EP3082759A1

EP3082759A1 - Dermal and/or transdermal pharmaceutical composition containing a terpenoid compound

Info

Publication number: EP3082759A1
Application number: EP14784183.7A
Authority: EP
Inventors: Hans-Michael Thiede; Wolfgang Kehr
Original assignee: Epinamics GmbH
Current assignee: Epinamics GmbH
Priority date: 2013-12-16
Filing date: 2014-08-22
Publication date: 2016-10-26
Also published as: DE102013020633A1; WO2015090262A1; US20160317661A1

Abstract

The invention relates to a method for dissolving an active pharmaceutical ingredient, the use of this method for producing a pharmaceutical composition in the form of a dermal and/or transdermal preparation, a pharmaceutical composition containing this compound and at least one active pharmaceutical ingredient, an aerosol dispenser having such a composition and a method for producing such a composition.

Description

Dermal and / or transdermal pharmaceutical

Composition containing a terpenoid compound

Field of the invention

The invention relates to a method for the Inlosungbringung a pharmaceutical composition and the

Use of such a method or a compound for the preparation of a pharmaceutical composition in the form of a dermal or transdermal preparation, wherein a pharmaceutical active ingredient in pharmacological

effective amount is dissolved in the compound. The

The invention further relates to pharmaceutical

Compositions containing such a compound,

Aerosol dispenser containing such a composition and a method for producing such

Composition.

Background of the invention and prior art

Another dosage form of drug compositions includes, for example, oral

Administration, inhalation, or injection the so-called transdermal systems. Here is the

Active ingredient composition applied to the skin of a human or animal and resorbed more or less rapidly depending on the design of the transdermal system. The

Active ingredients can act locally or systemically.

Advantages of transdermal administration over the

CONFIRMATION COPY Inhalation or oral administration include better tolerability, localized drug targeting, controlled rates of absorption, and thus avoidance of reduced bioavailability of the drug.

Transdermal systems can be formed, for example, as an adhesive patch, ie in the core consist of a sticker to be stuck to the skin, which is a substrate in or on which the active ingredient composition

is arranged, and comprises an adhesive layer through which the active ingredient composition by permeation reaches the skin and is absorbed there. An example here is a nicotine patch according to WO2000 / 033812 A. In this case, the transdermal preparation is applied to a transfer film or sprayed on. Here is closing

typically a coating of the dried ones

Transdermal preparation with an adhesive layer with a skin-friendly adhesive on. So the patch with the side facing away from the transfer film can be placed on the skin and taped out. Such patches are disadvantageous because they visually interfere (they are often

in terms of area, in order to provide a sufficient amount of active substance for transdermal use

Release) and also problems regarding the

Water resistance as well as the secure adhesive attachment on the skin develop with the result of reduced

Drug absorption by the patient, in particular the consequence of impaired controllability of the patient

Bioavailability of the drug over the given treatment period. However, coatings on the skin are also referred to as a patch, which are sprayed onto a target surface of the skin as an aerosol and form a coating adhering to the target surface. Typically, the aerosol compositions contain a film-forming polymer as a matrix, which forms the actual patch, as well as an active ingredient composition which is embedded in the matrix as it is sprayed onto the skin. The

Polymer of the matrix is selected and

designed so that the delivery rate of the drug is adapted to the skin of a preset. Most includes the

The aerosol composition also includes at least one solvent, typically a volatile, pharmacologically acceptable and solvent-compatible and polymer-compatible organic solvent. Sometimes the aerosol also contains a propellant, for example if the aerosol dispenser is designed as a spray bottle. The propellant can also act as a solvent

function. An example of a composition for spraying to form a patch is described in WO 2001/037890.

A disadvantage of such transdermal compositions is that many drugs are used in the solutions

used solvents are poor or not solvable. As a result, the patch, whether generated on a transfer sheet or generated directly on the skin by spraying, will contain a fairly small amount of active ingredient. Then high doses are transdermally unavailable. In addition, the patches need to be made unnecessarily large area. The above statements also apply analogously to dermal applications, ie, where the active substance contained exerts its effect on the site of the application.

The use of compounds such as carvacrol or thymol as a biocide, as an anti-inflammatory drug, as an antibiotic or antimycotic is from the practice

known, see for example

de. wikipedia. org / wiki / carvacrol.

Technical Problem of the Invention The invention is therefore related to the technical problem

Reason to specify means by which compositions for the production of patches can be produced, the

over the prior art contain an increased concentration of the active ingredient. The invention is based on the further problem of specifying means which the

Production of small patches allow over the prior art, with unchanged amount of active ingredient content (absolute).

Broad features of the invention and preferred embodiments

To solve this technical problem, the invention teaches a method for the release of a pharmaceutical active ingredient in an aqueous and / or organic

Solvent, wherein the solvent is a compound of Formula I or a mixture of various such

Compounds, or a mixture of the compound or the mixture of the various such compounds with an additional solvent, wherein the active substance first in the compound or in the compound containing

Solvent is dissolved

1

Formula I wherein R1 to R5 are independently, the same or different, selected from the group consisting of -H, -OH, methyl, ethyl, propyl, isopropyl, isopropenyl and alkoxy, wherein R6 is selected from -O-R7 and -CO -R7, with R7 selected from -H, C1-C3-alkyl, C6-aryl and C7-C10-aralkyl, substituted or unsubstituted, and wherein the aromatic ring of the representation of the formula I can be replaced by C6-cycloalkyl, saturated or mono- or diunsaturated, at any position of the cycloalkyl ring. Preference is given to R6 = -OH when R1 is methyl or methoxy, R2 is isopropyl, isopropenyl or -H and R3 to R5 are -H, or R1 is isopropyl, R2 is methyl and R3 to R5 are -H. It is also preferred if R 6 = -OCH ₃ or -C0-CH ₃ , with

at least one (random) radical Rl to R5 as methyl.

