac and saponins. Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine. Bronchoepasmodic relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, chromoglyclic acid and their prodrugs [described, for example, in International Journal of Pharmaceutics 7, 63-75 (1980)], terbutaline, ipratropium bromide, .salmeterol and theophylline and theophylline derivatives. Allergy and Immune System: • Antihistamines such as meclozine, cyclizine, chlorocyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, clemastine, doxylamine, mebhydroline, feniramina, tripolidina, azatadina, difenilpiralina, metdilazina, terfenadina, astemizole, loratidina and cetirizina. Neuromuscular blocking agents such as suamethonium, alcuronium, pancuronium, atracurium, galamin, tubocurarine and vecuronium. Smoking cessation agents such as nicotine, bupropion and ibogaine. Nutritional agents such as vitamins, essential amino acids, and essential fats. Keratolytics such as alpha-hydroxylic acids, cholic acid, salicylic acid. Psycho-energizers, such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole, and the like. Anticholinergic agents, which are effective for the inhibition of axillary wetting and for the control of military fever. The antiperspirant activity of agents such as metatropine nitrate, propantheline bromide, scopolamine, metscopolamine bromide, and the new class of mild antiperspirant, quaternary acyloxymethylammonium salts [described, for example, by Bodor et al., J. Med. Chem. 23, 474 (1980) and also UK Specification No. 2010270, published June 27, 1979]. Other physiologically active peptides and proteins, small or medium-sized peptides, e.g., vasopressin and human growth hormone.

Penetration of the active ingredient through the skin is preferably improved to an acceptable level by including in the composition an effective amount of a skin penetration enhancing compound in the form of a skin modifying agent of the types of skin. , Substituted 3-dioxacyclopentane and substituted 1,3-dioxacyclohexane described in the US Patent No. 4,861,764, the description of which is incorporated herein in its entirety by reference, the corresponding substituted acetal compound. Representative examples of the skin penetration enhancing compounds include: 1, 3-substituted dioxolanes of the formula (I): 1, 3-substituted 2-dioxanes of the formula (II) («) and substituted acetals of the formula (III): In the formulas (I), (II), and (III) above, R preferably represents a hydrocarbyl group of C? a C 4 4, R o, Ri, R 2 f R 3 r 4 R R s and z, i each independently, represents hydrogen or an alkyl group from C 1 to C 4. R'i and R'2, each independently represents an alkyl group from C to C. The hydrocarbyl group for R can be a straight or branched chain alkyl, alkenyl or alkynyl, especially alkyl or alkenyl, Preferably, R represents an aliphatic group of C7 to C? 2; especially aliphatic group from 'C7 to Cio- Examples of suitable alkyl groups include, for example, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl -octyl, 4-ethyl-decyl, 8-methyl-decyl, and the like. Straight chain alkyl groups, such as n-heptyl, n-octyl, n-nonyl and n-decyl, are especially preferred. Examples of alkenyl groups include, for example, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2 ', 6'-dimethyl-2', 6'-heptadienyl, 2 ', 6' -dimethyl-2 '-heptadenyl, and the like. The R group can also be substituted, for example, by halo, hydroxy, carboxy, carboxamide and carboalkoxy. The alkyl group of Ci to C4 can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the like. Preferred alkyl groups for R0, and for Ri to R8 and for R'i R'2 are alkyl having 1 to 2 carbon atoms, more especially ethyl, R0, and Ri to Re also preferably are hydrogen. Specific skin modification agents include, for example, 2-n-pentyl-l, 3-dioxolane, 2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2 • n-undecyl-1,3-dioxolane, 2-n-nonyl-l, 3-dioxane, 2-n-undecyl-l, 3-dioxane, 2-n-heptylaldehydeacetal, 2-n-octyl-aldehyde-acetal, 2-n-nonylaldehyde-acetal, 2-n-decylaldehyde acetal, 3,7-dimethyl-2,6-octadienal (citral), citronal and the like. 2-n-nonyl-l, 3-dioxolane is especially preferred and is commercially available from MacroChem Corporation of Lexington, Mass., Under the trademark SEPA®. Examples of other skin penetration enhancers and co-solvents that may be added in addition to the skin modifying agent include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, ethylene glycol, alkyl lactams, long chain amides, hexanol, fatty acids and its esters and derivatives of pyrrolidone.

The solubilizing agents and / or absorption promoters that can be used in the present invention means an agent that can dissolve the active or active or pharmaceutically acceptable salts thereof at a concentration of. at least 0.01% in relation to the total weight of the composition and further promote the absorption of the active substances or their pharmaceutically acceptable salts with a concentration of at least 0.01% in relation to the total weight of the composition, and also promote the absorption of the active substances or their pharmaceutically acceptable salts through the skin. In other words, the solubilizing agent and / or absorption promoter gives solubilizing and absorbing capacities to the active substances or their pharmaceutically acceptable salts. Examples of absorption promoters and / or solubilizers include: alkanedicarboxylic esters such as diallyl alkanedicarboxylic esters (dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate, dipropyl sebacate, etc.); and higher alkylated carboxylic alkylsters (myristate isopropyl, ethyl myristate, etc.). The amount of the skin modifying agent is selected to provide the desired delivery rate for the active compound taking into account such additional factors as, product stability, side effects, vehicle system and the like, while minimizing the dose size. Generally, depending on the particular active compound and other vehicles, amounts of people modifying the skin, and the scale of about 2.0 to 25%, preferably about 2 or 3 or 4 or 5% at 10 or 12 or 15 or 20 percent, especially from about 5 to 10 percent , of the composition, will provide optimal flow regime and 24-hour preload of the active ingredient. Usually, for gel formulations the amount of improving compound may be lower than for creamy formulations, such as from about 2 to about 10 percent of the formulation. In addition to the active ingredient and the penetration enhancer, the amount of delivery vehicle may comprise the balance of the composition. Accordingly, the delivery vehicle or vehicles may comprise up to approximately 98% &; for example, from about 50 to about 98%, for example, from about 70 to about 95%, for example, from about 70 to about 90% by weight of the composition. The compositions can be formulated as gels, especially aqueous alcoholic gels, lotions, creams, foams, sprays, ointments, lubricants, lacquers, patches, solutions, dyes, and the like, can be used as they are applied to the affected area of the skin, the formulation will be in place, that is, without running, during the time enough to allow an individual to disseminate it and retain the composition on and in the affected area. The carrier for any of the forms of the compositions of the invention may also include glycol, e.g., propylene glycol, butylene glycol, hexylene glycol, etc. (except in the case of the third embodiment described above), the lower alcohol, e.g., ethanol, isopropanol, and usually water. In addition, of course, the skin penetration, dioxane or acetal dioxolate enhancer is included in the formulations in an amount effective to improve the penetration of the active ingredient through the skin, including the stratum corneum.

