JP2009504566A - Low dosage administration of topical composition - Google Patents

Abstract

The need to treat the active ingredient in a topical drug delivery product by applying a product containing SEPA® penetration enhancer in the delivery vehicle to the upper arm and / or shoulder rather than the abdomen of the patient in need of the active ingredient The amount can be significantly reduced.
[Selection figure] None

Description

  This application claims the priority of US Provisional Application No. 60/679673, filed on May 11, 2005, which is hereby incorporated by reference in its entirety.

  The present invention relates to the field of topical drug delivery, and in particular to the field of improving the local delivery of bioactive compounds by applying the bioactive compound to the shoulder and / or upper arm skin.

  The administration of drugs and other biological substances to the bloodstream via administration by the transdermal route has received much attention in recent years. The average adult skin covers more than 2 square meters and accepts about one-third of the total blood circulation around the body. The skin is elastic, undulating and usually self-renews. Human skin consists of two layers, the epidermis (a multi-layered complex containing the stratum corneum) and the dermis. The stratum corneum (S.C.) represents the rate-limiting step in the diffusion of chemicals through the skin. The stratum corneum is composed of dead, keratinized, metabolically inactive cells that are tightly packed together and incorporated into an amorphous matrix composed mainly of lipoids and non-fibrous proteins with keratin fibers distributed inside. It is. The stratum corneum cells usually contain 20% water, while the underlying cells in the basal layer contain 70% water. The stratum corneum does not hydrate easily. Thus, percutaneous penetration is controlled primarily by diffusion through the stratum corneum.

There are several main reasons for the interest in transdermal delivery of drugs.
1) Eliminates absorption uncertainties from the gastrointestinal tract and irritation to the gastrointestinal tract that can occur when drugs are administered orally;
2) avoiding portal circulation and consequently elimination of first-pass metabolism in the liver; this is crucial for drugs with a short half-life or that can have undesirable effects on the liver;
3) Local delivery of the drug to the desired target site;
4) Deliver drug directly into the systemic circulation at a constant rate (similar to intravenous injection);
5) Occasional dosing of certain drugs (daily, weekly or more);
6) Improved ease of use and patient compliance.

  Transdermal delivery is generally limited to small molecule drugs that require delivery rates of less than 10 mg / day. To obtain higher blood levels, the drug delivery rate must be increased. There have been many proposals to achieve faster drug delivery through the use of absorption enhancers and the development of more easily absorbed prodrugs. Examples of existing absorption enhancers are dimethyl sulfoxide (DMSO), ethylene glycol, hexanol, fatty acids and esters, alkyl-2- (N, N-disubstituted amino) -alkanoate esters, (N, N-disubstituted, among others) Amino) -alkanol alkanoates, or mixtures thereof, cyclopentadecalactone, ester sunscreen agents and pyrrolidone derivatives. One accelerator compound that has received much attention is Azone (N-dodecylazacycloheptan-2-one).

  The use of such penetration enhancers has been done with a variety of small molecule drugs, as demonstrated. Prior patents relating to bioactive agent penetration enhancers include US Pat. No. 3,551,554 describing dimethyl sulfoxide, US Pat. No. 3,898,916 describing 1-substituted azacycloheptan-2-one, topical antibiotics and 2-pyrrolidone. Or U.S. Pat. No. 4,131,781, which describes n-lower alkyl-2-pyrrolidone, U.S. Pat. No. 4,017,761, which describes 2-pyrrolidone but with propylene glycol; other interesting ones are U.S. Pat. No. 3,903,256, 4343798, 4046886, 3934013, 4070462, 4130643, 4130667, 4287664, 4070462, 3527864, 3535422, 3598123, 3952099, 4379454, 4286592, 4299826, 4314557, 4343798 No. 4335115, No. 3598122, No. 4456616, No. 3896238, No. 3347931 and No. 4553934.

Applicants have previously developed a new class of compounds that are derivatives of 1,3-dioxane and 1,3-dioxolane for use as skin penetration enhancing compounds. These compounds are commercially available as SEPA® and are described in detail in US Pat. No. 4,861,664. Studies using this dioxolane accelerator have been described in several publications and patent publications. For example, Samour et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 183-184 (1989); Marty et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 179-180. (1989); Marty et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 17: 415-416 (1990); Michniak et al., Drug Delivery
2: 117-122 (1995); Marty et al., Abstract of Paper Presented at American Association of
Pharmaceutical Scientists, Washington, DC, Mar. 26-28, 1990.

Specific examples of SEPA® accelerators can be found in US Pat. Nos. 5,976566 and 5958919, which show the local delivery of nonsteroidal anti-inflammatory drugs and hormones. Even with penetration enhancers, it may be difficult to deliver a sufficient amount of a small molecule drug to achieve therapeutic blood levels. An example of this problem can be found in the difficulties associated with the delivery of testosterone hormone. Because testosterone requires high serum concentrations, it is necessary to apply very large amounts of topical testosterone formulations, approximately 5-10 g / day, to achieve therapeutic serum concentrations of testosterone. There is a need for a method that reduces the amount of active ingredient required when using local administration, even when using existing penetration enhancers. The Applicant has found a treatment method that makes it possible to significantly reduce the required amount of active ingredient during topical application.
US Patent No. 3551554 U.S. Pat.No. 3,898,816 U.S. Pat. U.S. Patent No. 4017641 U.S. Pat. No. 3903256 U.S. Patent No. 4343798 U.S. Patent No. 4046886 US Patent No. 3934013 U.S. Patent No. 4070462 U.S. Pat.No. 4130643 U.S. Pat.No. 4,130,667 U.S. Pat. No. 4,289764 U.S. Patent No. 4070462 US 3527864 U.S. Pat.No. 3,535,422 U.S. Pat.No. 3,598,123 U.S. Patent No. 3952099 U.S. Pat.No. 4,379,454 U.S. Pat. No. 4,286,592 U.S. Pat.No. 4,299,826 U.S. Pat.No. 4,314,557 U.S. Patent No. 4343798 U.S. Pat.No. 4,335,115 U.S. Pat.No. 3,598,122 U.S. Pat.No. 4,405,616 U.S. Pat.No. 3,896,238 U.S. Pat. No. 3,473,931 U.S. Pat. No. 4,455,934 U.S. Pat. No. 5,976566 U.S. Patent No. 5968819 Samour et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 183-184 (1989) Marty et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 179-180 (1989) Marty et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 17: 415-416 (1990) Michniak et al., Drug Delivery 2: 117-122 (1995) Marty et al., Abstract of Paper Presented at American Association of Pharmaceutical Scientists, Washington, DC, Mar. 26-28, 1990

  The main object of the present invention is to provide an improved method for topical delivery of bioactive compounds or ingredients by administration to the upper arm and / or shoulder skin. In certain embodiments, the improved method significantly reduces the dosage of active ingredient required to achieve the same therapeutic effect.

In one embodiment, a method of increasing total serum testosterone concentration in a testosterone deficient patient comprises an amount of C ₇ -C ₁₄ -hydrocarbyl substituted 1,3-dioxalane, 1 that promotes skin penetration in the upper arm and / or shoulder of the patient. , 3-dioxane, or applying a low dosage testosterone composition containing these acetals.

