MXPA06007717A - Topically applied medicament for animals - Google Patents

Abstract

The invention relates to pharmaceutical preparations, which are applied to the pelt or skin of animals and are then absorbed by the latter orally.

Description

PHARMACEUTICAL PRODUCTS FOR TOPICAL APPLICATION IN ANIMALS DESCRIPTION OF THE INVENTION The invention relates to pharmaceutical preparations that are applied to the hair or skin of animals, and which the latter then collect orally. In animals, the oral administration of pharmaceutical products depends on the flavor properties of the active compound and the formulation. In the case of domestic animals, the administration of bitter taste active compounds, such as fluoroquinolones and praziquantel, is particularly difficult. On the other hand, there is a great need for oral medicinal forms pleasing to the palate, which the pet voluntarily picks up from the hand of the owner of the animal or a feeding bowl. As a rule, the owner of the animal administers oral pharmaceutical products in one of the following ways: in the case of what is called the forced introduction method, the pharmaceutical product is placed on the basis of the tongue and the mouth is then closed . The head is moved to the normal position and the throat is gently massaged until the medicinal form is swallowed.

Occasionally, small amounts of fluid are then also administered in order to facilitate swallowing. In the second method, the medicinal form is hidden in a Ref .: 174167 portion of food and then administered. This method is inadequate if the active compound has to be administered in the fasted state or the highly bitter inherent taste of the active compound exceeds the flavor of the food. More rarely, - the medicinal form is crumbled and spread on food or dissolved in water. While these modes of use are often successful in dogs, which usually swallow immediately after oral uptake, cats are much more difficult to treat, since they retain the medicinal form, or the food that is provided with it, in the mouth for a relatively long time, a constituent of the formulation having an unpleasant taste has a suitable opportunity to come into contact with the oral mucosa.The unpleasant taste often leads to the pharmaceutical product, or at least parts of it, that is expectorated immediately In order to facilitate the administration of semisolid preparations (pastes) in cats, it is sometimes recommended that these preparations should be applied to the leg, from where they can be licked. very distrustful since the pastes often do not adhere well to the hair and can be removed by agitation. praying oral acceptance by the addition of a flavoring are equally rarely successful in cats, since the unpleasant taste can not be completely masked. It has now been found, surprisingly, that a preparation containing the active compound, which is preferably of liquid consistency and which gives rise to severe defensive reactions after being perorally administered in the oral cavity of a cat, is collected voluntarily, and virtually in a complete way, when applied to the hair of the animal. Obviously, the grooming reflex, which is controlled by the central nervous system, is so pronounced in cats that even the repulsive taste of the active compound is unable to prevent the active compound from being picked up by the grooming. It can even be assumed that the grooming reflex is stimulated precisely by the constituents of the pharmaceutical product that have a bad taste, with the reflex that is only abated when the active compound has been completely removed from the hair and has consequently been taken orally. The invention therefore relates to: a pharmaceutical composition for use in animals, which is applied to the animal's hair or skin and which the latter subsequently takes orally. The invention also relates to: a method for applying pharmaceutical active compounds in animals, in which a pharmaceutical preparation comprising the corresponding active compound is applied topically to the animal and the animal then orally collects the applied pharmaceutical preparation. In principle, any preparations that can be applied topically and which are also acceptable for oral administration are considered as preparations which are suitable according to the invention. Those that can be mentioned are: liquid, semi-liquid or pasty and solid preparations. Liquid preparations are particularly preferred. The topical application takes place, for example, in the form of immersion, spraying, bathing, washing, emptying, staining and rubbing. The solutions, emulsions and suspensions are suitable preparations. The solutions for topical application are dripped, painted, rubbed, sprayed, splashed or applied by immersion (dripping immersion, bathing or washing). The preparations according to the invention are preferably applied topically to the trunk, in particular, for example, to the back or to the flanks of the animal. The solutions are prepared by dissolving the active compound in a suitable solvent and adding any possible additives such as solubilizers, acids, bases, buffer salts, antioxidants or preservatives. Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate and benzyl benzoate, ethers such as ether alkylene glycol alkyl, dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones such as acetone and methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, such as medium chain triglycerides or propylene glycol esters with medium chain fatty acids, DMF, dimethylacetamide, N-methylpyrrolidone and 2-dimethyl-4-oxomethylene-1,3-dioxolane, as well as mixtures of the aforementioned solvents. Vegetable or synthetic oils, and their mixtures with solvents, are particularly suitable. The solubilizers that can be mentioned are: solvents that promote the solution of the active compound in the main solvent, or that prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethyleating castor oil and polyoxyethylated sorbitan esters. Examples of preservatives are benzyl alcohol, n-butanol, trichlorobutanol, p-hydroxybenzoic esters, benzoic acid, propionic acid and sorbic acid. The solutions can be used directly.

