WO2004047795A2 - Cutaneous application of flupirtine - Google Patents

Abstract

The invention relates to a medicament for cutaneously applying flupirtine or its salts.

Description

Dermal application of flupirtine

The invention relates to a system for dermal application of flupirtine and its salts to humans and animals.

Flupirtin (CAS name 2-Amino-6 - [[(4-fluorophenyl) methyl] amino] -3-pyridinyl] - carbamic acid ethyl ester) is a centrally effective, moderately potent analgesic which is used in human medicine in the form of capsules and suppositories and an injection solution is used. Its representation and application is described in US 3,513,171 and

US 4,481,205 (flupirtine maleate). The usual dosage is 4 - 8 mg / day and kg body weight (body weight) for oral, 6 - 12 mg / day and kg body weight for rectal and 1.5 mg / kg body weight for parenteral administration. The dosage in veterinary medicine differs depending on the species. The therapeutic efficacy after dermal application has not yet been described.

The dermal application of active pharmaceutical ingredients has been in medicine for a long time _. Time known. While it was initially only used for substances that should have a local effectiveness on the skin or on skin appendages (sweat glands, sebaceous glands, hair), systemically active ingredients have been increasingly supplied via the skin in recent years. Due to the generally poor skin permeation of many active ingredients, dermal application is often limited to substances that are effective even in low doses (<1 mg / kg body weight). So far, the highly effective substances buprenorphine (Transtec ^® ), estradiol (Estraderm ^® TTS,

Dermestril ^® among others), fentanyl (Durogesic ^® ), levonorgestrel (Fem7 ^® Combi), nicotine (Nicotinell ^® among others), norethisterone acetate (Estracomb ^® among others), scopolamine (Scopoderm ^® TTS) and testosterone (Androderm ^® ) administered as transdermal patches. Good Permeationsseigenschaften also have substances with low molecular weight, such as nitroglycerin (Nitroderm ^® TTS, Deponit ^® NT etc.) or pronounced lipophilicity. An increase in the pavement area and thus less applicability Effective substances in humans are not readily possible for cosmetic reasons.

In veterinary medicine, the dermal application of systemic active substances is easier because one is not bound to the limited area of a plaster, but in principle the entire body surface is available for application when a suitable formulation is given. However, systemic active ingredients can only be used here if they are effective in low doses or if they permeate the skin very well. In addition, they should be ecotoxicologically safe. Examples of highly effective and at the same time lipophilic drugs are the endoparasiticidal avermectins, such as ivermectin (Ivomec ^® ), Doramectin (Dectomax ^® ), Eprinomectin (Eprinex ^® ) and Selamectin (Stronghold ^® ) and the structurally related moxidectin (Cydectin ^® ). Praziquantel (Droncit ^® ) due to its pronounced lipophilicity and Levamisol (Citarin ^® ) due to its low molecular weight (MG 204) are also easy to get through in cats. Therefore, the dermal application of systemic drugs in both human and veterinary medicine has so far been largely limited to highly effective, lipophilic substances or those with a small molecular size.

Dermal application of an active pharmaceutical ingredient has numerous advantages over oral or parenteral administration: it is very easy and painless to use and can also be used if you have difficulty swallowing (e.g. after surgery). The slow flooding in the body prevents side effects caused by concentration peaks. Since an active ingredient depot forms in the skin, in the skin appendages or in the formulation itself, this has to be done

Medicines are administered less frequently. It can be used on animals without any restrictions, which significantly increases application safety.

Dermal application is particularly desirable in the case of chronic pain conditions, since therapy has to be carried out for a very long time. Flupirtin and its salts are particularly well suited for the treatment of chronic musculoskeletal pain due to their additional muscle-relaxing effects. The substance, however, is neither effective in low doses, nor is it pronouncedly lipophilic. Their molecular weight of 304.3 does not suggest a good skin penneation either.

Surprisingly, it has now been found that flupirtine and its salts, in a suitable formulation, have an extraordinarily high permeation rate through dog and cat skin.

The invention relates to a preparation of flupirtine or its salts, which is intended for dermal application.

The invention relates to:

A drug containing

(a) Flupirtin or, one of its salts and

(b) a carrier suitable for dermal application.

The medicine can be liquid, semi-solid or solid. It can also be in the form of a patch. It is possible to achieve sufficient systemic active ingredient levels with medicaments according to the invention for an effect. According to a preferred Ausföhiungsfoπri, the invention therefore relates to drugs for dermal systemic application of flupirtine and its salts.