In another embodiment, a method of delivering an active ingredient, the patient's upper arm and / or shoulder, the active ingredient and C ₇ -C ₁₄ - hydrocarbyl substituted 1,3-dioxalane, 1,3-dioxane or acetal thereof, Applying a composition comprising:

  The compositions used in the present invention are intended for topical non-invasive application to the skin that provides improved systemic delivery of the active ingredient and other co-active ingredients. Low dose administration of the composition can be applied as needed to the upper arm and / or shoulder skin of a patient seeking a therapeutic effect.

  Examples of active ingredients that are advantageously administered by the topical formulations of the present invention are any that are compatible with the skin penetration enhancers of the present invention and delivered through the skin with the aid of skin penetration enhancers to achieve the desired effect. Contains local or systemic active agents. The amount of active ingredient used depends on the ability of the active ingredient to be incorporated into the delivery vehicle as well as the therapeutic amount required. In part, this amount can depend on the solubility of the active ingredient in the particular solvent used in the delivery vehicle. Active agents (grouped by drug category) include:

Digestive system:
Antidiarrheal agents such as diphenoxylate, loperamide and hyoscyamine.

Circulatory system:
Antihypertensive drugs such as hydralazine, minoxidil, captopril, enalapril, clonidine, prozocine, debrisoquin, diazoxide, guanethidone, methyldopa, reserpine, trimetaphane. Calcium channel blockers such as diltiazem, ferodopine, amlodipine, nitrendipine, nifedipine and verapamil.
Antiarrhythmic drugs such as amiodarone, flecainide, disopyramide, procainamide, mexileten and quinidine.
Antianginal drugs such as glyceryl nitrate, erythritol tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexylene, isosorbide dinitrate, and nicorandil.
Β-blockers such as alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate.
Cardiac glycosides such as digoxin and other cardiac glycosides and theophylline derivatives.
Adrenergic stimulants such as adrenaline, ephedrine, fenoterol, isoprenaline, orciprenaline, limeterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine.
Vasodilators such as cyclandelate, isoxsuprine, papaverine, dipyrimadol, isosorbide dinitrate, phentolamine, nicotinyl alcohol, codergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol.
Antimigraine drugs such as ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan.

Drugs that act on blood and hematopoietic tissues:
Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as enoxaparin, streptokinase and its active derivatives. Hemostatic agents such as aprotinin, tranexamic acid and protamine.

central nervous system:
Antipyretics, including analgesics, opioid analgesics such as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretam, 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 other hypnotics and sedatives such as coral hydrate, chlormethiazole, hydroxyzine and meprobamate.

Anti-anxiety drugs such as benzodiazepine, alprazolam, bromazepam, chlordiazepoxide, clobazam, chlorazepart, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam, triazolam.
Phenothiazine, chlorpromazine, fluphenazine, periciazine, perphenazine, promazine, thiopropazate, thioridazine, trifluoperazine, and neuroleptic and antipsychotics such as butyrophenone, droperidol, and haloperidol, and others such as pimozide, thiothixene and lithium Antipsychotic drugs.
The tricyclic antidepressants amitriptyline, clomipramine, desipramine, dothiepine, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine, and the tetracyclic antidepressants mianserin and isocarboxazide, pheneridine And antidepressants such as monoamine oxidase inhibitors such as tranylcypromine and moclobemide, and selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline.

CNS stimulant like caffeine.
Anti-Alzheimer's like tacrine.
Amantadine, benserazide, carbidopa, levodopa, benztropine, biperidene, benzhexol, procyclidine, and S (-)-2- (N-propyl-N-2-thienylethylamino) -5-hydroxytetrali-n ( N-0923) and other anti-parkinsonian agents such as dopamine-2 agonists.
Antispasmodic drugs such as phenytoin, valproic acid, primidone, penobarbitone, methylphenobarbitone, carbamazepine, ethosuximide, methosuximide, fencesuximide, sultiamine, clonazepam.

Musculoskeletal system:
Ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac, alloxypurine, aproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxylindac, Includes non-steroidal anti-inflammatory drugs such as tenoxicam, tramadol and ketolalac and racemic mixtures or individual enantiomers where available.
Additional non-steroidal anti-inflammatory drugs that can be formulated in combination with dermal penetration enhancers are salicylamide, salicylsan, flufenisal, salsalate, triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, syntazone, flufenam. Acid, clonixeryl, clonixin, meclofenamic acid, flunixin, colchicine, demecorsin, allopurinol, oxypurinol, benzidamine hydrochloride, dimefadan, indoxol, intrasol, mimban hydrochloride, paranylene hydrochloride, tetridamine, benzindoprine hydrochloride, flupro Fen, ibufenac, naproxol, fenbufen, cinchophene, diflumidone sodium, phenamorphulthiazine, metaza Including de, retinyl bromide hydrochloride, Ne xenon lysine hydrochloride, Okutazamido, Morinazoru, neo Cinco Fen, Nimazoru, pro hexa sol citrate, Teshikamu, Teshimido, tolmetin, a triflumizole Dirt

Anti-rheumatic agents such as penicillamine, aurothioglucose, sodium aurothiomaleate, methotrexate, auranofin.
Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, metcarbamol, orphenadrine, quinine.
Drugs used for gout and hyperuricemia such as allopurinol, colchicine, probenecid and sulfinpyrazone.

Hormones and steroids:
Estrogens such as estradiol, estriol, estrone, ethinyl estradiol, mestranol, stilboestrol, dienoestrol, epioestriol, estropipart and zeranol.
Progesterone and other progesterone drugs such as allylestrenol, didrguesterone, linoestrenol, norgestrel, norethindrel, norethisterone, norethisterone acetate, guestden, levonorgestrel, medroxyprogesterone and megestrol.
Antiandrogens such as cyproterone acetate and danazol.

Antiestrogens and aromatase inhibitors such as tamoxifen and epithiostanol, exemestane and 4-hydroxy-androstenedione and their derivatives.
Androgens and anabolic agents such as testosterone, methyltestosterone, crostebol acetate, drostanolone, flazabol, nandrolone, oxandrolone, stanozolol, trenbolone acetate, dihydro-testosterone, 17-α-methyl-19-nortestosterone and fluoxy Mesterone.
5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306.

  Betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortron, halcinonide, halopredone, hydrocortisone, hydrocortisone, 17 Corticosteroids such as valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide.

  Further examples of steroidal anti-inflammatory agents for use in the composition include cortodoxone, fluoracetonide, fludrocortisone, difluorzone diacetate, flulandenolone acetonide, medrizone, amsinafel, amsinafide, betamethasone and others Esters, chloroprednisone, chlorocorterone, descinolone, desonide, dichlorizone, difluprednate, fluchloronide, flumethasone, flunisolide, flucortron, fluorometallone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, parameterzone, cortisone acetate , Hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, fullland renoro Acetonide, medrizone, amsinafal, amsinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, crocortron acetate, descinolone acetonide, desoxymethasone, dichlorizone acetate, difluprednate, fluchloronide, flumethasone pivalate, fluni Zolidoacetate, fluperolone acetate, fluprednisolone valerate, parameterzone acetate, prednisolamate, prednival, triamcinolone hexacettonide, cortibasol, formocortal and nivasol.