Concentrates are used after having been previously diluted to the concentration for use. It may be advantageous to add thickeners during the preparation. The thickeners are: inorganic thickeners such as bentonites, colloidal salicylic acid and aluminum monostearate, organic thickeners such as cellulose derivatives, xanthan, carrageenan, alginates, starch, gelatin, polyvinyl alcohols and their copolymers, acrylates and methacrylates. Colorants are any colorants that are authorized for use on animals and that can be dissolved or suspended. The antioxidants are sulphites or metabisulfites, such as sodium sulfite and potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylhydroxyanisole and tocopherol. The photosensitizers are, for example, substances belonging to the class of benzophenones or novantisolic acid. The tackifiers are, for example, derivatives of cellulose, xanthan, carrageenan, alginates, starch, gelatin, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

The emulsions are either water-in-oil or oil-in-water type. These are prepared by dissolving the active compound either in the hydrophobic phase or in the hydrophilic phase and homogenizing the latter with the solvent of the other phase, using suitable emulsifiers and, where appropriate, additional auxiliary substances such as dyes, preservatives, antioxidants, photostabilizers and viscosity-increasing substances. The hydrophobic phases (oils) which may be mentioned are: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil or castor oil, synthetic triglycerides such as caprylic / capric diglyceride, a mixture of triglyceride containing vegetable fatty acid having a chain length of 8 to 12 carbon atoms, or other naturally occurring, especially selected fatty acids, mixtures of partial glycerides of saturated and unsaturated fatty acids, and possibly also containing hydroxyl groups, and mono- and diglycerides of the fatty acids of 8 to 10 carbon atoms. Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, and dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols having a chain length of 16 to 18 carbon atoms, isopropyl myristate, isopropyl palmitate, caprylic / capric acid esters of saturated fatty alcohols having a chain length of 12 to 18 carbon atoms, isopropyl stearate, oleyl oleate, decyl oleate , ethyl oleate, ethyl lactate, esters of waxy fatty acid such as artificial fat of uropigial duck gland, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc. Fatty alcohols such as isotridecyl alcohol, 2-octidodecanol, cetylstearyl alcohol and elelyl alcohol. Fatty acids such as oleic acid and their mixtures. The hydrophilic phases which may be mentioned are: water, alcohols such as propylene glycol, glycerol and sorbitol and their mixtures. Emulsifiers which may be mentioned are: nonionic surfactants, for example, polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate and polyglycol ethers of alkylphenol; ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin; anionic surfactants such as Na-lauryl sulfate, fatty alcohol ester sulfates, and the monoethanolamine salt of the orthophosphoric esters of the mono / dialkyl-polyglycol ether; cationic surfactants such as cetyltrimethylammonium chloride. Other auxiliaries that can be mentioned are: substances that increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers composed of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes and colloidal salicylic acid, or mixtures thereof. the substances listed. The suspensions are prepared by suspending the active compound in a liquid carrier, where appropriate, in the added presence of other auxiliaries such as wetting agents, colorants, preservatives, antioxidants and photostabilizers. The carrier liquids that may be mentioned are any homogeneous solvents and solvent mixtures. The wetting agents (dispersing agents) that may be mentioned are the surfactants specified above. Other auxiliaries that may be mentioned are those that are specified above. The preparations according to the invention have to fulfill all the conditions for a topical pharmaceutical preparation and also be suitable for oral intake. In order to ensure good oral intake or capture, the preparation that is applied to the hair must adhere to it. "A particular consistency, as exhibited for example, by the examples according to the invention, is desirable for this purpose The viscosity of preparations according to the invention is therefore preferably from one to 1000 mPas, particularly preferably 10 to 500 mPas If the viscosity is too low, there is a risk that the formulation will drip off the hair On the other hand, highly viscous formulations can only be applied with difficulty.In addition to this, highly viscous preparations often they adhere only to the hair inappropriately and fall off, or are shaken, before they can be taken by the animal.It is also