In particular, the invention teaches the use of such a process for the preparation of a pharmaceutical composition in the form of a dermal or transdermal preparation, wherein a pharmaceutically active substance is dissolved in the compound in a pharmacologically effective amount.

Alkoxy here includes in particular alkyl radicals having 1, 2, 3, 4, or 5 C atoms, linear or branched.

The invention is based on the surprising finding that a great many pharmaceutical active compounds dissolve considerably better in such compounds than in solvents customary for dermal or transdermal systems. The compound used according to the invention thus does not constitute an active ingredient in the context of the invention, but functions as a solvent in the nucleus and optionally additionally as a penetration-promoting galenic adjuvant. It follows that with an inventive

Preparation of dermal and / or transdermal systems

can be produced, which either significantly higher

Contain amounts of active ingredient, smaller than previous patches can be designed, or both. In addition, in the context of a synergistic effect that a high proportion of

Compound of formula I the effect of a particular has effective penetration enhancement, ie the

Penetration of the pharmaceutical agent through the skin and into the body is improved. A dermal and / or transdermal preparation comprises, in addition to the compound of the formula I with the active ingredient dissolved therein, typically, but by no means necessarily, nor at least one film-forming polymer. If no such polymer is provided, the preparation does not form a patch after application to the skin;

Active substance absorbed directly into the skin. After the application of the preparation on the skin or on a

Transfer film evaporates the compound and it forms from the polymer a film in which the active ingredient

embedded and controlled is released. Typically, the active ingredient and the polymer are adapted to each other to ensure predetermined release rates to the skin. In the context of the invention, however, the choice of the polymer is fundamentally irrelevant since it is either dissolved in the compound or, in the case of the poor

Solubility, emulsified or suspended therein. In a preparation according to the invention, in addition to the compound of the formula I used according to the invention, it is also possible to use another customary organic additional solvent, for example for improving the

Solution of the polymer and / or to reduce the volatility of the compound of formula I.

In the following, preferred embodiments of the

Invention described. The pharmaceutical composition can be as follows

Components contain: a) at least one compound of formula I or a mixture of various such

C) optionally at least one film-forming polymer d) optionally at least one aqueous or organic additional solvent or a mixture of different such additional solvents (then a solution of the Active ingredient or the

Active ingredients in a mixture of the compound of the formula I and of the additional solvent (s) before, e) optionally at least one galenic adjuvant or a mixture of different such adjuvants, f) optionally at least one skincosmetically acting additive or a

Mixture of various such additives. The use of at least one additional solvent is recommended

especially in all those cases where the compound of formula I is not liquid or solid at room temperature (20 ° C).

The preparation typically contains at least 1% by weight, 5% by weight or 10% by weight, for example at least 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70

Wt .-%, 80 wt .-%, or 90 wt.% Of the compound of formula I (based on the total amount of freshly prepared preparation). The active ingredient is in the usual way

quantitatively dissolved in accordance with the desired pharmacological activity therein. The other components are included in the customary amounts in the preparation. This comprises for example 2 to 30 wt .-%, in particular 5 to 20 wt .-%, preferably 5 to 10 wt .-% polymer, the remainder to 100 wt .-% then by active ingredient or active ingredients and the others elsewhere mentioned optional components, in particular additional solvent, is formed.

A possibly used and different from the compound of formula I organic additional solvent is

typically a physiologically acceptable organic or aqueous co-solvent. Fall under this

For example, organic solvents such as benzyl alcohol, ethanol, methanol, butanol, isobutanol, diacetone alcohol, methylene chloride, carbon tetrachloride, trichlorethylene, chlorothene, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, amyl acetate, duPont DBE, Exxate 500, 700, 900, glycol and ether / ester derivatives, ethylene glycol, PM acetates, butyl cellosolve, carbitol acetate,

Butylcarbitol acetate, Ektapro EEP, toluene, xylene, VM & P naphtha, mineral solvents, Aromatic 100, Aromatic 150, acetone, methyl ethyl ketone, methyl butyl ketone,

Dimethyl ether, benzyl benzoates, isopropyl myristate,

Acetonitrile, ethyl oleates, glycerol, glycofurol

(tetraglycol), propylene glycol, polyethylene glycol (PEG), hexane, n-hexane, glycol ether, methylene chloride,

Methyl chloride, octyldodecanol, trichloroethane

Diethyl phthalate and dibutyl phthalate. The solvent is preferably selected from the group consisting of methanol, ethanol, butanol, 1-propanol, 2-propanol, 1-bromopropane, 1-octanol, dimethyl ether, diethyl ether,

Methyl ethyl ether, benzene, chloroform, DMSO, acetonitrile, Acetone, dioxane, ethylene glycol, propylene glycol,

Dimethylformamide, benzene, ethyl acetate, PEG400, hexane, trichlorethylene, ethylacrylate, N-methyl-2-pyrrolidone, toluene, DMSO, DMF, pyridine, isopropyl myristate,

Dichloromethane, 1,4-dioxane, and aniline.

Preferably, the insert is at least one

Additional solvent which reduces the volatility of the compound of formula I, i.e. ensures that this compound escapes as slowly as possible from the applied preparation or the patch, if appropriate in admixture with other additional solvents which per se do not reduce the volatility of the compound of the formula I. In this respect, the additional solvent can also act as a volatility reducing agent with respect to the compound of the formula I. This is advantageous because on the one hand unwanted crystallization of the present (in high concentration due to the compound of formula I) active ingredient in the preparation or the sprayed patch is prevented and on the other hand penetration-promoting (in relation to the penetration of the active ingredient through the skin )

Effect of the compound of formula I is retained for a long time. Examples of preferred additional solvents therefore include propylene carbonate, propylene glycol and isopropyl myristate. According to the preliminary example of example 2, it is not difficult for the person skilled in the art to identify other particularly suitable additional solvents.