The medicament according to the invention usually contains the flupirtine or its salt in an amount of 0.1-25% m / V, preferably 0.5-10% m / N (for example, 1 g of flupirtine or flupirtine salt corresponds to a content of 1 per 100 ml of medicament % m / V). All pharmaceutically acceptable salts are suitable as salts, flupirtine maleate being mentioned as a preferred example.

The flupirtine or its salt is present in the carrier in dissolved or suspended form.

Suitable carriers are, for example, 2-pyrrolidone, N-methylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, monohydric alcohols (for example short-chain alkanols with 1 to 5 carbon atoms such as ethanol, isopropanol and solketal, glycerol formal, tetrahydrofuryl alcohol, benzyl alcohol, octyldodecanol, 2-hexyldodecanol, polyhydric alcohols (e.g. glycerol, propylene glycol, polyethylene glycol), ethers (e.g. glycofurol, dicaprylyl ether), glycol ethers (e.g. diethylene glycol monoethyl ether, propylene glycol monomethyl ether), ketones (e.g. acetone, ethyl methyl ketone), esters (e.g. dibutyl adipate, propylene carbonate, diethyl hexylene) - Glycerides, triglycerides (e.g. medium-chain triglycerides, vegetable oils), fatty acid esters (e.g. propylene glycol dicaprylate / dicaprate, ethyl oleate, isopropyl palmitate, isopropyl myristate, polyoxyethylene glycol fatty acid esters), waxes (e.g. oleyl oleate, 2-octyldodyloethylolate, octyldateyloethyl, cetylateoateolate, cetylateoateolate, cetylateoateolate, octylateatolate, cetylate, cetylate, cetylate, cetylate, Octyl palmitate), hydrocarbons (e.g. Paraffins), silicone oils, dimethicone and water or mixtures of the substances mentioned.

Other carriers are possible, even if they are not mentioned here. The carriers mentioned can also serve at the same time as additives to improve the spread.

The medicament according to the invention usually contains at least 40% w / v, preferably at least 75% w / v on carrier.

Preferred carrier systems are mixtures of medium chain triglycerides or medium-propylene glycol fatty acid ester (as in various grades. E.g., under the trade name Miglyol ^® are available) and monohydric alcohols, particularly alkanols having from 1 to 5 carbon atoms. In these carrier systems the two mixture components are usually present in a ratio of 1: 9 to 9: 1, preferably 2: 8 to 8: 2.

The active ingredient can be applied to the skin in liquid, semi-solid or solid form. Liquid preparations are, for example, solutions, suspensions and

Emulsions. Semi-solid preparations are e.g. Gels, creams, ointments and pastes, solid preparations e.g. Powder.

The active ingredient can also be applied in the form of a patch. Here, for example, it is dissolved or suspended in a suitable carrier, filled into a reservoir and this is fixed on the skin with the aid of an adhesive layer. The reservoir can consist of a plastic bag, for example of polyethylene, polyethylene vinyl acetate or polyurethane. However, it is also possible to dissolve or suspend the active ingredient directly in an adhesive-containing matrix and to attach it to the skin with a carrier film. This matrix can next to the

Active ingredient and the adhesive also contain other auxiliaries, such as penetration-improving or solubility-improving additives, antioxidants, additives modifying the adhesive property or crystallization inhibitors. Active substances and adhesives can also be separated from one another in the form of a two-layer or multilayer matrix patch. Polyacrylates, polymethacrylates,

Polymethyl methacrylates, silicones or polyolefins (e.g. polyisobutylene) can be used.

Application to animals is preferred, especially to dogs or cats, application to cats being particularly advantageous. The is particularly suitable for this

Application of liquid formulations, e.g. as a spot-on, pour-on or spray.

The pharmaceutical forms mentioned are applied to the fur or skin of the animal.

While only a few milliliters are applied in spots with a spot-on, with a pour-on usually several milliliters are distributed on the fur. A spray brings the liquid containing the active ingredient to the skin or fur in finely divided form. In all In some cases, the preparation can spread over the surface of the skin after application and the active ingredient can enter the body through the skin.

The dermal application of flupirtine is much easier to administer than peroral or parenteral. The formation of a skin depot causes longer lasting

Blood level, which enables a lower application frequency. In addition, the slowly rising blood levels can prevent undesirable side effects. The central vomiting caused by high flupirtine concentrations is particularly worth mentioning here.

Depending on the type of formulation, the medicaments according to the invention can contain further customary, pharmaceutically acceptable additives and auxiliaries. Examples include:

Penetration accelerators such as fatty acids (e.g. oleic acid, linoleic acid),

Fatty acid esters (e.g. isopropyl myristate, ethyl oleate), fatty alcohol esters (e.g. octyldodecanol), ethers (e.g. diethylene glycol monoethyl ether (Transcutol ^® )), terpenes (limonene, .. eucalyptoi), laurocapram (Azqne ^® ), dimethyl sulfoxide. They can be contained in a concentration of 0.1 to 50% m / V, preferably 1-10% m / N.