Pituitary hormones such as corticotropin, thyrotropin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and gonadotropin releasing hormone (GnRH) and active derivatives or analogues thereof.
Antihyperglycemic drugs such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and metformin.
Thyroid hormones such as calcitonin, thyroxine and liothyronine, and antithyroid drugs such as carbimazole and propylthiouracil.
Other hormonal agents such as octreotide.
Pituitary inhibitors such as bromocriptine.
An ovulation inducer like clomiphene.

Urogenital system:
Thiazide, similar diuretics and loop diuretics, bendrofluazide, chlorothiazide, chlorothiaridone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefluside, methicorthiazide, metolazone, quinetazone, bumethamide, ethacrynic acid and frusemide, and potassium retention Diuretics such as sex diuretics, spironolactone, amiloride and triamterene.
Antidiuretics such as desmopressin, repressin and vasopressin, including active derivatives or analogs.

  Obstetric drugs, including drugs that act on the uterus, such as ergometrine, oxytocin and gemeprost. Prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2-alpha) and misoprostol.

Antibacterial agent:
Antibacterial agents including cephalosporin such as cephalexin, cefoxitin and cephalothin.
Amoxicillin, amoxicillin-clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, pheneticillin, phenoxymethylpenicillin, flucloxacillin, mediocillin, piperacillin, ticarcillin and apicillin
Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, metacycline, and oxytetracycline, and other tetracycline-type antibiotics.
Aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, and tobramycin.

Quinolones such as nalidixic acid, sinoxacin, ciprofloxacin, enoxacin and norfloxacin. Sulfonamides such as phthalyl sulfthiazole, sulfadoxine, sulfadiazine, sulfamethizole and sulfamethoxazole.
Sulfones like dapsone.
Chloramphenicol, clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estrat, erythromycin single part, erythromycin ethyl succinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spec Tinomycin, vancomycin, aztreonam, colistin IV, metronidazole, thymidazole, fusidic acid and trimethoprim; 2-thiopyridine N-oxide; halogen compounds, especially iodine and iodine compounds such as iodine PVP complex and diiodohydroxyquine; hexachlorophene; Chlorhexidine; chloroamine compounds; various other antibiotics such as benzoyl peroxide.

Antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin, and clofazimine.
Antimalarials such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine, and halofantrine.
Antiviral agents such as acyclovir and acyclovir prodrugs, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantazine and idoxuridine.
Anthelmintic agents such as mebendazole, thiabendazole, niclosamide, praziquantel, pirantel embonato and diethylcarbamazine.
Cytotoxic drugs such as pricamycin, cyclophosphamide, dacarbazine, fluorouracil and prodrugs thereof [eg described in International Journal of Pharmaceutics 111,223-233 (1994)], methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid .

metabolism:
Anti-appetite and weight loss medications including dexfenfluramine, fenfluramine, diethylpropion, mazindol and phentermine.
Agents used for hypercalcemia such as calcitriol, dihydrotaxosterol and their active derivatives or analogues.

Respiratory system:
Antitussives such as ethyl morphine, dextromethorphan and forcodin.
Expectorants such as acetylcysteine, bromhexine, emetine, guaifenesin, ipecakuanha (tocon), saponins.
Decongestants such as phenylephrine, phenylpropanolamine and pseudoephedrine.
Ephedrine, fenoterol, orciprenaline, limiterol, salbutamol, sodium cromoglycate, cromoglycic acid, and prodrugs thereof [eg described in International Journal of Phamaceutics 7,63-75 (1980)], terbutaline, ipratropium bromide, salmeterol and Bronchospasm relaxants such as theophylline and theophylline derivatives.

Allergy and immune system:
Meclozine, cyclidine, chlorcyclidine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine, doxylamine, mebhydroline, phenylamine, tripolyzine, azatadine, diphenylpyralin, methodirazine, terfenadine , Antihistamines such as astemizole, loratidine, cetirizine.
Neuromuscular blocking agents such as suxamethonium, arcuronium, panchlorium, atracurium, gallamine, tubocurarine, vecuronium.
Smoking cessation drugs such as nicotine, bupropion, and ibogaine.
Nutrients such as vitamins, essential amino acids, and essential fats.
Keratolytic agents such as alpha-hydroxy acid, glycolic acid and salicylic acid.
Psychoactive agents such as 3- (2-aminopropyl) indole and 3- (2-aminobutyl) indole.

Anticholinergic agent effective in inhibiting axillary sweating and controlling bruises. Metatropine nitrate, propantheline bromide, scopolamine, methoscopolamine bromide, and a new class of mild antiperspirant, quaternary acyloxymethylammonium salts [eg, Bodor et al. J. Med. Chem. 23,474 (1980) and 1979 6 Described in UK specification No. 2010270 published on May 27]].
Other physiologically active peptides and proteins, small to medium size peptides such as vasopressin and human growth hormone.

以下の式（II）の2-置換1,3-ジオキサン：

および、以下の式（III）の置換アセタール：

The penetration of the active ingredient through the skin is preferably a substituted 1,3-dioxacyclopentane disclosed in U.S. Pat. No. 4,861,664, the entire disclosure of which is incorporated herein by reference. By incorporating into the composition an effective amount of a skin penetration enhancing compound or a corresponding substituted acetal compound in the form of a substituted 1,3-dioxacyclohexane-type skin modifier, it is enhanced to an acceptable level. The Representative examples of skin penetration enhancing compounds include:
2-substituted 1,3-dioxolanes of the following formula (I):

A 2-substituted 1,3-dioxane of the following formula (II):

And a substituted acetal of the following formula (III):

In the above formulas (I), (II) and (III), R preferably represents a C _{7 to} C ₁₄ hydrocarbyl group, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group. R ′ ₁ and R ′ ₂ each independently represent a C ₁ -C ₄ alkyl group.

The hydrocarbyl group of R can be a linear or branched alkyl, alkenyl, or alkynyl group, especially an alkyl or alkenyl group. Preferably, R is C ₇ -C ₁₂ aliphatic group; represents a particular C ₇ -C ₁₀ aliphatic group. Examples of substituted alkyl groups are for example n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl-octyl, 4-ethyl-decyl, Including 8-methyl-decyl and the like. Linear alkyl groups such as n-heptyl, n-octyl, n-nonyl, n-decyl are particularly preferred. Examples of alkenyl groups are for example 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2 ', 6'-dimethyl-2', 6'-heptadienyl, 2 ', 6'-dimethyl-2'- Includes heptaenyl and the like. The R group may be substituted, for example with halo, hydroxy, carboxy, carboxamide and carboalkoxy groups.

C ₁ -C ₄ alkyl groups, for example methyl, ethyl, n- propyl, isopropyl, n- butyl, may be a tert- butyl and the like. Preferred alkyl groups for R ₀ , R _{1 to} R ₆ , R ′ ₁ and R ′ ₂ are alkyl having 1 or 2 carbon atoms, especially ethyl. R ₀ and R _{1 to} R ₆ may preferably be all hydrogen atoms.