A reduction in volatility refers to a

Volatility of the compound in the solvent with the

Additional solvents, which by at least 5%, preferably at least 10%, most preferably at least 20%,

in particular at least 50% is reduced compared to the volatility of the compound in a solvent without the additional solvent.

If the additional solvent is aqueous or if it is water or contains water, it is recommended that the pH be adjusted by customary additives in a range from 4.0 to 9.5, preferably 6.0 to 9.0, in particular 6.0 to 8.0, is set.

The ratio (based on the mass) between solvent to the additional solvent, if one

Can be used between 1:20 and 1000: 1, in particular between 1:10 and 10: 1,

for example, between 1: 5 or 1: 4 and 10: 1, lie. The upper limit of the range is only defined by possible traces of an additional solvent, for example from the admixture of other components of a preparation. A particularly interesting finding of the invention is that such mixtures often exhibit a significant synergistic effect, i. the

Solubility of the active ingredient in the mixture is significantly higher than in the solvent or the additional solvent alone. This applies, for example, especially for ethanol as an additional solvent.

The melting point of an inventively used

Solvent can be critical in that the solvent without the use of an additional solvent at

Room temperature (20 ° C) should be liquid. Preferably the melting point is below 10 ° C, for example below 0 ° C.

In the case of the use of an additional solvent, the melting point of the solvent but also above the

Room temperature are. The melting point is then preferably below 150 ° C., for example below 120 ° C., in particular below 100 ° C., or below 80 ° C., 60 ° C. or 50 ° C.

Interestingly, the effects according to the invention are therefore also determined when a solid solvent at room temperature is first dissolved in an additional solvent before the active ingredient in the mixture of

Solvent and additional solvent is dissolved. The invention is particularly useful in the context of pharmaceutical compositions for treatment

bacterial infections, fungal infections,

especially nail fungus (here also the high penetration enhancement of the compound according to formula I has an advantageous effect).

Examples of dermal and / or transdermal pharmaceuticals which can be used within the scope of the invention

Active ingredients include: antidiarrhoeal agents, such as

Diphenoxylates, loperamides and hyoscyamines; Cardiovascular agents such as hydralazine, minoxidil, captopril, enalapril, ramipril, clonidine, prazosin, debrisoquine, diazoxide, guanethidone, methyldopa, reserpine, trimetaphan,

Diltiazem, felodopine, amlodipine, nitrendipine,

Nifedipine and Verapamil, Amiodarone, Flecainide,

Disopyramide, Procainamide, Mexiletene, Quinidine, Glyceryl trinitrates, erythritol tetranitrates,

Pentaerythritol tetranitrates, mannitol hexanitrates,

Perhexilene, isosorbide dinitrates nicorandil, alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleates, digoxin, adrenaline, ephedrine, fenoterol, isoprenaline, orciprenaline,

Rimeterol, Salbutamol, Salmeterol, Terbutaline, Dobutambe, Phenylephrine, Phenylpropanolamine, Pseudoephedrine, Dopamine, Cyclandelate, Isoxsuprine, Papaverine,

Dipyrimadole, isosorbide dinitrate, phentolamine,

Nicotinyl alcohol, co-dergocrine, nicotinic acid,

Glyceryl trinitrates, pentaerythritol tetranitrates,

Xanthine, ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan; Anticoagulants and

thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as noxaparin,

Plasminogen activators such as streptokinase, t-pA, and hemostatic agents such as aprotinin, tranexamic acid and protamine; CNS agents such as buprenorphins, dextromoramides, dextropropoxyphenes, fentanyl, alfentanil, sufentarlil, hydromorphone, methadone, morphine, oxycodone,

Papaveretum, Pentazocine, Pethidine, Phenoperidine,

Codeine, dihydrocodeine, acetylsalicylic acid (ASA),

Paracetamol, phenazone, barbiturates, amylobarbitones, butobarbitones, pentobarbitones, choral hydrates,

Chloromethiazoles, hydroxyzines, meprobamates,

Benzodiazepines, lprazolam, bromazepam, chlordiazepoxides, clobazam, chlorazepates, diazepam, flunitrazepam,

Flurazepam, lorazepam, nitrazepam, oxazepam, temazepam, triazolam, phenothiazines, chlorpromazine, fluphenazine, Pericyazines, perphenazines, promazines, thiopropazates,

Thioridazine and trifluoperazine, butyrophenones,

Droperidol, haloperidol, pimozide, thiothixene, lithium, tricyclic antidepressants, amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine,

Nortriptytine, Opipramol, Protriptyline, Trimipramine, Tetracyclic Antidepressants, Mianserin, Monoamine Oxidase Inhibitors, Isocarboxazid, Phenelizine, Tranylcypromine, Moclobemide, Fluoxetine, Paroxetine, Citalopram,

Fluvoxamine, sertraline, caffeine, tacrine, amantadine,

Benserazides, carbidopa, levodopa, benztropines, biperiden, benzhexol, procyclidines, S (-) -2- (N-propyl-N-2-thienylethylamino) -5-hydroxytetralin (N-0923), phenytoin, valproic acid, primidone, phenobarbitone .