desirable for the preparation that it has a good dispersion capacity, so that it can also be used as a site on the hair that is difficult for him to have access to the grooming Good dispersion also leads to the preparation that is distributed in a It's the biggest hair. In this case, the animal requires more time to take orally the amount of the active compound that has been applied, resulting in the influx into the body, which is retarded and the residence time, and thus the activity time, which they are prolonged. Kinetic investigations have shown this therapeutically desirable prolongation of residence time in the body (see Figure 1 and Figure 2). The examples according to the invention show good dispersion capacity. According to the invention, particular preference is given to what are termed spotting formulations, in which small volumes, usually less than 10 ml, preferably 5 ml or less, of the pharmaceutical product are applied topically to the animal. The composition is then dispersed on the surface of the animal. Usually, only a relatively small oral intake has to be expected when only small volumes are applied, since the grooming reflex would have to be more likely stimulated by high amounts of the preparation, which the animal then considers as dirt. Surprisingly, the high levels of the active compound in the blood were obtained even after the application of only very small volumes. Thus, only about 1 ml of the formulation was applied in Examples 2 and 3. However, the plasma levels are comparable with those obtained with Example 1, which was applied in a volume of 4 ml (see Figure 2). ). The preparations according to the invention thus allow high oral availability even when only small volumes are applied. The pharmaceutical product is intended to be administered by the veterinarian according to the instructions, or even intended for subsequent administration by the owner of the animal in the home. A strongly odorous or staining preparation could be annoying to the owner of the animal. A repulsive odor, or any discoloration of the hair or skin and / or the environment should therefore be avoided in the case of the preparations according to the invention. It is also possible, consequently, to distribute pharmaceutical products that have a bad taste in a simple or reliable manner, using the mode of application according to the invention. The preparations according to the invention are preferably used in the case of animals having a grooming reflex or a grooming behavior that favors the taking. While "preparations are used, particularly in mammals, for example, cats, dogs, rabbits, hares, guinea pigs, hamsters, mice and rats, these are also used in birds." Particular preference is given to the use of these in rabbits and , in particular in cats In principle, any active compounds which are suitable for topical application and oral administration are considered as active compounds for the preparations according to the invention. The following may be mentioned by way of example: quinolone and related antibiotics, as described, inter alia, in the following documents: U.S. Patent No. 4,670,444 (Bayer AG), U.S. Patent No. 4,472,405 (Riker Labs), U.S. Patent No. 4,730,000 (Abbot), U.S. Patent No. 4,861,779 (Pfizer), U.S. Patent No. 4,382,892 (Daiichi), U.S. Patent No. 4,704,459 (Toyama) , of which the following specific examples can be mentioned: benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, gatifloxacin, ibafloxacin, levofloxacin, lomfloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, perfloxacin, pipemídico acid, pradofloxacin, temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin. Related penicillins, cephalosporins and ß-lactams, such as amoxicillin, ampicillin, azidocillin, aztreonam, benzylpenicillin, cefaclor, cefadroxil, cephalexin, cefetamet pivoxil, cefixime, cefodizime, cefotiam, cefpodox improxetil, cefsulodin, ceftibuten, ceftizoxime, cefuroxime, clavulanic acid, dicloxacillin, f lucloxacillin, imipenem, loracarbef, mezlocillin, oxacillin, phenoxymethylpenicillin, propicillin, sultamicillin, tazobactam. Likewise, preference is given to the use of the analgesics aceclofenac, acemetacin, acetylsalicylic acid, buprenorphine, carprofen, celecoxib, codeine, deracoxib, diclofenac, dihydrocodeine, felbinac, fentanyl, flufenamic acid, flunixin, flupirtine, flurbiprofen, hydromorphone, ibuprofen, indomethacin, ketoprofen, lonazolac, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methadone, mofebutazone, morphine, naproxen, nefopam, niflumic acid, oxaprozin, oxycodone, paracetamol, parecoxib, pentazocin, pethidine, phenazone, phenylbutazone, piroxicam, piritramide, proglumetacin , propifenazone, rofecoxib, tepoxaline, thiaprofenic acid, tilidine, tolfenamic acid, tramadol, valdecoxib, vedaprofen. It is also possible to use the following active compounds: 