Specific skin modifying agents include, for example, 2-n-pentyl-1,3-dioxolane, 2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2-n-undecyl- 1,3-dioxolane, 2-n-nonyl-1,3-dioxane, 2-n-undecyl-1,3-dioxane, 2-n-heptylaldehyde-acetal, 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-1,3-dioxolane is particularly preferred, and MacroChem Corporation of SEPA®
Commercially available from Lexington, Mass.

  Examples of co-solvents that may be added in addition to other skin penetration enhancers and skin modifying agents are dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, ethylene glycol, alkyl lactams, long chain amides, hexanol, fatty acids And their esters, and pyrrolidone derivatives.

  Solubilizers and / or absorption enhancers that can be used in the present invention are those in which the active agent or a pharmaceutically acceptable salt thereof is dissolved at a concentration of at least 0.01% with respect to the total weight of the composition. Means an agent capable of further promoting absorption of the active agent or a pharmaceutically acceptable salt thereof through the skin. In other words, the solubilizer and / or absorption enhancer imparts solubilization and absorption capabilities to the active agent or a pharmaceutically acceptable salt thereof. Examples of solubilizers and / or absorption enhancers are alkanes such as alkane dicarboxylic acid dialkyl esters (dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate, dipropyl sebacate, etc.) Dicarboxylic acid esters; and higher alkanecarboxylic acid alkyl esters (isopropyl myristate, ethyl myristate, etc.).

  The amount of skin modifying agent is chosen to give the desired delivery rate for the active compound, albeit at a minimum dosage, taking into account additional factors such as product stability, side effects, carrier system, etc. The In general, depending on the particular active compound and other vehicle, about 2.0-25% of the composition, preferably about 2, 3, 4 or 5% to 10, 12, 15 or 20%, especially about 5-10 An amount of skin modifying agent in the range of% gives an optimal flow rate of active ingredient and a 24-hour payload. Usually, for gelled formulations, the amount of facilitating compound may be lower than the creamed formulation, for example, about 2-10% of the formulation.

  In addition to the active ingredient and penetration enhancer, the delivery vehicle can include a balance of the composition. Thus, the delivery vehicle may comprise up to about 98%, such as from about 50 to about 98%, such as from about 70 to about 95%, such as from about 70 to about 90%, by weight of the composition.

  The composition can be formulated as a gel, especially an aqueous-alcoholic gel, lotion, cream, mousse, aerosol, ointment, lubricant, lacquer, patch, solvent, tincture, etc. when applied to the affected area of the skin, The formulation can be used as long as it remains in place, i.e., does not flow, so that the patient can spread the composition over the affected area.

  Vehicles for any form of the composition according to the present invention include glycols such as propylene glycol, butylene glycol, hexylene glycol and the like (except in the case of the third embodiment), lower alcohols such as ethanol, isopropanol, and Usually, it may contain water. Further, of course, skin penetration enhancing dioxolane, dioxane or acetal is included in the formulation in an amount effective to facilitate penetration of the active ingredient through the skin including the stratum corneum.

Vehicle Component The composition used in the present invention is a solid, to help the active ingredient and skin penetration enhancer be delivered to the skin or other membranes such as the mucous membrane of the nose or mouth in appropriate concentrations and amounts. Semi-solid or liquid pharmaceutically acceptable vehicles can also be included. The nature of the vehicle will depend on the method chosen for topical administration of the composition.

  Selecting a vehicle for such purposes represents a wide range of possibilities depending on the product form required for the composition.

  A vehicle is a composition that may include diluents, dispersants or solvents for active agents and penetration enhancers, thus ensuring that the agent can be uniformly applied and dispersed in appropriate areas of the skin. Should be explained.

  The composition according to the present invention may comprise water as a vehicle and / or at least one pharmaceutically acceptable vehicle other than water.

  Vehicles other than water that can be used in the compositions according to the invention include emollients and humectants, solvents, humectants, thickeners, preservatives, colorants, fragrances, propellants and solid additives. Contains solids or liquids. Examples of types of additives that can be used alone or as a mixture are as follows.

  The emollient component can also function as a cosmetically acceptable additive. These may be in the form of silicone oils and synthetic esters. The emollient component may be silicone oil, esters or mixtures thereof. The amount of emollient may range from 0.1 to 20%, such as 1 to 5%, based on the weight of the final composition.

  Silicone oils can be divided into volatile and non-volatile. As used herein, the term “volatile” refers to one having a measurable vapor pressure at ambient temperature. The volatile silicone oil is preferably selected from cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms. Linear volatile silicone materials generally have a viscosity of less than about 5 centistokes at 25 ° C., while cyclic materials typically have a viscosity of less than about 10 centistokes.

  Non-volatile silicone oils that can be used as humectants include polyalkyl siloxanes, polyalkylaryl siloxanes, and polyether siloxane copolymers. Essentially non-volatile polyalkylsiloxanes that can be used herein include, for example, polydimethylsiloxanes having a viscosity of from about 5 to about 25 million centistokes at 25 ° C.

  The silicone emulsifier can include dimethicone copolyol. These can include polydimethylsiloxane modified to include polyether side chains. Other modifications to the side chain can result in nonionic, anionic, cationic, amphoteric, and zwitterionic pendant sites.

Examples of the ester humectant include the following.
1. Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms. Examples include isoarachidyl neopentanoate, isononyl isononanoate, oleyl myristate, oleyl stearate, and oleyl oleate;
2. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols;
3. Polyhydric alcohol esters; ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, propylene Glycol 2000 monooleate, propylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol mono Stearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester Is sufficient polyhydric alcohol esters;
4). 4. wax esters such as beeswax, whale wax, myristyl myristate, stearyl stearate and arachidyl behenate; Sterol esters such as cholesterol fatty acid esters.

  Examples of typical 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 palmitate, dimethylpolysiloxane, sebacic acid Di-n-butyl, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil Acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate.

  Typical propellants include, for example, trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, monochlorodifluoromethane, trichlorotrifluoroethane, propane, butane, isobutane, carbon dioxide.

  Typical solvents include, for example, lower alcohols, polyols, polyethers, oils, esters, alkyl ketones, and the like. Examples include ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, and tetrahydrofuran. The solvent can be selected with respect to the ability to dissolve the active agent and one or more SPE compounds, and those skilled in the art will know which solvent is suitable for such purpose or which solvent is appropriate. You will understand how to determine if there is.

  Exemplary wetting agents include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, gelatin, and can be used in embodiments according to the present invention.

  In some compositions in gel form, thickeners such as hydroxypropyl cellulose can be included as gelling agents. However, other pharmaceutically acceptable thickening / gelling agents may be used. Examples include other cellulose ethers, polymer thickeners such as acrylic acid polymers, Carbopol.RTM thickeners, xanthan gum, guar gum, and the like, as well as inorganic thickener / gelators. The amount of thickener is not particularly critical and can be selected to give the desired product consistency or viscosity that can be easily applied to the skin so that it does not become too watery and loose enough to remain at the site of application. In general, depending on its molecular weight, an amount of thickener up to about 5% of the composition, such as from 0.1 to about 2%, will give the desired effect.