Methylphenobarbitones, carbamazepines, ethosuximides,

Methsimides, Phensuximides, Sulthiams, Clonazepam,

Phenothiazines, Prochloperazine, Thiethylperazine,

Ondansetron, granisetron, dimenhydrinate, diphenhydramine, metoclopramide, domperidone, hyoscine,

Hyoscine Hydrobromide, Hyoscine Hydrochloride, Clebopride, Compride; Anti-inflammatory agents, such as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac,

Aloxiprine, Aproxene, Diflunisal, Fenoprofen, Indomethacin, Mefenarnic Acid, Naproxen, Phenylbutazone, Piroxicam, Salicylamide, Salicylic Acid, Sulindac, Desoxysulindac, Tenoxicam, Tramadol, Ketoralac, Flufenisal, Salsalates, Triethanolamine Salicylates, Aminopyrins, Antipyrins,

Oxyphenbutazone, Apazone, Cintazone, Flufenamie Acid, Clonixeril, Clonixin, Meclofenarnie Acid, Flunixin,

Colchicine, demecolcine, allopurinol, oxypurinol,

Benzydamine hydrochlorides, dimefadans, indoxoles, intrazoles, Mimbanehydrochloride, Paranylenehydrochloride,

Tetrydamine, benzindopyrine hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamole, flutiazine, metazamide,

Letimidehydrochloride, Nexeridine hydrochloride,

Octazamides, Molinazoles, Neocinchophene, Nimazole,

Proxazolecitrates, Tesicam, Tesimide, Tolmetin,

Triflumidal, penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate, aurofanm, baclofen,

Diazepam, Cyclobenzaprine Hydrochloride, Dantrolene,

Methocarbamol, Orphenadrine, Quinine, Allopurinol,

Colchicine, probenecid and sulphinpyrazone; Hormones, steroids and steroidal substances, such as oestradiol,

Oestriol, Oestrone, Ethinyloestradiol, Mestranol,

Stilboestrol, dienoestrol, epioestriol, estropipate and zeranol, allyloestrenol, dydrogesterone, lynoestrenol, norgestrel, norethyndrel, norethisterone, norethisterone acetate, gestodene, levonorgestrel, medroxyprogesterone, megestrole, cyproterone acetate, danazol, epitestanol, exemestane, 4-hydroxy-androstenedione, testosterone, Methyltestosterone, Clostebol acetate, Drostanolone, Furazabol, Nandroloneoxandrolone, Stanozolol,

Trenbolone acetates, Dihydrotestosterone, 17-alpha-methyl-19-nortestosterone, Fluoxymesterone, Finasteride,

Turosterides, LY-191704, MK-306, betamethasone,

Betamethasone valerates, Cortisone, Dexamethasone,

Dexamethasone 21 -phosphate, fludrocortisone,

Flumethasone, fluocinonide, fluocinonide desonide,

Fluocinolones, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate methylprednisolone, prednisolone, prednisolone 21-phosphate, prednisone, triamcinolone, triamcinolone acetonide, cortodoxone, fluoroacetonide, fludrocortisone, difluoronediacetate, fluorandrenolone acetonide,

Medrysone, Arncinafel, Amcinafide, Betamethasone,

Chloroprednisone, Clorcortelone, Descinolone, Desonide, Dichlorisone, Difluprednate, Flucloronide, Flumethasone, Flunisolide, Flucortolone, Fluoromethalone, Fluperolone, Fluprednisolone, Meprednisone, Methylmeprednisolone, Paramethasone, Cortisone acetate, Hydrocortisone

cyclopentylpropionate, cortodoxone, flucononide,

Fludrocortisone acetate, flurandrenolone acetonide,

Medrysone, Amcinafal, Amcinafde, Betamethasone,

Betamethasone benzoate, chloroprednisone acetate,

Clocortolone acetate, Descinolone acetonide,

Desoximetasone, dichloroisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate,

Paramethasone acetate, Prednisolamate, Prednival,

Triamcinolone hexacetonide, cortivazole, formocortal,

Nivazole, corticotrophin, thyrotropin, follicle stimulating hormone (FSH), luteinizing hormone (LH), gonadotrophin releasing hormone (GnRH), insulin, chlorpropamide,

Glibenclamide, gliclazide, glipizide, tolazarnide,

Tolbutamide and metformin, calcitonin, thyroxine,

Liothyronine, Carbimazole, Propylthiouracil, Octreotide, Bromocriptine, Clomiphene; Diuretics and antidiuretics, such as thiazides, bendrofluazides, chlorothiazides,

Chlorthalidones, dopamine, cyclopenthiazides,

Hydrochlorothiazide, indapamide, mefruside,

Meiycholthiazide, Metolazone, Quinethazone, Bumetanide, Ethacrynic Acid, Frusemide, Spironolactone, Amiloride, Triamterene, Desmopressin, Lypressin An, Vasopressin, Ergometrine, Oxytocin, Gemeprost, Prostaglandins,

Alprostadil (PGE1), Prostacyclin (PGI2), Dinoprost

(Prostaglandin F2 -alpha), misoprostol; antimicrobial, antifungal or antiseptic agents, such as cephalosporins, cephalexin, cefoxytin, cephalothin, penicillins,

Amoxycillin, amoxycillin + clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin, ticarcillin, azlocillin, tetracyclines, minocycline, chlortetracycline, demeclocycine,

Doxycycline, Methaeycline, Oxytetracycline, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Amorolfine, Isoconazole, Clotrimazole, Econazole,

miconazole, nystatin, terbinafine, bifonazole,

Amphotericin, Griseofulvin, Ketoconazole, Fluconazole, Flucytosine, Fezatione, Ticlatone, Tolnaftate, Triacetin, Zinc, Pyrithione, Sodium pyrithione, Quinolone, Nalidixic acid, Cinoxacin, Ciprofloxacin, Enoxacin, Norfloxacin, Sulphonamides, Phthalylsulphthiazoles, Sulfadoxines,

Sulphadiazines, Sulphamethizole, Sulphamethoxazoles,

Sulphone, dapsone, chloramphenicol, clindamycin,

Erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin

ethyl succinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole,

Tinidazole, fusidic acid, trimethoprim, 2-thiopyridine N-oxide, iodine-PVP complex, diiodohydroxyquin, Hexachlorophenes, chlorhexidines, chloroamines, benzoyl peroxides, ethambutol, isoniazid, pyrazinamides.