Vehicle Components The composition used according to the invention may also comprise a solid, semi-solid or pharmaceutically acceptable carrier vehicle, to assist the active agent and skin penetration enhancer that will be transported to the skin or other membrane, such as the mucosa. Nasal or oral, at an appropriate concentration and quantity. The nature of the vehicle will depend on the method chosen for topical administration of the composition. The selection of a vehicle for this purpose presents a wide scale of possibilities depending on the form of product required of the composition.

It should be explained that the vehicles are compositions which may include diluents, dispersants or solvents for the active agent and the penetration of the improver which therefore ensures that they can be applied to, and evenly distributed over, an appropriate area of the skin. The compositions according to this invention may include water as a vehicle, and / or at least one pharmaceutically acceptable carrier other than water. Vehicles other than water that can be used in compositions according to the invention include solids 0 liquids such as emollients and humectants, solvents, humectants, thickeners, preservatives, dyes, fragrances, propellants and solid additives. Examples of types of said additives that can be used alone or as mixtures are the following. The emollient materials can also serve as cosmetically acceptable additives. These can take the form of silicone oils and synthetic esters. The emollient material may be a silicone oil, an ester or a mixture thereof. Amounts of emollients can vary anywhere from 0.1 to 20%, such as between 1 and 5% by weight of the final composition. Silicone oils can be divided into the volatile and non-volatile variety. The term "volatile" as it used herein refers to materials that have a vapor pressure that can be measured at room temperature. The volatile silicone oils are preferably chosen from cyclic or linear polydimethyl siloxanes containing from 3 to 9, preferably from 4 to 5, silicone atoms. Linear volatile silicone materials generally have viscosities of less than about 5 centistokes at 25 ° C, while cyclic materials typically have viscosities of less than about 10 centistokes. The non-volatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. The essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities from about 5 to about 25 million centistokes at 25 ° C. The silicone emulsifying agents may include dimethicone copolyols. These may include modified polydimethylsiloxanes to include polyether side chains. Other modifications to the side chains can result in nonionic, anionic, cationic, amphoteric and switerionic pendant portions. Among the ester emollients are: 1. Alkenyl esters or alkyl of fatty acids having from 10 to 20 carbon atoms. Examples of They include isoaraquidyl neopentanoate, isononyl isononanoate, oleyl myristate, oleyl stearate and oleyl oleate.; 2. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols; 3. Esters of polyhydric alcohol; esters of ethylene glycol mono- and di-fatty acids, esters of diethylene glycol mono- and di-fatty acids, polyethylene glycol mono- and di-fatty acid esters (200-6000), propylene glycol mono- and di-propylamino esters, polypropylene glycol monooleate 2000, monostearate - polypropylene glycol 2000, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid stress, polyglycerol polyglycerol esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, polyoxyethylene polyol fatty acid ester, fatty acid esters of sorbitan, and esters of polyoxyethylene sorbitan fatty acids, sorbitan fatty acid esters, and esters of polyoxyethylene sorbitan fatty acids, and satisfactory polyhydric alcohol esters; 4. Wax esters such as beeswax, whale sperm, myristyl myristate, stearyl stearate and arachidyl behente; and 5. Esters of sterols of which the fatty acid esters of cholesterol are examples thereof.