  As is well known in the art, other ingredients can be included in the formulation for aesthetic and / or functional effects. For example, the formulation may optionally include one or more humectants to moisturize the skin and one or more emollients to soften and smooth the skin. Glycerin is an example of a suitable moisturizing additive. When present, the additive is incorporated in an amount up to about 5%, for example up to about 0.1-5%, by weight of the composition.

The hydrophobic or lipophilic component of the formulation can be a fatty acid substance. “Fatty acid material” can include a mixture of fatty acids, typically including fatty acid moieties of C _{8 to} C ₃₀ chain length. The fatty acid material may contain a relatively pure amount of single chain long fatty acid moieties. Suitable fatty acids from which the fatty acid / nonionic surfactant-based mixture is derived are pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, ricinoleic acid, arachin Contains acids, behenic acid and erucic acid. Although normally saturated, suitable fatty acid materials may contain unsaturated fatty acid moieties or fatty acid moieties containing some degree of substituents such as hydroxy fatty acids. The chain length of the fatty acid component determines the rheological properties of the resulting skin composition. Fatty acid material mixtures containing stearic and palmitic acid moieties in relatively high proportions have been found to be particularly suitable for use in making skin creams and lotions that may be used in hot weather On the other hand, fatty acid material mixtures containing relatively high amounts of lower chain length fatty acid moieties (eg, fatty acid moieties having a chain length of C ₈ -C ₁₄ are greater than 50%) are used in relatively cold climates Suitable for the preparation of dermatological compositions.

  Further additives in the composition are acidic skin care actives in aqueous solution, eg fatty acids such as alpha hydroxy fatty acids including lactic acid and glycolic acid; and peroxides such as hydrogen peroxide, vitamins such as vitamin B3 And polysaccharides such as chitosan, and particularly preferred alpha hydroxy fatty acids are lactic acid and glycolic acid.

  Typical solid additives include, for example, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, tetraalkyl and / or trialkylaryl ammonium smectites, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay. Hydrous aluminum silicate, fumed silica, carboxyvinyl polymer, hydroxyalkylated cellulose derivative, sodium carboxymethylcellulose.

The composition according to the invention may be prepared and formulated as an emulsion. Emulsions are typically heterogeneous systems in which one liquid is dispersed in the other as droplets with diameters usually exceeding 0.1 μm (Idson, “Pharmaceutical Dosage Forms,” Lieberman, Rieger
and Banker (Eds.), 1988, volume 1, p. 199; Rosoff, "Pharmaceutical Dosage
Forms, "Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245;
Block "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker
(Eds.), 1988, volume 2, p. 335; Higuchi et ai., "Remington's
Pharmaceutical Sciences, "Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often two-phase systems in which two immiscible liquid phases are intimately mixed and dispersed with each other. In general, emulsions can be water-in-oil (w / o) or oil-in-water (o / w) If the aqueous phase is finely divided into a large amount of oil phase and dispersed as fine droplets, The resulting composition is called a water-in-oil (w / o) emulsion, whereas if the oil phase is finely divided into a large amount of water phase and dispersed as fine droplets, the resulting composition is Called oil-type (o / w) emulsions, emulsions are in addition to the dispersed phase, additional components, and active agents that may exist as a solvent in the aqueous phase, a solvent in the oil phase, or as a separate phase itself. Such as emulsifiers, stabilizers, dyes and antioxidants. Pharmaceutical excipients may also be present in the emulsion if desired, for example, oil-in-water-in-oil (o / w / o) and water-in-oil-in-water (w / o / w) It may be a multiple emulsion consisting of more than two phases, such as an emulsion, and such a composite formulation offers advantages that a simple two-component emulsion does not provide. A multiple emulsion in which small oil droplets enclose small water droplets constitutes a w / o / w emulsion.Similarly, a system in which oil droplets are encapsulated in water particles stabilized in an oily continuous phase is Provide w / o emulsion.

In many cases, the dispersed or discontinuous phase of the emulsion is well dispersed in the outer or continuous phase and is maintained in that form by the emulsifier or by the viscosity of the formulation. Each phase of the emulsion may be semi-solid or solid in the case of emulsion-type ointment bases and creams. Another means of stabilizing the emulsion involves the use of emulsifiers that are incorporated into each phase of the emulsion. Emulsifiers are generally classified into four categories: synthetic surfactants, natural emulsifiers, absorption bases, and finely dispersed solids. (Idson, "Pharmaceutical Dosage Forms," Lieberman, Rieger
and Banker (Eds.), 1988, volume 1, p. 199).

  Usable oils are safflower oil, castor oil, palm oil, cottonseed oil, herring oil, palm kernel oil, palm oil, peanut oil, soybean oil, jojoba oil, linseed oil, bran oil, pine oil, sesame oil, and sunflower Seed oil, and vegetable oils and hydrogenated vegetable oils containing these hydrides can be included. Further usable oils can include cod liver oil, and animal fats and oils such as lanolin and its derivatives, mineral oil, and petrolatum.

Synthetic surfactants (also known as surfactants) can be used in carriers in forming emulsions and are reviewed in the literature (Rieger, "Pharmaceutical Dosage Forms" Lieberman, Rieger and
Banker (Eds.) 1988, volume 1, p.285; Idson, "Pharmaceutical Dosage
Forms "Lieberman, Rieger and Banker (Eds.) 1988, volume 1, p.199). Surfactants are typically amphiphilic and contain a hydrophilic and a hydrophobic moiety. The ratio of hydrophilicity to hydrophobicity, referred to as the hydrophilic / lipophilic balance (HLB), is a valuable tool in classifying and selecting surfactants during formulation preparation. Surfactants can be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic, zwitterionic, and amphoteric (Rieger, “Pharmaceutical Dosage Forms” Lieberman, Rieger and
Banker (Eds.) 1988, volume 1, p.285).

Common nonionic surfactants are polyoxyethylene ester and ether surfactants, a specific example of which is Tween 60. Other suitable nonionic surfactants are McCutcheons "Detergents and emulsifiers", North American published by Allured Publishing Corporation
edition (1986), the contents of which are incorporated herein by reference. Examples of common nonionic surfactants may be derived from the condensation reaction between a long chain alcohol (C ₈ -C ₃₀₎ with a sugar or starch polymers. Other nonionic surfactants that can be used are condensates of alkylene oxides and fatty acids (alkylene oxide esters of fatty acids or alkylene oxide diesters of fatty acids) or condensates of alkylene oxides and fatty alcohols (alkylenes of fatty alcohols). Ether).

Other non-ionic emulsifiers which may be used are sugar esters, polyesters, alkoxylated sugar esters and _{polyesters, C 1 ~C 30 C 1 ~C} 30 fatty acid esters of fatty alcohols, C ₁ -C of C ₁ -C ₃₀ fatty alcohols alkoxylated derivatives of ₃₀ fatty acid esters, C ₁ -C ₃₀ alkoxylated ethers of fatty alcohols, polyglyceryl esters of C ₁ -C ₃₀ fatty acids, C ₁ -C ₃₀ esters or ethers of polyols, alkyl phosphates, polyoxyalkylene fatty ether Including phosphates, fatty acid amides, acyl lactylates and mixtures thereof.