4-aminosalicylic acid, abacavir, abamectin, acaprosate, acebutolol, acepromazine, acetylcysteine, acyclovir, acitretin, adapalene, albendazole, alendronic acid, alfuzosin, alprostadil, aluminum chloride, aluminum oxide, amantadine , ambroxol, amidotrizoic acid, amlodipine, amorolfine, amphotericin B, ascorbic acid, atenolol, atorvastatin, azithromycin, baclofen, benazepril, betamethasone, bezafibrate, bifonazole, biotin, bisoprolol, brivudine, bromhexine, bumetanide, bupranolol, calcium acetate, carbonate calcium, candesartan, captopril, carbidopa, carbocysteine, carteolol, carvedilol, celiprolol, cerivastatin, cetirizine, chenodeoxycholic acid, quinine, chlorambucil, chloramphenicol, chlormadinone, chloroquine, chlorthalidone, chlortetracycline, cyclosporine, cidofovir, cilastatin, cilazapril, clarithromycin, clenbuterol, clindamycin, clodronic acid, clomipramine, dapsone, dexamethasone , didanosine, diethylcarbamazine, dipotassium clorazepate, diltiazem, dinoprost, diphenylhydramine, doramectin, doxazosin, doxycycline, dutasteride, econazole, efavirenz, emodépside, enalapril, ephedrine, eprinomectin, eprosartan, erythromycin, esmolol, ethacrynic acid, ethambutol, etidronic acid, famciclovir , fenbenzadol, fendiline, fenticonazole, fexofenadine, finasteride, florfenicol, flubendazole, fluconazole, flucytosine, flumetasone, fluvastatin, folic acid, fosferstrol, fosfomycin, fosinopril, fumaric acid, furosemide, gabapentin, gallopamil, ganciclovir, gemfibrozil, halofantrine, heparin, acid hyaluronic acid, hydrochlorothiazide, s uccinado hydrocortisone acid, ibandronic acid, iloprost, imidapril, indinavir, irbesartan isoconazole, isoniazid, itraconazole, ivermectin, josamycin, potassium canrenoate, kanamycin, ketoconazole, ketotifen, lamivudine, leflunomide, levocabastine, levodopa, leovthyroxine, linezolid, lincomycin, acid lipoic acid, lisinopril, lodoxamide, loperamide, lopinavir, losartan, mebendazole, medroxyprogesterone, mefloquine, megestrol, melarsoprol, mepindolol, mesalazine, mesna, metamizole, methionine, methotrexate, methylprednisolone, metoclopramide, metoprolol, metronidazole, miconazole, minocycline, moexipril, montelukast, moxidectin, nadolol, sodium dibunate, naftifine, sodium picosulfide, natamycin, nateglinide, nelfinavir, neomycin, neviparin, nicardipine, nicergoline, niclosmaide, nicotinic acid, nifedipine, nifuratel, nifurpirinol, nifutimox, nimodipine, nimorazole, nisoldipine, nitrofurantoin , nitroxoline, nystatin, olsalazine, omeprazole, orotic acid, osel tamivir, oxamniquine, oxfendazole, oxybendazole, oxiconazole, oxprenolol, oxybutynin, oxytetracycline, pamidronic acid, pangamic acid, penbutolol, penicillamine, pentamidine, perindopril, phenobarbital, phenoxybenzamine, phenylpropanolamine, pimobendan, piretanide, ponazuril, pravastatin, praziquantel, prednisolone, primaquine, probenecid, progesterone, proglumide, proguanil, proligethone, propentofylline, propiverine, propranolol, pyrantel embonate, pyrazinamide, pyrimethamine, pirvinium embonate, quinapril, ramipril, repaglinide, reviparin, ribarvirin, rifabutin, rifampicin, risedronic acid, roxithromine, saquinavir, selamectin , selegiline, sevelamer, sotalol, spectinomycin, spiramycin, spirapril, stavudine, streptomycin, sulfaclorpiridazine, sulfadiazine, sulfadimethoxine, sulfadimidine, sulfadoxine, sulfalene, sulfamethoxazole, sulfanilamide, sulfasalazine, talinolol, tamsulosin, teicoplanin, telithromycin, telmisartan tenofovir disoproxil, terazosin, terbina fine, tetracycline, tetroxoprim, theophylline, thiabendazole, tiagabine, tiludronic acid, tinidazole, thioconazole, tolterodine, totrazuril, trandolapril, tranexamic acid, tretinoin, triamcinolone acetonide, triclabendazole, trimethoprim, tripelenamine, tromantadine, trospium chloride, tryptophan, ursodeoxycholic acid, valaciclovir, valproic acid, vancomycin, verapamil, vidarabine, vigabatrin, zalcitabine, zidovudine, and zoledronic acid. The aforementioned compounds can also be used in the form of their esters or salts. The hydrates of the compounds are also included according to the invention. It is understood that the pharmaceutically usable salts, for example, are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, maleic acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. In addition, the compounds can also be linked to the acid or basic ion exchangers. The pharmaceutically usable salts that can be mentioned are the alkali metal salts, for example the sodium or potassium salts, alkaline earth metal salts, for example, the magnesium or calcium salts, the zinc salts, the silver salts and the guanidinium salts. It is understood that hydrates are the hydrates of the free compounds themselves and the hydrates of their salts. The active compounds can also be present in the preparations, mixed with synergists or in combination with other active compounds.