Representative emollients and humectants include, for example, stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid. , isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitt, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid , palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate. Representative propellants include, for example, trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, monochlorodifluoromethane, trichlorotrifluoroethane, propane, butane, isobutane, carbon dioxide. Representative solvents include, for example, lower alcohols, polyols, polyethers, oils, esters, alkyl ketones, and the like. For example, you can mention may be made of ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, or dimethylformamide, tetrahydrofuran. The solvent can be selected for its ability to dissolve the active agent and the SPE compound or SPE compounds and someone of ordinary skill in the art could understand which solvents would be suitable for those purposes or how to determine which solvents would be appropriate. Representative humectants include, for example, glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, gelatin, can be used in embodiments according to the invention. In some compositions having the form of a gel, a thickening agent, such as hydroxypropylcellulose, may be included as a gelling agent. However, any other pharmaceutically acceptable thickening / gelling agent can be used. For example, other cellulose ethers, polymeric thickening agents, e.g., acrylic acid polymers, Carbopol RTM thickeners, etc., xanthan gum, guar gum and the like as well as inorganic thickeners / gelling agents can be mentioned. The amount of the thickening agent is not particularly critical and can be selected to provide the consistency or viscosity of desired products to allow easy application to the skin but which can not be very watery or loose so that it stays where it is applied. Generally, depending on their molecular weight, amounts of thickening agent of up to about 5% such as, for example, from 0.1 to about 2% of the composition will provide the desired effect. As is well known in this matter, it is possible to include other ingredients in the formulations for particular aesthetic and / or functional effects. For example, the formulations, optionally, may include one or more humectants to hydrate the skin and emollients to soften and even the skin. Glycerin is an example of such a suitable wetting additive. When the additive is present it will usually be incorporated in an amount of up to about 5 per cent by weight of the composition, for example, from about 0.1 to 5%. The hydrophobic or lipophilic components of the formulation may be of fatty acid material. The "fatty acid material" can include mixtures of fatty acids, typically containing portions of fatty acids with chain lengths of C8 to C30. The fatty acid material may also contain relatively pure amounts of a long chain fatty acid portion. Suitable fatty acids from which the base fatty acid / nonionic surfactant mixtures can be derived include pelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic, linoleic, ricinoleic, arquidic, behenic and erucic acids. Although suitable, normally saturated fatty acid materials may contain portions of unsaturated fatty acids and may contain portions of fatty acids having a degree of substitution, such as e.g., hydroxy acids. The chain length of the components of the fatty acid material also determines the rheological properties of the resulting skin composition base. A mixture of fatty acid materials containing relatively large portions of portions of stearic and palmitic acids has been found particularly suitable for use in the manufacture of skin creams and lotions that can be used in both warm and hot climates, while mixtures of materials of fatty acids containing relatively high amounts of fatty acid portions of lower chain length (e.g., more than 50% of the portion of fatty acids having a chain length of C8-C14) may also be suitable for the preparation of skin compositions for use in relatively cold climates. Additional additives in the compositions may include skin care actives that are acidic in aqueous solution, such as, for example, fatty acids, such as alpha hydroxy acids including lactic acid and glycolic acid; as well as peroxides such as hydrogen peroxide, vitamins such as vitamin B3, and polysaccharides such as chitosan; The alpha hydroxy fatty acids are lactic acid and glycolic acid. Representative solid additives include, for example, lime, talc, earth fillers, kaolin, starch, gums, colloidal silicon dioxide, tetra alkyl aryl and / or trialkyl ammonium smectites, chemically modified aluminum and magnesium silicate, modified montmorillonite clay organically, hydrated aluminum silicate, fumed silica, carboxyvinyl polymers, hydroxyalkylated cellulosics, sodium carboxymethyl cellulose. The compositions of the present invention can be prepared and formulated as emulsions. Emulsions are usually heterogeneous systems of one liquid dispersed in another in the form of droplets that usually exceed 0.1 μm in diameter. (Idson, in "Pharmaceutical Dosage Forms," Lieberman, Riger and Banker (Eds.), 1988, Volume 1, p.199, Rosoff, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (eds.), 1988, Volume 1, p.245, Block in "Pbarmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, Volume 2, p.335, Higuchi and others, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 1985, p.301). Emulsions are often two-phase systems comprising two liquid phases immiscibles intimately mixed and dispersed among them. In general, emulsions can be of the water-in-oil (w / o) variety, or oil-in-water (o / w) variety. When an aqueous phase is finely divided into and it is dispersed as minute droplets in a voluminous oily phase. The resulting composition is called a water-in-oil (w / o) emulsion. Alternatively, when an oil phase is finely divided into and dispersed as minute droplets in a bulky aqueous phase, the resulting composition is called an oil in water (o / w) emulsion. The emulsions may contain additional components in addition to the dispersed phases and the active drug which may be present as a solution in either the aqueous phase, oil phase or by itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, colorants and antioxidants may also be present in emulsions as needed. The pharmaceutical emulsions can also be multiple emulsions which are comprised of more than two phases such as, for example, in the case of oil in water in oil (o / w / o) and water in oil in water (w / o) emulsions. / w). Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which the individual oil droplets of an o / w emulsion enclose water droplets small constitutes an emulsion of w / o / w. Likewise, a system of oil drops enclosed in water globules stabilized in a continuous oil provides an emulsion of o / w / o. Frequently, the dispersed or discontinuous phase of the emulsion is dispersed either in the external or continuous phase and is maintained in this way through the emulsifying media or the viscosity of the formulation. Any of the phases of the emulsion may be a semi-solid or a solid, as is the case with ointment bases and creams of the emulsion style. Other means for stabilizing emulsions include the use of emulsifiers that can be incorporated in any phase of the emulsion. Emulsifiers can be broadly classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds), 1988, volume 1 , 199). Useful oils may include hydrogenated vegetable and vegetable oils including sunflower oil, castor oil, coconut oil, cottonseed oil, Menhaden oil (fish), palm kernel oil, palm oil, peanut oil, soybean oil, jojoba oil, linseed oil, rice oil, pine oil, sesame oil, and sunflower seed oil and their hydrogenated varieties. Useful additional oils may include animal fats and oils such as cod liver oil and lanolin and its derivatives, mineral oil and petrolatum. Synthetic surfactants, also known as surface active agents, can be used in the vehicle to form emulsions and have been reviewed in the literature (Rieger, in "Pharmceutical Dosage Forms", Lieberman, Fieger and Banker (Eds.), 1988). volume 1, page 285, Idson, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, page 199). The surfactants are usually amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to hydrophobic nature of the surfactant has been called the hydrophilic / lipophilic balance (/ HLB) and is a valuable tool for categorizing and selecting surfactants in the preparation of formulations. The surfactants used can be classified into different classes based on the nature of the hydrophilic group in: nonionic, anionic, cationic, zwitterionic and amphoteric (Rieger, in "Pharmaceutical Dosage Forms", Liebberman, Rieger and Banker (Eds.), 1988 , volume 1, page 285). Common nonionic surfactants are polyoxyethylene ester and ether surfactants, a specific example thereof is Tween 60. Other suitable nonionic surfactants are described in McCutcheons "Detergents and emulsifiers", North American edition (1986), published by Allured Publishing Corporation, the content of which is specifically incorporated herein by reference. Examples of nonionic surfactants can be derived from condensation reactions between long chain alcohols (C8-C30) with sugar or starch polymers. Other useful nonionic surfactants are the condensation products of alkylene oxides with fatty acids (alkylene oxide esters of fatty acids or alkylene oxide diesters of fatty acids), or the condensation products of alkylene oxides and fatty alcohols. (alkylene ethers of fatty alcohols). Other useful nonionic emulsifying agents include sugar esters, polyesters, alkoxylated sugar esters and polyesters, C 1 -C 30 fatty acid esters of Cl-30 fatty alcohols, alkoxylated esters of C 1 -C 30 fatty acids of fatty alcohols of Cl-30, alkoxylated ethers of fatty alcohols of Cl-30, polyglyceryl esters of fatty acids of C1-C30, esters of C1-C30 or ethers of polyols, alkyl phosphate, ether fatty phosphates of polyoxyalkylene, amides of fatty acids, lactylates of acyl and its mixtures.