Typical cationic emulsifier is McCutheon's
Detergents and Emulsifiers, North American Edition (1986), the entire contents of which are incorporated herein by reference. Cationic surfactants that can be used include quaternary ammonium salts and cationic ammonium salts such as aminoamides.

  Anionic emulsifiers that can be used include alkoxy isethionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and fatty acid soaps.

An ionic polyamide polymer containing acrylamide propane sulfonic acid (AMPS) and / or a salt thereof as a comonomer can be used as an ionic polymer stabilizer. These polymers may be unsubstituted or substituted, formed from a variety of monomers (preferably C ₁ -C ₅₎ one or two alkyl groups containing or N- vinylpyrrolidone good acrylamides and methacrylamides substituted by Don be able to. In one embodiment, the acrylate amides and methacrylate amides are unsubstituted on the amide nitrogen or substituted with one or two C ₁ -C ₅ alkyl groups (preferably methyl, ethyl or propyl). Monomers, such as acrylamide, methacrylamide, N-methacrylamide, N-methylmethacrylamide, N, N-dimethylmethacrylamide, N-isopropylacrylamide, N-isopropylmethacrylamide, and N, N-dimethylacrylamide . In another embodiment, the polyacrylamide-AMPS copolymer is a product with the CTFA name of polyacrylamide (and) isoparaffin (and) laureth-7, and Seppic
Available from Corporation (Fairfield, NJ) under the trade name Sepigel 305. In another embodiment, a copolymer of ammonium AMPS and N-vinyl pyrrolidone, which is commercially available under the trade name Aristoflex®, can be used. As a specific embodiment, a mixture comprising sodium AMPS (also known as acryloyldimethyltaurate) copolymer, isohexadecane, and polysorbate 80, commercially available under the trade name Simulgel 600, can be used. Mixtures of two or more ionic polymer stabilizers can also be used.

  The ionic stabilizer of the present invention is included in an amount sufficient to avoid visible separation of the composition. The stabilizer is generally present at a concentration of about 0.1 to about 10% by weight. One of ordinary skill in the art will inevitably determine the amount of ionic polymer stabilizer, the hydrophobic and hydrophilic phases, the intended use, the intended storage, and conditions of use, as well as other ingredients used in the composition. It will also be appreciated that the optional ingredients and mixing conditions depend on the mixing equipment used in preparing the emulsion or dispersion.

  The ionic polymer stabilizer of the present invention enables the preparation of a composition that is stable at a lower concentration of alcohol as compared to a composition that does not contain the ionic stabilizer described above. In other embodiments, the ionic polymer stabilizer is present in the range of about 1 to about 10% by weight, such as in the range of about 2 to about 8% by weight, based on the composition.

  Antioxidants are also commonly added to emulsion formulations to avoid formulation degradation. Antioxidants used are tocopherols, alkyl gallates, butylated hydroxyanisole, free radical scavengers such as butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and citric acid Antioxidant synergists such as tartaric acid and lecithin may also be used.

  The composition according to the invention may further comprise other auxiliary ingredients normally found in pharmaceutical compositions at the level of use established in the art. Thus, for example, the composition comprises additional, compatible, pharmaceutically active substances such as antipruritic agents, astringents, steroids, local anesthetics or anti-inflammatory agents, skin conditioning agents such as oils and vitamins. And additives that can be used to physically formulate various dosage forms of the compositions according to the invention, such as dyes, fragrances, preservatives, antioxidants, opacifiers, thickeners and stabilizers An agent can be included.

  The above ingredients can be formulated with skin penetration enhancers and active agents to form compositions suitable for topical application, including creams, lotions, ointments, gels, sprays, aerosols Agents and the like. In one embodiment, the active agent and skin permeation enhancer are dispersed in a cream base or ointment base to form a cream or ointment.

  Topical carriers can include conventional emulsifiers or other excipients, including alginate, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propylparaben, butylparaben, sorbitol, polyethoxyl. Sorbitan, fatty acid ester (TWEEN), white petrolatum (petrolatum), triethanolamine, aloe vera extract, lanolin, cocoa butter and the like. Suitable topical carriers are well known to those skilled in the art.

Preparation and Administration Traditionally, cosmetic or pharmaceutical creams have been limited to oil-in-water emulsions containing more than 50% by weight of water. According to some embodiments of the present invention, stable creams can also include those having less than 50% water by weight. Such cream formulations have the advantage of being able to incorporate large amounts of organic solvents such as alcohol (eg ethanol) while maintaining acceptable cream properties. Traditionally, in creams incorporating skin penetration enhancers, high concentrations of skin penetration enhancers can lead to emulsion destabilization, thus typically limiting the concentration of these compounds low (eg, <5% by weight). Or they needed an organic solvent like alcohol that would destroy the cream. Therefore, the cream embodiment of the present invention provides, inter alia, a cream comprising a high concentration of skin penetration enhancer while maintaining an acceptable cream feel.

  The term “cream” as used herein refers to an opaque or emulsified composition at room temperature, and is an oil-in-water emulsion in which a hydrophobic phase is emulsified and dispersed in a hydrophilic phase in a micelle structure. Some cream composition embodiments according to the present invention are transparent or liquefied when in contact with animal skin, such as human skin, so as not to discolor or otherwise give the user an unpleasant aesthetic quality. A cream composition may be included. Such “burnishing creams” typically clear at temperatures above ambient temperature, for example, greater than about 30 ° C., greater than about 33 ° C., or greater than about 35 ° C. Such quality of the vanishing cream is believed to occur due to temperature disruption of the micelle structure of the cream at high temperatures, resulting in emulsion separation and loss of opacity.

  The components of some cream base embodiments according to the present invention may comprise a hydrophobic component and a hydrophilic component. Such a cream formulation may further comprise an emulsifier and a skin penetration enhancer. The active agents of the present invention may be dispersed, dissolved or suspended in a cream base formulation according to the present invention, for example, one or both of the hydrophobic or hydrophilic components.

a. Hydrophilic component Some compositions according to the invention comprise a hydrophilic component, such as water and / or other water-soluble or water-miscible compounds. Suitable water soluble or water dispersible components may include alcohols, carboxylic acids, diols, triols, polyols and the like.

  According to one embodiment of the invention, the hydrophilic component comprises water and one or more alcohols. Suitable alcohols of the present invention include linear or molecular alkyl, aromatic or alkylene alcohols. In one embodiment, the alcohol used in the hydrophilic component is 1-6 such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1-pentanol or 1-hexanol. It is a linear alkyl alcohol containing a carbon atom. Polyols including diols and triols may be present with or instead of monoalcohols. Exemplary polyols include, for example, ethylene glycol, propylene glycol, diethylene glycol, butylene glycol, and the like. The amount of alcohol used in the hydrophilic component is selected to complete the emulsion described herein and may generally comprise from 1 to 99% by weight based on the total weight of the hydrophilic component. The alcohol can comprise about 15 to about 85% by weight of the hydrophilic component, such as about 30 to about 70% by weight, about 35 to about 55% by weight.