Examples Example 1 1.5 g of flupirtine base are dissolved in a mixture composed of 40 g of propylene glycol dicaprylate / dicaprate (Miglyol 840) and 40 g of isopropanol. 3.5 g of the same mixture are used to gauge up to 100 ml. This results in a clear solution having a flupirtine concentration of 1.5% m / v. In each case 4 ml were applied to several sites on the backs of 4 healthy cats (15-20 mg of flupirtine base / kg body weight (BW)). The blood samples were removed after 0, 0.5, 1, 2, 4, 6, 10, 24, 30 and 48 hours and analyzed by HPLC. The following plasma concentrations were obtained: Tajbla 1: Plasma levels of flupirtine after the application of 4 ml of the formulation according to the Example 1 at the back of cats, n = 4, dose, 15-20 mg of flupirtine base / kg body weight Example 2 0.2 g of sodium sulfite are dissolved in 8 g of water; 90 g of propylene glycol are added and 3 g of flupirtine maleate are suspended in the mixture. After the mixture has been adjusted to pH 6 with 2.35 g of 2 N sodium hydroxide solution, the active compound is completely dissolved. The final volume is calibrated up to 100 ml with 1.15 g of water. This results in a clear solution having a flupirtine maleate concentration of 3.0% m / v. In each case a volume, corresponding to a dose of flupirtine maleate of 10 mg / kg body weight, was applied to a site on the backs of 4 healthy cats. Blood samples were taken after 0, 0.5, 1, 2, 3, 4, 6, 10, 24, 30 and 48 hours and analyzed by HPLC. The following plasma concentrations were obtained: Table 2: Plasma levels of flupirtine after the application of a formulation corresponding to Example 2 to the backs of cats, n = 4, dose, 10 mg of flupirtine maleate / kg body weight Example 3 3.0 g of flupirtine maleate were suspended in 92.2 g of medium chain triglycerides (Migliol 812) and dispersed using a rotor-stator homogenizer (Ultra-Turrax). This results in 100 ml of a suspension having a flupirtine maleate concentration of 3.0% m / v. In each case a volume, corresponding to a dose of flupirtine maleate of 10 mg / kg body weight, was applied to a site on the backs of 4 healthy cats. Blood samples were taken after 0, 0.5, 1, 2, 3, 4, 6, 10, 24, 30 and 48 hours and analyzed by HPLC. The following plasma concentrations were obtained: Table 3: Plasma levels of flupirtine after the application of a formulation corresponding to Example 3 to the backs of cats, n = 4, dose, 10 mg of flupirtine maleate / kg body weight The same formulation was applied to the same animals at the same dose, one day after a castration operation. Blood samples were removed after 0, 0.5, 1, 2, 4, 6, 10, 24, 30 and 48 hours and analyzed by HPLC. The following plasma concentrations were obtained: Table 4: Plasma levels of flupirtine after the application of a formulation corresponding to Example 3 on the backs of cats, after a sterilization operation, n = 4, dose, 10 mg of flupirtine maleate / kg of body weight The Figure • 1 summarizes the plasma levels obtained after the application of the examples according to the invention, and compares them with the plasma level obtained after the peroral administration of a tablet (dose, 4 mg of flupirtine maleate / kg body weight ). The pharmacokinetic data are more easily compared by standardization of the different doses at a standard dose of 1 mg of flupirtine base / kg body weight (Figure 2). The plasma concentrations of the active compound that corresponded to those obtained after the peroral administration of a tablet were found in the case of all the examples according to the invention. The delayed grooming behavior that is observed after an operation in this case shifts the tmax markedly from 3-6 hours to 24 hours. The maximum concentrations are also lower due to the delayed intake. In order to ensure post-operative analgesia, the application must take place in a period of time before the operation, which is sufficient for the animal to still be able to take therapeutically relevant quantities. The data shows that, after a formulation containing the active compound has been applied to the hair of a cat, it is almost completely taken orally due to the grooming behavior. In this way, even the active compounds having a bad taste, such as flupirtine, fluoroquinolones or praziquantel, can be perorally administered in a reliable manner.