Illustrative cationic emulsifying agents are those described in McCutheon's, Detergents and Emulsifiers, North American Edition (1986), the content of which is incorporated herein by reference in its entirety. Useful cationic surfactants include cationic ammonium salts such as ammonium salts quaternary and amino acids. Useful anionic emulsifying agents include alkoxyl isethionates, alkyl and ether alkyl sulfates and salts thereof, alkyl phosphates and alkyl ether and salts thereof, alkyl methyl laurates and fatty acid soaps. An ionic polymer of polyamide containing acrylamidopropanesulfonic acid (AMPS) and / or its salts as a comonomer can be used as an ionic polymeric stabilizing agent. These polymers can be formed from a variety of monomers including acylamide and methacrylamide, which can be unsubstituted or substituted with one or two alkyl groups (preferably Cl to C5), or N-vinylpyrrolidone. In one embodiment the amide acrylate and amide methacrylate are monomers in which the amide nitrogen is unsubstituted or substituted with one or two alkyl groups of Cl to C5 (preferably methyl, ethyl or propyl), for example, acrylamide, methacrylamide , N-methacrylamide, N-methylmethacrylamide, N, N-dimethylmethacrylamide, N- isopropylacrylamide, N-isopropylmethacrylamide, and N, N-dimethylacrylamide. In another embodiment, the polyacrylamide copolymer-AMPS is the product given by the CTFA designation of polycarilamide (y) isoparaffin (y) laureth-7, available under the form of an ammonium copolymer AMPS and N-vinylpyrrolidone, commercially available under the trade name Aristoflex®. In a particular embodiment, a mixture containing sodium AMPS copolymer (also known as acryloyldimethyl laurate), isohexadecane and polysorbate 80, commercially available under the. trade name Sumulgel 600. Mixtures of two or more ionic polymeric stabilization agents can also be used. The ion stabilization agents are included in an amount sufficient to avoid visible separation of the composition. The stabilizers are generally present in a concentration of about 0.1 to about 10% by weight. One skilled in the art will also recognize that the amount of ionic polymeric stabilizing agent needed will depend on the hydrophobic and hydrophilic phases, intended use, intended storage and conditions of use, and other optional ingredients that can be used within the composition as well as the conditions of mixing and mixing apparatus used to prepare the emulsion or dispersion.

The ionic polymeric stabilizing agents of the present invention allow the formation of a stable composition at lower concentrations of alcohol than the compositions without these ionic stabilizing agents. In one embodiment, the polymeric stabilizing agent is present in from about 1 to about 10 percent, for example, from about 2 to about 8 percent by weight of the composition. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. The antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid and lecithin. The compositions used in the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their established levels of use in the art. Therefore, for example, the compositions may contain additional, compatible, pharmaceutically active materials such as, for example, antipruritic, astringent, steroidal, local anesthetic or anti-inflammatory agents, skin conditioning aqns such as oils and vitamins or may contain additional materials useful in various dosage forms of physical formulation of the composition of the present invention, such as colorants, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. The ingredients described above can be formulated with the penetration enhancer and active agent to form a composition suitable for topical application, including creams, lotions, ointments, gels, sprays, aerosols and the like. In one embodiment, the active agent and skin penetration enhancer is dispersed within cream bases or ointment bases to form a cream or ointment. Topical carriers may include conventional emulsifiers or other excipients including alginates, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propyl paraben, butyl paraben, sorbitols, polyethoxylated sorbitan, fatty esters (TWEENS), soft white paraffin (petrolatum), triethanolamine, aloe vera extract, lanolin, cocoa butter, and the like. Suitable topical vehicles are well known to experts.