The amount of hydrophilic component present depends on the additional components present in the compositions described herein.
Some compositions of the present invention comprise from about 40 to about 90% by weight based on the total weight of the hydrophilic component. In one embodiment, the composition of the present invention comprises from about 45 to about 85% by weight hydrophilic component, such as from about 50 to about 80% by weight, from about 60 to about 70% by weight hydrophilic component.

  For example, in one embodiment, the hydrophilic phase comprises water, at least about 5%, such as at least about 10%, at least about 15%, at least about 20%, at least about 5%, based on the total weight of the composition. 25%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%. The amount of water is less than about 85% by weight based on the total weight of the composition, such as less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, Less than 50%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35% by weight.

  The hydrophilic phase may comprise from about 15 to about 89%, such as from about 20 to about 80%, from about 25 to about 70%, from about 30 to about 60% by weight of water, based on the weight of the composition. .

  In one embodiment, the ethanol is at least 15% by weight relative to the total weight of the composition, such as at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60% may be present. The amount of ethanol should be, for example, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35% Can do.

b. Hydrophobic component The hydrophobic component of at least one embodiment of the present invention comprises from about 5 to about 60% by weight of the total weight of the composition, such as from about 12 to about 40% by weight of the total weight of the composition. One or more of the oily or fatty components described above may comprise from about 15 to about 30% by weight of the weight.

  The composition according to the present invention is suitable for topical, eg, transdermal administration, and may be prepared by mixing various components in selected ratios in a conventional manner. Different active ingredients will produce different results with different skin penetration enhancers, solvents or carrier systems, or other ingredients in the formulation, but those skilled in the art will take into account the disclosure herein, It would be possible to select a suitable accelerator and system for a given active agent.

The compositions of the present invention can be applied a predetermined area of skin, for example 10 to 100 cm ^2, for example in the area of 50 cm ² by any means.

  When the pharmaceutical composition of the present invention is in the form of a lotion, cream, emulsion, gel, solution, ointment or similar composition, the composition is spread as a film on a selected area of the skin, for this purpose. In order to achieve this, an intermediate propellant gas is not necessarily required. Alternatively, the topical transdermal composition may be incorporated into a transdermal delivery device such as a patch.

  In another embodiment of the invention, the composition may be administered by direct spraying using a well known and commercially available type of dosing pump that is used without the need for a propellant. In this case, however, the composition of the invention may be administered by spraying from a container fitted with a dosing valve, additionally containing the compressed propellant gas described above.

  The methods of the present invention require a composition comprising one or more of the above active ingredients in combination with a SEPA® penetration enhancer in a delivery vehicle comprising the above and well known ingredients in the art. Including applying to the patient's upper arm and / or shoulder. By applying the composition to the upper arm and / or shoulder rather than the patient's abdomen, the required dosage of the active ingredient-containing composition can be significantly reduced.

  By reducing the amount of composition and active ingredient required, the possibility of cross-contamination was reduced while delivery efficiency was increased. Furthermore, by reducing the amount of composition required, the time required for drug application is reduced. In addition, the lower the possible dose used, the lower the risk of side effects, including blood and liver effects, and other events associated with processing and receiving excessive amounts of any active ingredient in the body. Many examples of the importance of reducing dosages to lower levels to reduce side effects and other events are well known to those skilled in the art. One example of this is the experience in the pharmaceutical field regarding estrogen replacement therapy.

In one embodiment, the method of the present invention comprises a lower amount of active ingredient included in conventional topical treatment, based on daily dosage, on the upper arm and / or shoulder of a patient in need of the active ingredient, and SEPA. By applying a composition containing a cream base containing a (registered trademark) accelerator, the serum concentration of the active ingredient can be increased to a therapeutic level. For example, in one embodiment, the serum total testosterone concentration in a testosterone deficient patient (a patient who continues to have a serum total testosterone concentration below physiological criteria, eg, about 280 ng / dL or less) is measured in the upper arm and / or shoulder of the patient. the amount of C ₇ -C ₁₄ hydrocarbyl substituted 1,3-dioxalane to promote skin penetration, 1,3-dioxane, or by applying a testosterone composition containing these acetals 4.5 grams / day or less, the treatment / normal Can be raised to level. In contrast, existing comparable topical treatments required application of 5-10 g / day. In other embodiments, a testosterone composition of 3.5 g / day or less, such as 3.0 g / day, or 2.5 g / day is applied. The testosterone composition may be 2% or less testosterone, for example 1.5%, more preferably 1% testosterone. The composition can be 0.5% or more testosterone.

  In at least one embodiment, the patient's serum total testosterone concentration is at a level higher than 280 ng / dL, such as 290 ng / dL, preferably higher than 300 ng / dL, such as 310 ng / dL or 320 ng / dL, but 1500 ng / dL. It is raised to dL or less, preferably 1000 ng / dL or less.

  In another embodiment, a low dose topical administration of a composition comprising an active ingredient is applied to the patient's upper arm and / or shoulder at 7.5 g / day or less, such as 6.0 g / day, 4.0 g / day, 3.5 g / day or Applying a 3.0 g / day composition may be included. In another embodiment, a low dose topical administration of a composition comprising an active ingredient is applied to the patient's upper arm and / or shoulder at 2.5 g / day or less or 1.0 g / day, such as 0.5 g / day, 0.1 g / day. Applying the composition can be included.

  In yet another embodiment, a low dose administration of a composition comprising an active ingredient is applied to the patient's upper arm and / or shoulder with 100 mg / day or less of the active ingredient, such as 75 mg / day or less, 60 mg / day, 50 mg / day, Applying 40 mg / day or 30 mg / day of the active ingredient can be included. In yet another embodiment, a low dose administration of a composition comprising the active ingredient is applied to the patient's upper arm and / or shoulder at 25 mg / day or less of the active ingredient, such as 15 mg / day or less, 10 mg / day, 5 mg / day, Applying 2.5 mg / day, 1 mg / day or 0.5 mg / day of active ingredient may be included.

  In another embodiment of the invention, the daily dose of the composition or active ingredient is one or more doses within 24 hours, for example 2 doses, 3 doses, 4 doses, 5 doses or 6 doses. Can be applied. In one embodiment, dosing of the composition or active ingredient can occur every 24 hours, every 12 hours, every 8 hours, every 6 hours, or every 4 hours.

  In another embodiment, the method of delivering the active ingredient comprises applying a composition comprising the active ingredient and a SEPA® accelerator to the patient's upper arm and / or shoulder. Such methods treat patients with sexual dysfunction, patients on testosterone replacement therapy, patients with decreased libido, male patients, patients over 40 years of age, or patients with HIV-related muscle atrophy. Can do. Embodiments of this method can treat women, such as anorexia nervosa, or when a patient is ovariectomized or has female sexual dysfunction. This embodiment can also be used when the patient is undergoing anti-acupuncture or opiate therapy or suffers from hypopituitarism.

  In another embodiment, similar delivery is achieved by applying about half the amount of composition required to achieve the same delivery of active ingredient when applied to the abdomen of the patient. Delivery is measured by comparing the 24-hour mean serum concentration level of the active ingredient, by comparing the area under the concentration curve over time of the active ingredient, or by comparing the maximum serum concentration level of the active ingredient it can.