Figures: Figure 1: Plasma concentration of flupirtine after the application of the preparations containing the active compound to the hairs of cats (n = 4-8). Figure 2: Plasma concentration of flupirtine after the application of the preparations containing the active compound to the hairs of cats (n = 4-8), data normalized to a dose of 1 mg of flupirtine base / kg body weight.

Example 4 3.75 g of ponazuril are suspended in 44.25 g of glycerol and dispersed using a rotor-stator homogenizer. This results in 50 ml of a suspension having a ponazuril concentration of 7.5% m / m.

Example 5 0.75 g of pradofloxacin are suspended in 49.25 g of polyethylene glycol 400 and dispersed using a rotor-stator homogenizer. This results in 50 ml of a suspension having a pradofloxacin concentration of 1.5% m / m.

Example 6 1.25 g of enrofloxacin are suspended in 48.75 g of medium chain triglycerides (Migliol 812) and dispersed using a rotor-stator homogenizer. This results in 50 ml of a suspension having a enrofloxacin concentration of 2.5% m / m. A volume corresponding to a dose of enrofloxacin of approximately 5 mg / kg body weight was applied to a site in the region of the back line between the shoulder blades of each of four healthy cats. At the listed times, blood samples were withdrawn and serum aliquots were analyzed by HPLC. Up to 4 hours after the application, the animals wore a neck collar that was intended to prevent any licking / grooming of the application site. The following serum concentrations of enrofloxacin and the active metabolite ciprofloxacin were obtained: Table 5: Serum concentrations of enrofloxacin after the application of 0. 7-0. 9 ml of the formulation, corresponding to Example 6, on the cat's backs, n = 4, dose, approximately 5 mg of enrof loxacin / kg of body weight, the neck collars were removed at 4 hours after the application Serum Time Concentration enrofloxacin [μg / 1] in animal No: Medium 0.463 .0.464 0.510 0.504 [μg / 1] Before the < LoQ < LoQ < LoQ < LoQ < What application 1 h < LoQ < LoQ < LoQ < LoQ < LoQ Concentration in serum of Time enrofloxacin [μg / 1] in animal No: Medium 0.463 0.464 0.510 0.504 [μg / i] 2 h < LoQ < LoQ < LoQ < LoQ < LoQ 4 h < LoQ < LoQ < LoQ < LoQ < LoQ 5 h 135 97 504 706 361 6 h 94 85 664 733 394 8 h 86 66 483 516 288 10 h • 80 68 433 419 250 14 h 126 - 303 327 252 28 h 36 30 63 90 55 34 h < LoQ < LoQ 28 40 < LoQ 52 h < LoQ < LoQ < LoQ < LoQ < LoQ Table 6: Serum concentrations of ciprofloxacin after the application of 0. 7-0. 