Preparation and Administration Traditionally, cosmetic or pharmaceutical creams were limited to oil-in-water emulsions containing more than 50% by weight of water. According to some embodiments of the present invention, stable creams may include those with less than 50% water. Such cream formulations have the advantage of being able to incorporate larger amounts of organic solvents, such as alcohols (e.g., ethanol) while still maintaining acceptable cream properties. Creams, in the past, that incorporated skin penetration enhancing agents have normally been limited to low concentrations of these compounds (e.g., <5% p) because the higher concentrations of such skin enhancers Penetration into the skin resulted in the destabilization of emulsion, or required more organic solvents, such as alcohols, which will break down the cream. Therefore, the cream modalities of the present invention provide among other things, creams with higher concentrations of penetration enhancers to the skin, while maintaining an acceptable creamy feel. The term "cream" as used herein, refers to a composition that is opaque or milky at room temperature and is an oil-in-water emulsion with a hydrophilic phase in which a base is emulsified. hydrophobic and dispersed, in a micellar structure. Some embodiments of the cream composition of the present invention may include cream compositions that are lightened or liquefied when in contact with the skin of an animal, e.g., human, so as not to discolor or discolor. somehow an unpleasant aesthetic quality for the user. Said "fade creams" will normally be rinsed at temperatures above the ambient temperature, for example, above about 30 ° C, such as above about 33 ° C or above about 35 ° C. These qualities of a fade cream are thought to occur by the thermal breakdown of the micellar structure of the cream at elevated temperature, resulting in separation of the emulsion and loss of opacity. The components of some cream base embodiments of the present invention may include a hydrophobic component and a hydrophilic component. These cream-based formulations may also comprise an emulsifying agent and a skin penetrating enhancing people. The active agent of the present invention can be dispersed, dissolved or suspended within the cream base formulation of the present invention. For example, in one or both of the hydrophobic or hydrophilic components. to. Hydrophilic Component Some compositions of the present invention include a hydrophilic component, e.g., water and / or compounds soluble in water or miscible in water. Suitable water soluble or dispersible ingredients may comprise alcohols, carboxylic acids, diols, triols, polyols and the like. According to one embodiment of the present invention, the hydrophilic component includes water and one or more alcohols. Alcohols suitable in the present invention include alkyl, aromatic or straight or branched chain alkylene alcohols. In one embodiment, the alcohol used in the hydrophilic component is a linear alkyl alcohol containing between 1 and 6 carbon atoms, for example, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, 1-pentanol, or J-hexananol. In another embodiment, the alcohol is methanol or ethanol. The polyols, including diols and triols may be present in place of or in conjunction with the monoalcohol. Representative polyols include, for example, ethylene glycol, propylene glycol, diethylene glycol, butylene glycol, and the like. The amount of alcohol used in the hydrophilic component can be selected to achieve the emulsions described herein and can generally comprise between 1 and 99% by weight relative to the total weight of the hydrophilic component. Alcohol can constitute between about 15 and about 85% by weight of the hydrophilic component, such as between about 30 and about 70% by weight, for example between about 35 and about 55% by weight of the hydrophilic component. The amount of the hydrophilic component present will depend on the additional components present in the composition as described herein. Some of the compositions of the present invention will include between about 40 to about 90% by weight relative to the total weight of the hydrophilic component in one embodiment, the compositions of the present invention will include between about 45 and about 85% by weight of the component hydrophilic, such component about 50 and about 80% by weight or between about 60 to about 70% by weight. For example, in one embodiment, the hydrophilic phase comprises water in at least about 5% by weight, for example, at least about 10% by weight, such as at least about 15% by weight, at least about 20% by weight. % by weight, at least about 25% by weight, at least about 30% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, per at least about 55% by weight, at least about 60% by weight or at least about 70% by weight, based on the total weight of the composition. The amount of water may be less than about 85% by weight, based on the total weight of the composition, for example, less than about 80% by weight, such as less than about 75% by weight, less than about 70% by weight. weight, less than about 65% by weight, less than about 60% by weight, less than about 50% by weight, less than about 55% by weight, less than about 50% by weight, less than about 45% by weight, less than about 40% by weight or less than about 35% by weight of water. The hydrophilic phase may comprise water between about 15 to about 890% by weight, for example, between about 20 and about 80% by weight, or about 25 to about 70% by weight, or about 30 to about 60% by weight. % by weight of the composition. In one embodiment, ethanol may be present in at least 15% by weight relative to the total weight of the composition, for example, in at least about 20% by weight, such as at least about 25% by weight, per at least about 30% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, or at least about 60% by weight. The amount of ethanol can be less than, for example, less than about 65% by weight, such as less than about 60% by weight, or less than about less than about 55% by weight, or less than about 50% by weight , or less than about 45% by weight, at least about 50% by weight, at least about 55% by weight, or at least about 560% by weight. The amount of ethanol may be less than, for example, less than about 65% by weight, such as less than about 60% by weight, or less than about 55% by weight or less than about 50% by weight, or less than about 45% by weight or less than about 40% by weight, or less than about 35% by weight. b. Hydrophobic Component The hydrophobic component of any of at least one embodiment of the present invention may include one or more of oily or fatty components as exemplified above, comprising from about 5 to about 60% by weight of the total weight - of the composition , for example, from about 9 to about 50% by weight of the total weight of the composition, such as about 12 to about 40% by weight of the total weight of the composition, such as about 15 to about 30% by weight of the total weight of the composition. The compositions according to the invention are suitable for topical, eg transdermal, administration and can be prepared in a conventional manner by mixing together the different constituents in the chosen proportions. Different active agents can give different results with different penetration enhancers of the skin, solvent or vehicle systems or other ingredients in the formulation in view of the present description, the skilled person could be layers of selecting an appropriate improver with the appropriate system for a active agent given. The compositions of the invention can be applied by any means to a predetermined area of skin, for example, to an area between 10 and 100 cm2, for example 50 cm2. When the pharmaceutical compositions of this invention take the form of a similar lotion, cream, emulsion, gel, solution, ointment or composition, the compositions can be spread as a film over the selected area of the skin and, for this purpose, is not necessary require intermediate propellant gases. Alternatively, the topical transdermal composition can also be incorporated into a transdermal delivery device, e.g., a patch.