Rifampicin, clofazimines, primaquine, pyrimethamine,

Chloroquine, hydroxychloroquine, quinine, mefloquine, halofantrine, acyclovir, acyclovir prodrugs, famciclovir, penciclovir, zidovudine, didanosinc, stavudine,

Lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n -docosanol, tromantadine, idoxuridine, mebendazole,

Thiabendazole, niclosamide, praziquantel, pyrantel

embonate, diethylcarbamazine, plicamycin,

Cyclophosphamide, dacarbazine. Fluorouracil, procarbazine, 6-mercaptopurine, mucophenolic acid, alcohols, ethanol, isopropanol, quaternary ammonium compounds,

Benzalkonium Chloride, Detrimide, Cetypyridinium Chloride, Bisdequalinium Diacetate, Dequalinium Chloride,

Chlorhexidine, chlorhexidine acetate, PMMB; Chloramines, sodium dichloroisocyanate, sodium hypochlorite;

Metabolics, such as dexfenfluramine, fenfluramine diethylpropion, mazindol, phentermine, calcitriol,

dihydrotachysterol; Active substances for the immune system, such as meclozine, cyclizines, chlorcyclizines, hydroxyzines,

Bromopheniramine, chlorpheniramine, clemastine,

Cyproheptadine, Dexchlorpheniraraine, Diphenhydramine, Diphenylamine, Doxylamine, Mebhydroline, Mepyramine,

Phenirarnine, tripolidine, azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole, loratidine,

Cetirizine; Anesthetics, such as bupivacaine, amethocaine, lignocaine, cinchocaine, dibucaine, mepivacaine,

Prilocaine, Etidocaine; Neuromuscular blockers, like

Suxamethonium, Alcuronium, Pancuronium, Atracurium,

Gallamines, tubocurarines, vecuronium; Smoking article substitutes, such as nicotine, bupropion,

ibogaine; dermatological agents, such as vitamin A, vitamin E, vitamin E acetate, vitamin E sorbate, vitamin D;

Allergens for desensitization, such as pollen or house dust allergens; Anti-acne remedies like

Isotretinoin, tretinoin, benzoyl peroxide; Anti-psoriasis agents, such as etretinate, cyclosporin, calcipotriol; Anti-itching agents, such as capsaicin or nonivamide;

Antiperspirant agents, such as methatropine nitrate,

Propantheline bromide, Scopolamine, Methscopolamine bromide; Physiologically active peptides and proteins, such as vasopressin or human growth hormone.

Particularly preferred are antimycotics, such as

for example, terbinafine, amorolfine, itraconazole,

Ciclopirox, or Clotramizole are also usable

Bexarotene, oxybutinin, or tolterodine.

Dose levels for an active ingredient may range from 0.01 ng to 50 g, especially 0.01 mg to 10 g,

for example, 0.1 mg to 1 g or 1 mg to 300 mg per application.

As physiologically compatible organic

Monomer / polymer for film formation are for example in question: acrylic acid, methacrylic acid and derivatives,

Polyacrylates and polyacrylate derivatives, such as

Polybutyl methacrylate and polymethacrylic acid,

Polymethacrylate, ascorbyl palmitate, carbomer, carnauba wax, cellulose derivatives, such as cellulose acetate phthalate, rosca mellose sodium, hydroxyethyl cellulose,

Hydroxypropylcellulose, hydroxypropylmethylcellulose, Ethylcellulose, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, crospovidone its derivatives,

Cetyl alcohol and its derivatives, microcystalline wax, poloxamer, polyethylene glycol, polyurethanes,

Polyvinyl acetates, polyvinyl acetate phthalate, polyvinyl alcohol, povidone, silicone gums and its derivatives,

Shellac, triglyceride derivatives. Also usable are derivatives, mixtures and / or copolymers of such polymers, in particular mixtures or copolymers of polyurethane or polyurethane derivatives and polymethacrylate or

Polymethacrylatderivaten. Optionally, at least one plasticizer is included to establish the required elasticity. Examples of these are: polybutyl phthalate, benzyl benzoate, dibutyl sebacate, dimethyl phthalate,

Dibutyl phthalate, triacetin, glycol and its derivatives, benzyl benzoate, glycerine, mineral oil, lanolin, alcohols (e.g., C8 alcohols), petroleum, lanolin alcohols,

Polyethylene glycol, sorbitol, triethylene citrates,

Propylene glycol, chlorobutanol, castor oil and gelatin.

The monomers / polymers used may be in the form of solutions in the preparation of the composition

be used. These solutions may themselves be aqueous and / or contain customary organic solvents, for example those mentioned above, or consist thereof.

Suitable galenic adjuvants and / or diluents are all customary adjuvants for transdermal systems in accordance with the dosage form and / or release rates. Quantity and type of excipients should of course with the other component used

be compatible. Examples include: cosolvent,

Surfactants, emulsifiers, antioxidants,

Preservative, stabilizer. Examples of galenic adjuvants are paraffin oils, isopropyl esters, yristates, ethanol, silicone oils and oils obtained, for example, from olives, peanuts or sesame. Suitable surfactants are ethoxylated fatty acids, glycerol monostearate, phosphate esters and other customary emulsifiers and surfactants. An example of a preservative is hydroxybenzoate ester. Typical cosolvents and adjuvants are ethanol, propanol, isopropanol, acetone,

Dimethyl ether, glycol ethers, as

Diethylene glycol monoethyl ether. These excipients should of course be compatible with the requirement that the composition after application to the skin or a transfer film in a sufficiently short time,

typically 10 seconds to 10 minutes. , forms a touch-dried film.

The pharmaceutical composition may be applied to the skin or a substrate in any manner. This includes painting, brushing, knife coating or spraying.