Preservatives such as carboxylic acids (sorbic acid, benzoic acid, lactic acid), phenols (cresols, p-hydroxybenzoic acid esters such as methylparaben, propylparaben etc.), aliphatic alcohols (benzyl alcohol, butanol etc.), quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride)

Antioxidants such as, for example, sulfites (Na sulfite, Na metabisulfite), organic sulfides (cystine, cysteine, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols (tocopherols, butylhydroxyanisole, butyl-hydroxy-toluene, octylgallat and dodec) , organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid) and their salts and esters Wetting agents such as, for example, fatty acid salts, fatty alkyl sulfates, fatty alkyl sulfonates, linear alkylbenzenesulfonates, fatty alkyl polyethylene glycol ether sulfates, fatty alkyl polyethylene glycol ethers, alkylphenol polyethylene glycol ethers, alkyl polyglycosides, fatty acid N-methylglucamides, polysorbates, sorbitan fatty acid esters.

Crystallization inhibitors such as cellulose ethers (e.g. methyl cellulose, hydroxyethyl cellulose, Na-carboxymethyl cellulose, hydroxypropyl cellulose, methyl hydroxypropyl cellulose, ethyl cellulose), polyvinyl pyrrolidone, sugar (e.g. glucose, sucrose, fructose), sugar alcohols (e.g. sorbitol, mannitol, xylitol), polyethylene

Additives that increase the viscosity, such as cellulose ethers, polyacrylates, polymethacrylates, polymethane methacrylates, polysaccharides (e.g. xanthan, guar, gum arabic, tragacanth), highly disperse silicon dioxide, aluminum stearate

Pharmaceutically acceptable dyes such as iron oxides, carotenoids, etc.

The pharmaceuticals according to the invention can be produced by dissolving or suspending the active ingredient and, if appropriate, further auxiliaries in the carrier.

The illustrations show the following:

Figure 1: In vitro permeation of flupirtine from saturated solutions through dog skin, Franz diffusion cell, diffusion area 1, 77 cm ² .

Figure 2: In vitro permeation of flupirtine from saturated solutions through cat skin, Franz diffusion cell, diffusion area 1, 77 cm ²

Figure 3: Plasma level of flupirtine after application of 4 ml of a 1.5% solution of flupirtine base in Miglyol 840 / isopropanol (1: 1)

Cats, n = 4 Examples

Preparation of the formulations:

example 1

6.42 g flupirtine base were homogeneously suspended in 1000 ml of medium-chain triglycerides (Miglyol ^® 812). The determination of the in vitro permeation through dog skin is described below in the biological example.

Example 2

6.31 g of flupirtine maleate were homogeneously suspended in 1000 ml of medium-chain triglycerides (Miglyol 812). The determination of the in vitro permeation through dog skin is described below in the biological example.

Example 3

42.1 g flupirtine base were dissolved in 1000 ml of a mixture of Propylenglykoldicapry- lat / dicaprate (Miglyol ^® 840, 50% m / m) and isopropanol (50% m / m) homogeneously suspended. The determination of the in vitro permeation through dog and cat skin is described below in the biological example.

Example 4

25.1 g flupirtine maleate were dissolved in 1000 ml of a mixture containing one part propylene glykoldicaprylat / dicaprate (Miglyol ^® 840) and a portion isopropanol homogeneously suspended. The determination of the in vitro permeation through dog and cat skin is described below in the biological example. Example 5

25.0 g flupirtine maleate were dissolved in 1000 ml of a mixture of Propylenglykoldi- caprylate / dicaprate (Miglyol ^® 840, 47.5% m / m), isopropanol (47.5% m / m) and oleic acid (5% m / m) suspended. Determination of in vitro permeation by

Dog skin is described below in the biological example.

Example 6

25.0 g of flupirtine maleate were dissolved in 1000 ml of a mixture of propylene glycol dicylate / dicaprate (Miglyol ^® 840, 47.5% m / m), isopropanol (47.5% m / m) and limonene (5% m / m) suspended. The determination of the in vitro permeation through dog skin is described below in the biological example.

Example 7

25.1 g of flupirtine maleate were dissolved in 1000 ml of a mixture of propylene glycol dicaprylate dicapraf (Miglyol ^® 840, 47 _J 5% _. M / m), _^ isopropanol (47.5% m / m) and laurocapram (Azone ^® , 5% m / m m) suspended. The determination of the in vitro permeation through dog skin is described below in the biological example.