In another embodiment of the present invention, the compositions may be administered by direct spraying using a metering pump of a type that is known and marketed for use without the aid of a propellant. If desired, the compositions of the invention, however, can be administered by spraying from a suitable container with a metering valve, additionally containing a compressed propellant gas such as mentioned above. The method of the present invention includes the application of a composition comprising one or more of the active ingredients identified in combination with a SEPA® penetration enhancer in a delivery vehicle comprising the components discussed above and which is well known in the art. matter, to the upper arms and / or shoulders of an individual that needs the active ingredient. By applying the composition to the upper arms and / or shoulders of the individual instead of the abdomen, the required dose of composition containing active ingredient can be significantly reduced. By reducing the amount of required composition of active ingredient, the efficiency of the supply has increased, while the probability of cross contamination has been reduced. In addition, by reducing the amount of composition required, the time required to apply the dose is reduced. In addition, while the possible dose is lower used, the lower the risk of side effects, including effects on blood and liver and other events associated with excess amounts of processing and reception of any active ingredient in the body. Examples abound of the importance of reducing the dose to lower levels in order to reduce side effects and other events, and are well known to those skilled in the art. An example of this is the experiences of the pharmaceutical sector with estrogen replacement therapy. In one embodiment, the method of the present invention may be a method for raising the therapeutic levels, serum levels of an active ingredient by applying to the upper arm and / or shoulder of an individual in need of the active ingredient a composition comprising a cream base with a SEPA® improver and a reduced amount of active ingredient than that included in traditional topical therapies - based on daily dose. For example, in one embodiment, the total serum testosterone concentration in a testosterone deficient individual (individual having a total serum testosterone level sustained below physiological norms, such as below approximately 28.0 ng / dL. they can be raised to therapeutic / normal levels by applying to the upper arms and / or shoulders of said individual no more than 4.5 grams / day of a testosterone compositions comprising a skin penetration enhancing amount of a 1,3-dioxalan substituted with C7 to C4 hydrocarbyl, 1,3-dioxane, or acetal thereof, while existing comparable topical therapies require the application of 5-10 g / day In another modality, no more than 3.5 g / day, for example, 3.0 g / day or 2.5 g / day of testosterone composition is applied. The testosterone composition can be no greater than 2% testosterone, for example, 1.5% or more, preferably 1% testosterone. The composition can be not less than 0.5% of testosterone. In at least one embodiment, the total serum testosterone concentration of the individual is raised to a level greater than 280 ng / dl such as 290 ng / dl or more preferably more than 300 ng / dl, such as 310 ng / dl or 320 ng / dl but not higher than 1500 ng / dl and more preferably greater than 1000 ng / dl. In another embodiment, low dose topical administration of a composition containing an active ingredient may include application of no more than 7.5 g / day, eg, no more than 6.0 g / day, 4.0 g / day, 3.5 g / day , or 3.9 g / day of the composition to the upper arms and / or shoulders of an individual. In another embodiment, low dose administration of a composition containing an active ingredient may include application no greater than 2.5 g / day, or 1.0 g / day, or for example 0.5 g / day or even 0.1 g / day of the composition to the upper arms and / or shoulders of an individual. In yet another embodiment, low dose administration of a composition containing an active ingredient may include the application of not more than 100 mg / day of an active ingredient, for example, not greater than 75 mg / day, 60 mg / day , 50 mg / day, 40 mg / day, or 30 mg / day of the active ingredient to the upper arms and / or shoulders of an individual. In another embodiment, low dose administration of a composition containing an active ingredient may include the application of not more than 25 mg / day of active ingredient, for example, not greater than 15 mg / day, 10 mg / day, 5 mg / day of active ingredient, for example no greater than 15 mg / day, 10 mg / day, 5 mg / day, 2.5 mg / day, 1 mg / day, or even 0.5 mg / day of the active ingredient to the arms upper and / or shoulders of an individual. In one embodiment of the invention, the daily dose of the composition or active ingredient can be administered in no less than 2 applications, for example, 2 applications, 3 applications, 4 applications, 5 applications or even 6 applications within the same 24-hour period . In one embodiment, the dosage of the active ingredient or composition can occur every 24 hours, or every 12 hours, or every 8 hours, or 6 hours or even 4 hours.

In another embodiment, a method for delivering an active ingredient includes applying a composition with the active ingredient and SEPA® enhancer to the upper arms and / or shoulders of an individual. The active ingredient can be testosterone. Said method can treat an individual who is hypogonadal, an individual who has been prescribed testosterone replacement therapy, an individual who has a reduced libido, a male individual, or an individual older than 40 years, or when a Guy exhibits muscle wasting associated with HIV. This method modality can treat a woman, such as by anorexia nervosa, or when they remove ovaries from a patient or have female sexual dysfunction. This modality can also be used when the individual receives antiepileptic therapy, or placebos therapy, or have hypopituitarism. In another modality, the same supply is achieved by applying approximately half of the amount of said composition as would be necessary to achieve the same supply of the active if applied to the individual's abdomen. The supply can be measured by comparing the average serum concentration levels of 24 hours of the active ingredient or by comparing the area under a concentration curve against the time graphs of the active ingredient, or by comparing the maximum serum concentration levels of the active ingredient.

The effects of the topical compositions according to the invention are further illustrated by way of the following representative examples, which are in no way intended to limit the scope of the invention.