The pharmaceutical composition may be in a

Aerosol dispenser for spraying the composition onto the skin of a human or an animal. Possibly. the composition also contains a propellant when the aerosol dispenser pressure is to be applied. The invention also relates to a pharmaceutical composition for dermal and / or transdermal

Application containing at least one compound of formula I or a mixture of various such

Compounds, at least one dermal-acting and / or transdermally absorbable pharmaceutical agent or a mixture of different such agents, optionally at least one film-forming organic monomer or

Polymer or a mixture of such monomers and / or

Polymers, optionally at least one aqueous or organic additional solvent or a mixture of different such additional solvents, optionally at least one galenic excipient or a mixture of various such

Excipients, optionally at least one skin cosmetic additive or a mixture of various such additives.

The invention further includes an aerosol dispenser with a pharmaceutical according to the invention

Composition. In principle, all come for this

customary aerosol dispenser in question, wherein the term aerosol also includes spray.

A particularly suitable aerosol dispenser for the application of transdermally active pharmaceutical active ingredients has a pharmaceutical active ingredient in one

containing liquid solution vessel whose interior is under pressure by means of a propellant gas or the interior of which is pressurizable by means of a pumping device, one with the interior of the vessel

connected atomizing device, one between the An operable dispensing valve disposed in the interior of the vessel and the atomizing device, and a spray head connected to the dispensing valve, wherein optionally an attachment hood is arranged, which has a

Container opening which is placed on the container and wherein the attachment hood has an application opening with a Aufsetzlippe for placing the Aufsetzhaube on the skin. In the embodiment with Aufsetzhaube is achieved that upon actuation of the dispensing valve, the interior of the Aufsetzhaube is filled with the patch forming aerosol or spray, wherein the

Atomizer device preferably directs the aerosol jet towards the landing lip, i.e. the

Sputtering device has an outlet opening facing in the direction of the Aufsetzlippe. The fact that the attachment hood with the container opening to the vessel and with the Aufsetzlippe the skin is virtually tight, the aerosol can not leave this interior of the attachment hood. Contamination of adjacent skin areas, clothing, third persons or the environment can not take place. In particular, unwanted inhalation of the aerosol is excluded. In addition, a patch with a defined circumference is formed by the edge of the placement lip, wherein, in addition, the thickness of the patch is formed almost homogeneously over the surface of the patch thus formed.

This achieves a particularly well-defined kinetics of drug delivery to the skin and consequently a very readily controllable bioavailability of the active ingredient. In principle, the attachment hood can be formed from any medically compatible material.

Preferably, an organic polymer is used, For example, a thermoplastic such as polyolefins such as PE or PP, or a thermoplastic elastomer, as given below. It is preferred if at least the Aufsetzlippe or Aufsetzhaube is formed entirely from one or more different rubber-elastic material. These include, for example, natural rubber, modified natural rubber, silicone rubber, EPDM, olefin-based thermoplastic elastomers such as PP / EPDM, urethane-based thermoplastic elastomers,

thermoplastic polyester elastomers or copolyesters,

Styrene block polymers such as SBS, SEBS, SEPS, SEEPS, or MBS, and thermoplastic copolyamides such as PEBAX. The

Aufsetzhaube may have a shape in the field of Aufsetzlippe, which for complete contact with a

Target area on the skin is suitable. While are

In principle, many such forms conceivable, but should be useful training, which has circular or oval ring shape in cross section. Preferably, the cross-sectional area of the landing lip is greater than the cross-sectional area of the vessel opening, i. the

Attachment hood widens from the container opening to

Aufsetzlippe out on. In this case, the Aufsetzhaube may be formed with a substantially conical shell surface, with a cross-section in the plane of the central axis of the cone straight, convex or concave conical surface. It will be useful if the

Aufsetzhaube in the field of Aufsetzlippe has a lower hardness than in the area outside the Aufsetzlippe. The Aufsetzlippe can for example have a Shore A hardness of up to 10, while the Aufsetzhaube

otherwise a Shore A hardness of 20, especially 40, to to 120 and more. The attachment hood can be firmly or reversibly connectable to the vessel. In the former case, the Aufsetzhaube in the manufacture of the

Aerosol dispenser connected to the vessel, through

Positive locking, adhesion or material bond. It is then not destructively removable. In the latter case, vessel and attachment hood can be made available separately to the operator, who then the Aufsetzhaube, for example via a clamp connection or a

Latching connection, touches on the vessel and possibly also decreases again, for example, a space-saving

Allow storage of the aerosol dispenser. When the atomizing device has an outlet opening pointing in the direction of the Aufsetzlippe is

ensures that the majority of the aerosol gets on the skin and only a small part is reflected on the inner wall of the attachment hood and so on

get lost. The cross-sections of the container opening and the application opening may be aligned parallel to one another or angled relative to each other, i.e. the

Aufsetzhaube may also have an angle in the container opening.

The invention further relates to a dermal or

transdermal patch for sticking to the skin of a

Human or animal, obtainable by spraying or applying a pharmaceutical according to the invention

Composition on a Subtratfolie (for example, transfer film). A dermal or transdermal patch can be produced on the skin of a human or animal by applying or spraying a pharmaceutical composition according to the invention onto the skin.

A pharmaceutical composition according to the invention can be prepared by having at least one dermally acting and / or transdermally absorbable pharmaceutical

Active substance in pharmacologically effective amount with at least one compound according to formula I and optionally with at least one film-forming organic monomer or polymer, at least one aqueous or organic

Additional solvent, at least one galenic adjuvant and / or at least one hautkosmetisch acting

Additive is mixed.