  The effect of the topical composition according to the present invention is further illustrated by the following representative examples which are not intended to limit the scope of the invention.

  For adults with hypogonadism 2.5 g Opterone® (1% testosterone in a cream base containing 5% SEPA® penetration enhancer) on the upper arm and shoulder at a time When applied, a three-way crossover study was performed, where 2.5 g Opterone® was applied to the abdomen between the rib cage and the pubic bone, and 5.0 g Opterone® was applied to the abdomen. . Ten eligible patients were randomly assigned to three different treatment regimens using the study cream. Each patient was evaluated for 3 study periods, including a pre-dose evaluation, administration on day 1 (once / day), followed by a 6 day no treatment (washout) period. Each dose is thus evaluated over a week, then each patient is given a second treatment followed by a 6 day washout followed by a third treatment and washout, then A final safety assessment was performed. A time frame of ± 3 days was allowed on the treatment day. The patient reported to the hospital on the visit.

  On the first day, the patient went to the hospital where he stayed overnight (about 24 hours). The patient was instructed to receive a whole blood sample for serum testosterone (total, free and metabolite DHT) evaluation at 30, 15, and 1 minute prior to administration, and 1, 2, 4, 6, Collected after 8, 12, 16, 18, 20 and 24 hours. Blood samples taken 30 minutes prior to dosing were also used for serum estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG) measurements. Prior to discharge on the second day, the patient received a diary and event record to record any adverse events and / or changes in medication. Patients were instructed not to use any testosterone products or OTC supplements during the study period. This procedure was repeated for the remaining two treatments for each patient. Similar schedules and procedures were followed for all three treatment methods. After a 6-day washout period (Day 1 of Week 4), the patient is instructed to come to the final blood sample for serum collection and safety assessment at the same time as all other visits It was done.

  Prior to the first application, the patient was informed about the application area, ie either the upper arm and shoulder or abdomen used for test article application. Sample cream was applied only to certain areas according to the assigned treatment method. The cream was applied so that as much of the predetermined skin area as possible was covered with the cream.

  The same method was used for all applications. Prior to applying the first dosage, the selected area was washed with soap and water and allowed to dry completely. The upper arm including the abdominal surface or shoulder between the rib cage and the pubic bone was used as the predetermined application area. When assigned to Treatment Method 1, 2.5 g of Opterone® was applied to the upper arm and shoulder, designated areas of this method. When assigned to Treatment Method 2 (2.5 g) and / or Treatment Method 3 (5.0 g), the test article was applied to the abdominal surface between the rib cage and the pubic bone. A single cream was used for each application. For drug application studies, the entire contents of one glass jar were taken using a plastic application bar (provided by the sponsor) and applied to the area selected for the treatment method. After applying the dose, the patient gently massaged the skin with two fingers until the test article disappeared to spread as much as possible in the predetermined area. At the end, the hands were thoroughly washed with soap and water, while the application site was unclothed and exposed to air drying for 10 minutes without being affected by contact. After the test article had dried, the application site was covered with clothing for at least 12 hours. Vigorous activities / exercises that are likely to promote showers, bathing, swimming, or heavy sweating were prohibited for at least 6 hours after application of the test article. Prior to discharge on the second day, the patient was released with an indication of completion along with the patient's diary and event records and instructed to come to the hospital by 8:00 am (± 1 hour) the following week. Patients brought diaries and event records to the hospital for examination and collection.

Total Testosterone (TTEST) Concentration-Time Data Table 1 shows the average total testosterone concentration versus time. Total testosterone (TTEST) is an endogenous compound that was detectable in all patients prior to receiving the first dose. Descriptive statistics of mean total testosterone concentrations are listed for each treatment in Table 1 below.

  Descriptive statistics of total testosterone concentrations adjusted at baseline are shown in Table 2 below at dose levels at each measurement time point.

Total Testosterone Pharmacokinetic Parameter Evaluation Pharmacokinetic non-compartmental analysis was performed on unregulated total testosterone levels. TTEST pharmacokinetic parameters were adjusted to reflect the effects of baseline observation. To account for differences in baseline total testosterone values between patients, baseline modulated pharmacokinetic parameters were calculated. Mean unadjusted and baseline adjusted TTEST pharmacokinetic parameters are shown in Table 3.

Claims (29)

4.5 g / day or less of the testosterone composition containing C ₇ -C ₁₄ hydrocarbyl-substituted 1,3-dioxalane, 1,3-dioxane, or an acetal thereof in an amount that promotes skin penetration on the patient's upper arm and / or shoulder A method of increasing serum total testosterone levels in testosterone deficient patients, including applying in.   2. The method of claim 1, wherein a testosterone composition of 2.5 grams / day or less is applied.   The method of claim 1, wherein the testosterone composition comprises 2.0% or less by weight of testosterone relative to the total weight of the composition.   The method of claim 1, wherein the testosterone composition comprises 1.0% by weight of testosterone relative to the total weight of the composition.   The method of claim 1, wherein the amount that promotes skin penetration comprises 2% or more of the total weight of the composition.   The method of claim 1 wherein the composition comprises a skin cream.   The method of claim 1, wherein the serum total testosterone concentration in the patient is increased to a level greater than 280 ng / dL.   8. The method of claim 7, wherein the serum total testosterone concentration in the patient is increased to a level of 1500 ng / dL or less. The patient's upper arm and / or shoulder, the active ingredient and C ₇ -C ₁₄ hydrocarbyl substituted 1,3-dioxalane, 1,3-dioxane or method of delivery active ingredient comprising applying a composition containing these acetals, .   The method according to claim 9, wherein the active ingredient is testosterone.   11. The method of claim 10, wherein the patient has hypogonadism.   11. The method of claim 10, wherein the patient is prescribed testosterone replacement therapy.   11. The method of claim 10, wherein the patient suffers from decreased libido.   The method of claim 10, wherein the patient is male.   11. The method of claim 10, wherein the patient is over 40 years old.   11. The method of claim 10, wherein the patient exhibits muscle atrophy associated with HIV.   The method of claim 10, wherein the patient is female.   11. The method of claim 10, wherein the composition is used to treat anorexia nervosa.   18. The method of claim 17, wherein the patient is undergoing ovariectomy.   18. A method according to claim 17, wherein the composition is used for female sexual dysfunction.   The method of claim 10, wherein the patient is undergoing anti-acupuncture therapy.   11. The method of claim 10, wherein the patient is receiving anti-opiate therapy.   11. The method of claim 10, wherein the composition is used for hypopituitarism.   10. The method of claim 9, wherein the patient is in need of the active ingredient.   10. Similar delivery of the active ingredient is achieved by applying about half of the amount of composition required to achieve similar delivery of the same active ingredient when applied to the abdomen of a patient. the method of.   26. The method of claim 25, wherein delivery is measured by comparing the 24-hour average serum concentration level of the active ingredient.   26. The method of claim 25, wherein delivery is measured by comparing the area under the active ingredient concentration curve plotted against time.   26. The method of claim 25, wherein delivery is measured by comparing the maximum serum concentration level of the active ingredient.   The method of claim 9, wherein the composition comprises a skin cream.