Examples A three-way crossover study was conducted comparing a 2.5 g dose of Opterone® (1% testosterone in a cream base containing 5% SEPA® penetration enhancer) applied to the upper arms and shoulders and 2.5 g of Opterone® and 5.0 g of Opterone® applied to the abdomen between the ribs and the pubis in hypogonadal adults. Ten eligible subjects were randomized to receive three different treatment regimens of the study creams. Each subject was evaluated during 3 identical test periods that included evaluations before the doses, one day of dosing (once a day), followed by a period without treatment of six days (washing). Each dose was evaluated over this one-week period and then each subject was dosed with the second, followed by a six-day wash and then followed by the subject's third treatment and washout period and then a final safety evaluation. There was a window of ± 3 days that was allowed for days of treatment. The subjects reported to the clinic at the same time for each visit. On Day 1, the subjects reported to the clinic and remained there during the night (approximately 24 hours). They received their treatment allowance and specimen evaluations of whole serum for serum testosterone (total, libe and DHT metabolite) were obtained 30, 15 and 1 minute before dosing, and 1, 2, 4, 6, 8 , 12, 16, 18, 20 and 24 hours after dosing. The blood specimen collected at 30 minutes before dosing was also used for measurements of serum estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin (SHb). Before the discharge on Day 2, subjects received a diary and record of events to record any adverse events and / or change in medication. They are instructed to use any product with testosterone and OTC supplements at the time of the study. This procedure was repeated for the two remaining treatments for each subject. The same programs and procedures were followed for the three treatment regimens. After a period - six days of washing (Week 4, Day 1), subjects were instructed to return to the clinic to take blood samples final for serum culture and safety evaluations as in the other visits. Before the first application, the subjects of the application region were informed; either the upper arms and shoulders or abdomen that was used for the application of the test article. The sample cream was applied only in the designated area according to the assigned treatment sequence. The cream was applied to cover as much as possible of the area of skin designated by the cream. All the application of the dose used the same procedures. Before the first dose was applied, the selected area was washed with soap and water and allowed to dry evenly. The surface of the abdomen between the ribs and the pubis or the upper arms including the shoulders was used as the designated application area. When randomized for Treatment 1, 2.5 g of Opterone® was applied to the upper arms and shoulders as the designated area for that regimen. When Treatment 2 (2.5 g), and / or Work 3 (5.0 g) was assigned, the test article was applied to the surface of the abdomen between the ribs and the pubis. A single dose of cream was used per application. For the application of the study drug, the entire content of a glass jar was removed using the plastic applicator rod (provided by the sponsor) and then applied to the selected region for said sequence of treatment. After the dose was applied, the subject was gently massaged with the cream on the skin over most of the possible area of the designated site using two fingers until the test article was no longer visible. When finished, the hands were vigorously washed with soap and water while the application site was left open to dry air for a minute of 10 minutes uncovered and not altered by touch. After the test article was dried, the application site remained covered for at least 12 hours. Rebalancing, bathing, swimming, or strenuous activity / exercise that could promote profuse sweating for at least 6 hours after the application of the test article was not allowed. Before downloading on Day 2, subjects were released with a Journal and Record of Patient Examples with instruction for completion, and were instructed to return to the clinic the following week at 8:00 AM (± 1 hour ). Subjects submitted their Journal and Event Record to the clinic for review and compilation.

Total Testosterone Concentration Data (TTEST) - Time The mean total testosterone concentration against time was given in Table 1. Total testosterone (TTEST) is an endogenous compound and was detected in all subjects before receiving the first dose. The descriptive statistics of mean total testosterone concentrations are listed by treatment in the following Table 1.

Table 1: Unadjusted Concentrations of Average Total Testosterone After Doses of 2.5 g in Shoulders (1), 2.5 and 5.0 g in Abdomen (2 and 3) of Opterone® to Male Subjects Hypogonaceal Adults Concentrations of the Treatment Group; (ng / dl) Time after Treatment 1 Treatment 2 Treatment 3 dose (2.5 g (2.5 g (5.0 g brazc (/ shoulder) Abdomen) Abdomen) (in = JO) (n = 10) (in = 10) Day 1- -OJ? Or hr 263.80 + 82.-15 264.30 and 46.79 249.80 ± 69.21 Day 1 - -0, .25 hr 271.60 + 78.22 257.50 ± 50.56 254.50:! :: 75.16 Day 1 - -0, .01 hr 261.80 + 86.32 270.60 ± 49.38 260.70 + 95.25 Line be ise - 0 hr 265.73 + 81.08 264.13 ± 44.44 255.00 + 77.15 1 hr 349.80 + 81.96 297.10 + 52.76 380.70 + 71.36 2 hr 367.00 ± 28.82 331.40 ± 78.50 453.40 + 113.69 4 hr 419.90 ± 187.36 317.00 ± 90.99 411.00 + 108.81 6 hr 417.20 ± 218.05 278.30 ± 76.98 333.30 ± 73.04 8 hr 357.30 i 72.64 271.80 ± 56.98 331.30 + 51.22 12 hr 319.70 + 43.80 291.10 ± 69.13 307.10 + 108.14 16 hr 372.40 + 106.04 301.10 + 71.99 379.90 + 57.29 18 hr 408.00 + 112.32 341.10 + 59.37 436.60 + 135.65 1 20 hr 421.40 ± 122.5 336.60 + 60.61 374.40 + 74.52 24 hr 466.90 ± 111.31 357.10 + 84.62 373.80 ± 99.95 Mean ± SC 1 m = 9 The descriptive statistics for the baseline of adjusted total testosterone concentrations are presented by the dose level at each time point measured in Table 2.