An aspect of independent importance in the context of the invention relates to the use of the compound of formula I in forms other than in

dermal / transdermal systems, for example in

Solutions, which are applied to the inner mucous membranes and / or other Körperinnenwandungen. It is thus possible, for example, to formulate in pharmaceuticals customary in veterinary pharmaceuticals for the treatment of mastitis in cows in high amounts in milk, in particular in solution when the compound is admixed according to formula I, for example in an amount of up to 50 volumes -%, In particular from 10 to 45% by volume, preferably from 20 to 40% by volume, of the resulting mixture. The milk thus treated can then be applied again into the udder, where the active ingredient then its has a healing effect. These agents can also, as described above, transdermally by

Order of a transdermal composition are presented to the udder.

The explanations concerning uses and components according to the invention apply correspondingly to all the above aspects of the invention. In the following the invention is based on only

Exemplary embodiments illustrative examples explained in more detail.

Example 1: Solubilities of various classes of active substances in carvacrol or carvacrol-containing formulations.

The solubilities of the active ingredients which can be used within the scope of the invention mentioned in Table I were determined in

Carvacrol or carvacrol-containing formulations measured. The solubilities are consistently significantly higher than the solubilities of the same drugs in other conventional transdermal solvents.

Mixing ratios are always given as volume fractions. Liqui-patch ^® are formulations of finished products

Mixtures of polymers and other additives for the production of transdermal systems and available from epinamics GmbH. In the here used

Formulation contains Liqui-patch ^® the following

Components: Mixture of 10 g of triethyl citrate, 100 g

Water (demineralized or medical), 100 g DynamX ^® , 790 g of ethanol. The following tabular elements using Liquipatch and in admixture with carvacrol therefore also represent examples of preparations according to the invention.

Similar results are obtained, for example, with the isomer thymol, as shown by some

Table elements visible.

Tab. I: Solubilities of active substances in carvacrol

Thymol preparations

Active ingredient solvent dissolved amount

Lidocaine HCl Carvacrol 260 mg / ml

Testosterone Carvacrol 220 mg / ml

Erythromycin Carvacrol 110 mg / ml

Uric acid carvacrol <20 mg / ml

8-hydroxyquinol in carvacrol> 100 mg / ml

6 -Aminouracil carvacrol <50 mg / ml

Coumarin carvacrol> 200 mg / ml

Rutin carvacrol /

Methanol (1: 1) 20 mg / ml

Thymoquinone carvacrol> 100 mg / ml

Curcumin Carvacrol 20 mg / ml

Nalidixine. Carvacrol 108 mg / ml

Salicylsre. carvacrol /

Methanol (1: 1) 240 mg / ml

Sulfamethoxazole carvacrol 50 mg / ml

Bexarotene carvacrol 60 mg / ml

Bexarotene carvacrol /

Liqui-patch (1: 1) 30 mg / ml

Laurinsre. Carvacrol 500 mg / ml

Laurinsre. carvacrol / Liqui-patch (1: 1) mg / ml

Terbinafine thymol /

Ethanol (1: 1) mg / ml

Granisetron carvacrol 62.5%

Methanol 31.25%

2M NaOH / H ₂ O 6, 25% 71.25 mg / ml

Clotrimazole Carvacrol 410 mg / ml

Haloperidol carvacrol 100 mg / ml

Flunarizine * 2HCl Carvacrol 60 mg / ml

Cromoglicinsre. -Na carvacrol 50 mg / ml

Itraconazole Carvacrol 300 mg / ml (after warming

Ketoconazole Carvacrol 140 mg / ml

Ciprofloxacin carvacrol 80 mg / ml

Clotrimazole carvacrol 410 mg / ml

5 -fluorouracil carvacrol 25 mg / ml

Ellagic acid carvacrol 60 mg / ml

Protoporphyrin IX carvacrol 64 mg / ml

Cromog1icinsäure

Disodium salt carvacrol 50 mg / ml

Example 2: Solubilities of Two Exemplary

Active ingredients in various solvents

In Table II the solubilities in mg / ml of

Clotrimazole and testosterone are shown. One recognizes the comparatively much higher solubilities in

Solvents with inventively used compounds "LP" stands for LiquiPatch ^® . Tab. IIa

Solubility Solubility

Solvent Clotrimazole Testosterone Ethanol 70 mg / ml 90 mg / ml Carvacrol 410 mg / ml 230 mg / ml

20% thymol / 80% EtOH 230 mg / ml 330 mg / ml 20% carvacrol / 80% EtOH 240 mg / ml 260 mg / ml guaiacol 250 mg / ml 270 mg / ml 20% guaiacol / 80% EtOH 260 mg / ml 300 mg / ml 20% guaiacol / 80% LP 270 mg / ml 270 mg / ml acetone 110 mg / ml 60 mg / ml

20% thymol / 80% acetone 240 mg / ml 180 mg / ml 20% carvacrol / 80% acetone 240 mg / ml 170 mg / ml LP 50 mg / ml 190 mg / ml

20% thymol / 80% LP 250 mg / ml 300 mg / ml

20% carvacrol / 80% LP 240 mg / ml 250 mg / ml

Tab. IIb

solubility

Solvent testosterone

Ethanol 90 mg / ml

Anisole <100 mg / ml

4-methyl anisole <250 mg / ml

Methyl salicylate (4MS) <100 mg / ml

20% anisole / 80% EtOH 500 mg / ml

20% 4MS / 80% EtOH 335 mg / ml

p-Cymene insoluble (<100)

20% p-cymene / 80% ethanol 300

Gamma-terpinene insoluble (<100) Gamma-terpinene / 80% Ethal 200

(S) - (-) syllables insoluble (<100)

20% (S) - (-) -lemonene / 80% ethanol 200

Example 3: Volatility of carvacrol

To investigate whether carvacrol is suitable for transdermal systems or whether carvacrol is sufficiently long in

Transdermal systems is included

Volatility examined with different admixtures. The volatility is important for keeping the active ingredients in solution for a sufficient length of time in the film. For the measurements were two spots of 5μ1 each