9 ml of the formulation, corresponding to Example 6, on the cat's backs, n = 4, dose, approximately 5 mg of enrof loxacin / kg of body weight, the neck collars were removed at 4 hours after the application Serum Time Concentration enrofloxacin [μg / 1] in animal No: Medium 0.463 0.464 0.510 0.504 [μg / i] Before the < LoQ < LoQ < LoQ < LoQ < What application 1 h < LoQ < LoQ < LoQ < LoQ < LoQ 2 h < LoQ < LoQ < LoQ < LoQ < LoQ Serof Time Concentration of enrofloxacin [μg / 1] in animal No: Medium 0.463 0.464 0.510 0.504 [μg / i] 4 h < LoQ < LoQ < LoQ < LoQ < LoQ 5 h < LoQ < LoQ 57 64 37 6 h < LoQ < LoQ 79 81 46 8 h < LoQ < LoQ 71 70 42 10 h < oQ < LoQ 83 70 45 14 h < LoQ - 82 73 56 28 h < LoQ < LoQ 28 34 < LoQ 34 h < LoQ < LoQ < LoQ < LoQ < LoQ 52 h < LoQ < LoQ 0 < LoQ < LoQ < LoQ The data shows that, after a formulation containing the active compound has been applied to the hair of cats, the substance is taken orally as a result of the grooming behavior; no percutaneous uptake was observed.

Example 7 7.5 g of toltrazuril were suspended in 92.5 g of paraffin subliquidum and dispersed using a rotor-stator homogenizer. This results in 100 ml of a suspension having a toltrazuril concentration of 7.5% m / m EXAMPLE 8 4.0 g of toltrazuril are suspended in 96 g of sesame oil and dispersed using a rotor-stator homogenizer. This results in 100 ml of a suspension having a toltrazuril concentration of 4% m / m. A volume corresponding to a dose of enrofloxacin of about 5 mg / kg body weight was applied to a site in the region of the line of the back between the shoulder blades of each of four healthy cats. At the listed times, blood samples were withdrawn and serum aliquots were analyzed by HPLC. Up to 4 hours after the application, the animals wore a neck collar that was intended to prevent any licking / grooming of the application site. The following serum concentrations of toltrazuril and the active metabolite toltrazuril-sulfone were obtained: Table 7: Toltrazuril serum concentrations after the application of 0. 6-0. 7 ml of the formulation corresponding to Example 8 on the backs of cats, n = 4, dose, approximately 15 mg toltrazuril / kg body weight; neck collars removed at 4 hours after application Serum Time Concentration enrofloxacin [μg / 1] in animal No: Medium 0472 D 0470 D 0.493 D 0.494 D [μg / i] Before the < LoQ < LoQ < LoQ < LoQ < What application 1 h 42 < LoQ < LoQ < LoQ < LoQ 2 h 142 < LoQ < LoQ < LoQ 45 4 h 214 188 < LoQ < LoQ 107 h 417 397 319 358 373 6 h * 617 1006 1063 895 8 h 383 539 1134 1579 909 h 539 617 - 1171 1590 979 14 h 684 918 1074 1623 1075 28 h 2035 1204 1763 5335 2584 34 h 1442 898 1369 3980 1922 52 h 1717 893 1906 2853 1842 Table 8: Serum concentrations of toltrazuril sulfone after the application of 0. 6-0. 7 ml of the formulation corresponding to Example 8 on the backs of cats, n = 4, dose, approximately 15 mg toltrazuril / kg body weight; neck collars removed at 4 hours after application The data shows that, after a formulation containing the active compound has been applied to the hair of cats, the substance is taken orally as a result of the grooming behavior; no percutaneous uptake was observed. The serum levels that were measured before the collar was removed, most likely result from a lower oral uptake due to the licking of the inner side of the neck collar that has been in contact with the application site.