Table 2: Adjusted Concentrations of the Baseline of Total Testosterone Stockings After Arm / Shoulder Dose 2. 5 (1), Abdomen 2.5, and Abdomen 5.0 g of Opterone® to Subjects Adult Men Hypogonadal Concentrations; (ng / ml) Med; The (± SD) of the Treatment Group Hours after Treatment 1 Treatment 2 Treatment 3 of the dose (2.5 g (2.5 g (5.0 g arm / shoulder) Abdomen) Abdomen) (n = 10) (n = 10) (n = 10) 0 hr 0 0 0 1 hr 84.07 + 63.28 32.97 + 46.35 125.70 + 108.24 2 hr 101.27 +63.44 67.27 ± 79.79 198.40 + 151.04 4 hr 154.17 + 206.98 52.87 + 80.01 156.00 ± 109.10 6 hr 151.47 + 248.54 14.17 ± 59.72 7B.30 + 74.20 8 hr 91.57 + 120.68 7.67 + 49.03 76.30 + 76.56 12 hr 53.97 + 96.49 26.97 + 50.03 52.10 + 108.42 16 hr 106.67 ± 104.77 36.97 + 72.90 124.90 + 93.81 18 hr 135.63 ± 114.511 76.97 ± 56.40 181.60 + 125.65 20 hr 155.67 + 86.06 72.47 + 62.57 119.40 + 71.02 24 hr 201.17 ± 141.78 92.91 ± 66.27 118.80 ± 53.37 1 m = 9 Estimates of Pharmacokinetic Parameters of Total Testosterone The analysis without pharmacokinetic compartment was carried out in total unadjusted testosterone levels. The TTEST pharmacokinetic parameters were adjusted to reflect the impact of observations from the baseline. The adjusted pharmacokinetic parameters of the baseline were calculated in order to take into account the differences in the total testosterone values of the baseline across several subjects. The pharmacokinetic parameters of TTEST adjusted for baseline and unadjusted media were presented in Table 3.

Table 3: Total Testosterone Pharmacokinetic Parameters After Arm / Shoulder Dose 2.5 (1), Abdomen 2.5 (2), and Abdomen 5.0 g (3) of Opterone® to Subject Men Adult Hypogonadic Medium Dose Group (± SD) Parameter Treatment Treatment 2 Treatment 3 Pharmacokinetic (n = 10) Data no (n = 10) (n = 10) adjusted AUC (0-ult.) 9186.0 + 1221.2 7397.4 ± 1237.1 8800.3 + 1420.1 ( hr + ng / dL) C ax (ng / dL) 576.50 + 192.96 407.90 ± 53.403 533.30: t 118.76 Cavg (ng / dL) 382.15 + 50,373 308.31 ± 50,629 366.14 + 58,686 Tmaxt (hr) 19.05 (1.00 - 19.03 (2.0224.98) 11.01 (1.97- 24.00) 24.23) Conc. Baseline (ng / dL) 265.73 ± 81.08 264.13 ± 46.439 255.00 ± 77.147 Adjusted Baseline Data AUC (0-6) ult.) (hr * ng / dL) 2800.6 + 1923.2 1056.2 + 893.85 2869.2 + 1589.1 Cmax (ng / dL) 310.77 ± 221.64 143.77 + 47.033 278.30 ± 123.74 Cavg (ng / dL) 116.42 + 79.707 44.172 ± 37.460 111.14 + 66.313 Mean ± SD t Time parameters set as Average (Range)

Claims (1)

1. CLAIMS 1. A method for raising the total serum testosterone concentration in a testosterone-deficient individual comprising, applying to the upper arm and / or shoulder of said individual no more than 4.5 grams / day of a testosterone composition comprising an amount of improvement of penetration into the skin of a 1, 3-dioxolane substituted with hydrocarbyl from C7 to Ci4, 1,3-dioxane, or acetal thereof. 2. The method of claim 1, wherein no more than 2.5 g / day of the testosterone composition is applied. 3. The method of claim 1, wherein the testosterone composition contains no more than 2.0% by weight of testosterone relative to the total weight of the composition. 4. The method of claim 1, wherein the testosterone composition contains 1.0% by weight of testosterone relative to the total weight of the composition. 5. The method of claim 1, wherein an amount of skin penetration improvement comprises not less than 2% by total weight of the composition. 6. The method of claim 1, wherein the composition comprises a skin cream. 1 . - The method of claim 1, wherein said total serum testosterone concentration of the individual is elevated to a level greater than 280 ng / dL. 8. The method of claim 7, wherein said total serum testosterone concentration of the individual is raised to a level no greater than 1500 ng / dL. 9. A method for delivering an active ingredient comprising, applying a composition comprising said active ingredient and a 1,3-dioxolane substituted with C7 hydrocarbyl to Ci4, 1,3-dioxane, or acetal thereof to the shoulders and / or upper arms of an individual. 10. The method of claim 9, wherein the active ingredient is testosterone. 11. The method of claim 10, wherein the individual is hypogonadal. 12. The method of claim 10, wherein the individual has been prescribed testosterone replacement therapy. 13. The method of claim 10, wherein the individual has a reduced libido. 14. The method of claim 10, wherein the individual is a man. 15. The method of claim 10, wherein the individual is over 40 years old. 16. The method of claim 10, wherein the individual exhibits muscle wasting associated with HIV. 17. The method of claim 10, wherein the individual is female. 18. The method of claim 10, wherein the composition is used to treat anorexia nervosa. 19. The method of claim 10, wherein the individual's ovaries are removed. 20. The method of claim 10, wherein the composition is used for female sexual dysfunction. 21. The method of claim 10, wherein the individual receives antiepileptic therapy. 22. The method of claim 10, wherein the individual receives opioid therapy. 23. The method of claim 10, wherein the composition is used for hypopituitarism. 24. The method of claim 9, wherein the individual needs the active ingredient. 25. The method of claim 9, wherein the same supply of said active is achieved by applying approximately half of the amount of said composition as would be necessary to achieve the same supply of the active if applied to the individual's abdomen. 26. - The method of claim 25, wherein the delivery is measured by comparing the average serum concentration levels of 24 hours of the active ingredient. 27. The method of claim 25, wherein the supply is measured by comparing the areas under the concentration curves against the dot plots of the active ingredient. 28. The method of claim 25, wherein the delivery is measured by comparing the maximum serum concentration levels of the active ingredient. 29. The method of claim 9, wherein the composition comprises a skin cream.