Formulation containing 1 mg of carvacrol, applied per time to a tempered to 35 ° C glass plate. Two spots of each time point (30 minutes and 3 hours after the spots had been applied) were mixed with a cotton swab

wiped off. The amount of wiped carvacrol was determined. The difference to the 100% target recovery is the volatile carvacrol. The results are shown in Table III. The abbreviation V. stands for "volatil", the abbreviation C. for carvacrol.The proportion of carvacrol is always 20%, the remainder to the sum of carvacrol and the additive is ethanol. Quantities are given in volume%. Tab. III: Volatility of carvacrol

Additive V.C. 30 min. V.C. 3 h

Isopropyl myristate 10% 26% 46%

Isopropyl myristate 20% 24% 32%

Ethyl methyl ketone 10% 33% 100%

Ethyl methyl ketone 20% 45% 100%

Propylene glycol 10% / menthol 5% 40% 97%

Propylene glycol 20% / menthol 10% 0% 46%

Water 10% 18% 94%

Water 20% 0% 94%

Propylene carbonate 10% 29% 49%

Propylene carbonate 20% 11% 24%

Glycerol 10% 28% 96%

Glycerin 20% 33% 88%

Propylene Glycol 10% 40% 51%

Propylene glycol 20% 1% 33%

It can be seen that the volatility of carvacrol

For example, by propylene carbonate, propylene glycol or isopropyl myristate is advantageously reduced.

Claims

Claims:

A process for the dissolution of a pharmaceutical active ingredient in an aqueous and / or organic solvent, wherein the solvent is a compound of formula I or a mixture of different such compounds, or a mixture of the compound or mixture of the various such compounds with an additional solvent, wherein the active ingredient in the compound or in the solvent containing the compound is dissolved,

wherein R 1 to R 5 are independently, the same or different, selected from the group consisting of -H, -OH, methyl, ethyl, propyl, isopropyl, isopropenyl and alkoxy, wherein R 6 is selected from -O-R 7 and -CO-R 7 compound selected from -H, Cl-C3-alkyl, C6-aryl and C7-C10 aralkyl, substituted or unsubstituted, and wherein the aromatic ring of the representation of the formula I can be replaced by C 6 -cycloalkyl, saturated or mono- or diunsaturated, anywhere on the cycloalkyl ring.

2. The method of claim 1, wherein Rl is methyl or

Methoxy, R2 is isopropyl, isopropenyl or -H and R3 to R5 are -H, or R1 is isopropyl, R2 is methyl and R3 to R5 are -H.

Use of a method according to claim 1 or 2 for the preparation of a pharmaceutical composition in the form of a dermal or transdermal preparation, wherein the active pharmaceutical ingredient is dissolved in a pharmacologically effective amount in the solvent.

Use according to claim 3, wherein the pharmaceutical composition contains the following components: a) at least one compound according to formula I or a mixture of different such compounds,

b) at least one dermal-acting and / or transdermally resorbable pharmaceutical active substance or a mixture of different such active substances, c) optionally at least one physiological

compatible film-forming monomer or polymer or a mixture of different such monomers and / or

polymers d) optionally at least one aqueous or

organic additional solvent or a mixture of various such additional solvents,

e) optionally at least one galenic adjuvant or a mixture of various such adjuvants, f) optionally at least one skin-cosmetic

acting additive or a mixture of various such additives.

Use according to any one of claims 3 or 4, wherein the pharmaceutical composition is adapted for spraying on the skin.

Use according to claim 3 to 5, wherein the organic co-solvent is selected from the group

consisting of methanol, ethanol, butanol, 1-propanol, 2-propanol, 1-bromopropane, 1-octanol, dimethyl ether, diethyl ether, methyl ethyl ether, benzene, chloroform, DMSO, acetonitrile, acetone, dioxane, ethylene glycol, propylene glycol, dimethylformamide, benzene, Ethyl acetate, PEG400, hexane, trichlorethylene, ethyl cycatate, N-methyl-2-pyrrolidone, toluene, DMSO, DMF, pyridine, isopropyl myristate, dichloromethane, 1,4-dioxane,

Propylene carbonate and aniline, or mixtures of such solvents, in particular selected from the

Volatility of the compound inhibiting

Additional solvents, such as propylene carbonate,

Propylene glycol, isopropyl myristate. Use according to any one of claims 3 to 5, wherein the pharmaceutical composition is in a

Aerosol dispenser prepared for spraying the composition onto the skin of a human or an animal

Pharmaceutical composition for dermal and / or transdermal administration containing at least one compound according to formula I or a mixture

various such compounds, at least one dermal acting and / or transdermally resorbable pharmaceutical agent or a mixture

various such actives, optionally at least one film-forming organic monomer or polymer or a mixture of different such monomers and / or polymers, optionally at least one aqueous or organic co-solvent or a mixture of various such co-solvents, optionally at least one galenic adjuvant or a mixture of different such adjuvants, optionally at least one skin-cosmetically active additive or a mixture of various such additives

9. Aerosol dispenser with a pharmaceutical

Composition according to Claim 8. Dermal or transdermal patch for adhering to the skin of a human or animal obtainable by spraying or applying a pharmaceutical

A composition according to claim 8 on a substrate film

Method for producing a dermal or

Transdermal patches on the skin of a human or animal, wherein a pharmaceutical composition according to claim 8 applied to the skin or

is sprayed on.

Process for the preparation of a pharmaceutical

A composition according to claim 8, wherein at least one dermal acting and / or transdermally resorbable pharmaceutical active ingredient in pharmacological

effective amount with at least one compound according to formula I and in each case optionally with at least one additional aqueous or organic solvent, at least one galenic adjuvant and / or at least one skin-cosmetically active additive is mixed.