A volume of each, corresponding to a toltrazuril dose of 8 mg / kg body weight, was applied to a site in the flank region of 4 healthy rabbits. At the times listed, blood samples were withdrawn and serum aliquots were analyzed by HPLC. Up to 4 hours after the application, the animals were fixed in a restriction device that prevented any licking of the application site. The following serum concentrations of toltrazuril and the active metabolite toltrazuril-sulfone were obtained: Table 9: Serum concentrations of toltrazuril after application of 1 ml of the formulation corresponding to Example 8, to the flanks of rabbits, n = 4, dose, 10. 7-11.2 mg toltrazuril / kg body weight; the animals were fixed up to 4 hours after the application Serum Time Concentration enroflox.icina [μg /. .] in the animal No: Medium 2564 2589 2548 2562 [μg / i] Before the < LoQ < LoQ < LoQ < LoQ < What application 1 h < LoQ < LoQ 103 < LoQ 35 2 h < LoQ < LoQ 104 < LoQ 35 4 h < LoQ < LoQ 100 < LoQ 34 5 h < LoQ < LoQ 452 25 126 6 h 56 47 856 91 263 Serum Time Concentration enrofloxacin [μg / 1] in animal No: Medium 2564 2589 2548 2562 [μg / i] 8 h 232 245 2143 949 892 10 h 484 897 3018 1486 1471 14 h 1329 1409 3735 1717 2048 28 h 2992 2548 4692 3035 3317 34 h 4112 2955 4420 2767 3564 52 h 3843 3014 4245 4308 3853 Table 10: Serum concentrations of toltrazuril sulfone after application of 1 ml of the formulation corresponding to Example 8, to the flanks of rabbits, n = 4, dose, 10. 7-11.2 mg toltrazuril / kg body weight; the animals were fixed up to 4 hours after the application Concentration in serum with the Time enrofloxcicina [μg /; .] in ailimal No: Medium 2564 2589 2548 2562 [μg / i] Before the < LoQ < LoQ < LoQ < LoQ < What application 1 h < LoQ < LoQ 30 < LoQ 35 2 h < L? Q < LoQ 31 < LoQ 35 4 h < LoQ < LoQ 31 < LoQ 34 5 h < L? Q < LoQ 32 < LoQ 126 6 h < LoQ < LoQ 31 < LoQ 263 Serum Time Concentration enrofloxacin [μg / 1] in animal No: Medium 2564 2589 2548 2562 [μg / i] 8 h < LoQ < LoQ 41 < LoQ 892 10 h < LoQ < LoQ 64 < LoQ 1471 '-: 14 h 30 26 155 25 2048 28 h 251 223 554 198 3317 34 h 491- • 391 747 245 3564 52 h 1240 780 1349 709 3853 The data shows that, after a formulation containing the active compound has been applied to the hair of rabbits, the substance is collected orally as a result of the grooming behavior; no percutaneous uptake was observed.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical preparation for use in animals, characterized in that it is applied to the hair or skin of the animal and which subsequently takes it orally.

2. The pharmaceutical preparation according to claim 1, characterized in that it is intended for use in cats.

3. The pharmaceutical preparation according to claim 1 or 2, characterized in that it shows a liquid consistency.

4. The pharmaceutical preparation according to any of the preceding claims, characterized in that it comprises flupirtine or its salts.

5. The pharmaceutical preparation according to any of claims 1 to 3, characterized in that it comprises enrofloxacin or its salts.

6. The pharmaceutical preparation according to any of claims 1 to 3, characterized in that it comprises pradofloxacin or its salts.

7. The pharmaceutical preparation according to any of claims 1 to 3, characterized in that it comprises toltrazuril or its salts.

8. The pharmaceutical preparation according to any of claims 1 to 3, characterized in that it comprises ponazuril or its salts.

9. The use of orally effective pharmaceutical active compounds - to produce pharmaceutical preparations according to claim 1.

10. A method for the application of pharmaceutical active compounds in animals, characterized in that the pharmaceutical preparation comprising the corresponding active compound , it is applied topically to the animal and the animal then orally captures the pharmaceutical product that has been applied in this way.