Example 8

25.2 g of flupirtine maleate were dissolved in 1000 ml of a mixture of propylene glycol dicylate / dicaprate (Miglyol ^® 840, 47.5% m / m), isopropanol (47.5% m / m) and diethylene glycol monoethyl ether (Transcutol ^® , 5% m / m) suspended. The determination of the in vitro permeation through dog skin is described below in the biological example. Example 9

0.75 g of flupirtine base were dissolved in about 40 g of a mixture of Propylenglykoldicapry- lat / dicaprate (Miglyol ^® 840, 50% m / m) and isopropanol (50% m / m) dissolved. The mixture was made up to 50 ml with the solvent mixture in the volumetric flask and filled into 4 ml HDPE pipettes (1.5% m / N flupirtine base).

Example 10

0.2 g of Νa sulfite are dissolved in 9.15 g of water. 90.0 g propylene glycol and 3.0 g

Flupirtin maleate are added. After adjusting the solution to pH 6 with 2.35 g of 2N NaOH solution, the active ingredient (3.0% m / V flupirtine maleate) is dissolved.

Example 11

3.0 g of flupirtine maleate are suspended in 92.2 g of medium-chain triglycerides (for example Miglyol ^® 812) and homogenized with a rotor stator (for example Ultra-Turrax) (3.0% -m / N fiupirtine maleate).

Biological examples:

1. In vitro permeation of flupirtine through dog and cat skin

3 ml of the suspension were applied to a 1.77 cm ² piece of dog or cat skin clamped in a Franz diffusion cell. The acceptor compartment was mixed with 40 ml of a mixture of phosphate buffer pH 7.4 (Ph.Eur.) (59.9% m / m) + propylene glycol (40% m / m) + sodium azide (0.1% m / m) filled. The permeation of flupirtine through the skin was determined after 6, 24, 48 and 72 hours by measuring the active substance concentration in the acceptor solution by HPLC The measured in vitro permeation of Examples 1-8 through dog and cat skin is shown in Figure 1, Figure 2 and Table 1.

Figure 1 shows the ner run of in vitro permeation through dog skin after application of saturated solutions, Figure 2 shows the ner run of in vitro permeation through cat skin after application of saturated solutions.

Table 1 shows the amount of active ingredient permeating in steady-state (48 - 72 h) per time and area (flux).

Table 1: Amount of flupirtine which permeates through dog and cat skin in steady-state (48-72 h) per time and area in vitro

nb: not determined 2. In vivo permeation

The bioavailability of the preparation according to Examples 9-11 was checked on 4 cats each. The contents of a pipette (Example 9) or an amount corresponding to 10 mg / kg body weight of active ingredient (Examples 10 and 11) were distributed evenly along the back line. Blood samples were taken after 0 - 0.5 - 1 - 2 - 4 - 6 - 10 - 24 - 30 and 48 h and examined for the concentration of flupirtine. The determined blood level curve of the active ingredient is shown in Figure 3.

The high in vitro permeation rates were confirmed in the pharmacokinetic studies in cats (Figure 3). Since the analgesic effect of flupirtine is detectable at blood levels of 500 μg / 1 and higher, the plasma levels measured here suggest a strong and long-lasting therapeutic effect.

Claims

Patentansprflche 1. Medicament for dermal application, containing (a) Flupirtine or one of its salts (b) a carrier suitable for dermal application wherein flupirtine or its salt is dissolved or homogeneously suspended in the carrier. 2. Medicament according to claim 1, which contains flupirtine or one of its salts in a concentration of 0.1 to 25% m / N. 3. Medicament according to claim 1, which contains a triglyceride or a mono- or polyhydric alcohol as carrier. 4. Medicament according to claim 1, which contains as carrier a mixture of a triglyceride with a mono- or polyhydric alcohol. 5. Medicament according to claim 1, which contains as a carrier a mixture of medium-chain triglycerides or medium-chain propylene glycol fatty acid esters and monohydric alcohols in a ratio of 9: 1 to 1: 9. 6. Medicament according to claim 3, which contains an alkanol having 1 to 5 carbon atoms as monohydric alcohol. 7. Use of flupirtine for the manufacture of drugs for dermal, systemic application. 8. Use according to spoke 5 for the manufacture of medicaments for dermal, systemic application in animals. 9. Use according to spoke 5 for the manufacture of medicaments for dermal, systemic application in mammals. 10. Use according to spoke 5 for the manufacture of medicaments for dermal, systemic application in dogs or cats.