CZ300495A3 - Pharmaceutical preparation for prophylactic and/or healing tranasdermal application of cholinesterase re-activators - Google Patents

Abstract

This invention involves a pharmaceutical product for prophylactic and therapeutic transdermal application of cholinesterase reactivators containing a substance and/or a mixture of substances selected from the group which includes 1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane, pralidoxime, methoxime, obidoxim, trimedoxime or a mixture of at least one of these cholinesterase reactivators with at least one cholinolytic substance selected from the group which includes atropine, homatropine, scopolamine, benactyzine, biperiden. The pharmaceutical product according to this invention consists of an impermeable covering foil the periphery of which is equipped with an adhesive layer limiting the application area, and of an ointment, cream, foam or hydrogel containing cholinesterase reactivators or possibly cholinolytic substances, or it consists of an impermeable foil equipped with an adhesive layer used to fix the product to the skin while an anchoring water-free hydrophilic matrix with an incorporated substance or mixture of substances from the group of cholinesterase reactivators, possibly mixed with a cholinolytic substance, and a removable protective foil, after the removal of which the matrix is impregnated with a solvent and the product is attached to the skin, or it consists of a carrier foil equipped with an adhesive layer used to fix the product to the skin and an anchoring water-free hydrophilic matrix with a removable antiadhesive foil after the removal of which the matrix can be impregnated with a solution of cholinesterase reactivators that may be mixed with a cholinolytic substance and the product can be attached to the skin.

Description

Technical Field (J <5 [

The present invention relates to a pharmaceutical composition for the prophylactic treatment of transdermal administration of cholinesterase reactivators or cholinesterase reactivators in combination with cholinolytics and / or other drugs which, for at least 8 hours after administration, allow continuous drug delivery to systemic body circulation for effective prophylaxis or subsequent treatment with cholinesterase inhibitors solving the problems associated with the short half-life of cholinesterase reactivators, the relatively low bioavailability from the gastrointestinal tract following oral administration of these substances, and their poor chemical stability.

BACKGROUND OF THE INVENTION

Prophylactic administration of cholinesterase reactivators is well-founded in situations involving an increased risk of poisoning by substances that produce a cholinomimetic effect by inhibiting cholinesterases (acetylcholinesterase, butyrylcholinesterase, or possibly other hydrolase).

Cholinesterase inhibitors can be divided into non-acylating and acylating inhibitors (Melichar, B. et al., Chemical Drugs. 3rd ed. Avicenum / SNZL, Prague 1987. p. 290). The molecular mechanism of action of acylating inhibitors is the acylation of serine hydroxyl at the esterase center of cholinesterases. Depending on the acid involved in the acylation, the individual groups of inhibitors and their effect can be distinguished.

Known non-acylating and also therapeutically used carbamate inhibitors of cholinesterases include, for example, salostlanine physostigmine, neostigmine bromide or pyridostigmine bromide.

Acylating inhibitors include those for which the term organophosphorus inhibitors (OFI) has been known. For the most part, these are esters of phosphoric or thiophosphoric, phosphonic and thiophosphonic acids. Substituted amides of these acids are less common. The remaining hydroxyls in their molecule are variously substituted.

OFIs are widely used in agriculture to protect plants as an insecticide, to disinfect stables, to lavage farm animals infected with ectoparasites, but also as medicines in human and veterinary medicine. In addition, some OFIs serve as biochemical and pharmacological standards. Some are also used in industry.

Given that the OFI group includes substances with contrastingly different toxicity, there is a potential attempt to limit the risks associated with the occurrence of professional, accidental or suicidal poisoning. These risks are also significantly extended to the potential misuse of OFIs with extremely escalated toxicity (called nerve agents) in the context of war conflicts and terrorist acts. These include, for example, isopropyl fluorine (methyl) phosphonate (sarin), ethyl (dimethylamido) cyanophosphate (tabun), 1- (1,2,2-trimethyl) propyl fluorine (methyl) phosphonate (soman), and phosphonylated thiocholines ( V-substances).

The risk of poisoning with cholinesterase inhibitors can be medically managed using several principles (Melichar, B., et al., Chemical Drugs. 3rd ed. Avicenum / SNZL, Prague 1987. p. 295):

1) reducing the amount of locally accumulated acetylcholine by inhibiting its synthesis

2) preventive protection of receptors against access of acetylcholine with cholinolytics

3) protection of cholinesterase from irreversible inhibition by the use of reversible cholinesterase inhibitors

4) the interaction of the inhibited cholinesterase with a reactivator

In practice, cholinolytics (principle 2), such as atropine, benactyzine and buscopan (in the form of various salts such as sulfates, halides, acetates, nitrates, citrates, methanesulfonates), which react with β- anionic site of cholinesterases and competitively exert their protective or displacement mechanism.

However, the best results so far have been provided by the practical application of Principle 4, which has brought a number of causal cholinesterase reactivators to this area. These substances are well known and their pharmacological properties are described in detail (Bajgar, J., Patočka, J .: In: Extremely Toxic Low Molecular Poisons. Collection of Scientific Papers VLVDÚ, Vol. 79, VLVDÚ, Hradec Králové 1979. p. 61; Hero , V., et al. Toxicology of chemical warfare agents and medical-chemical protection.

1 part. VLVDÚ textbooks. St. 189., VLVDÚ, Hradec Králové 1993. 237 pp.). These include hydroxamic acids (e.g., N-methyl-nicotinhydroxamic acid), monoquartemic pyridinaldoximes, i.e. pralidoximes (e.g., 2-hydroxyiminomethyl-1-methylpyridinium iodide, 2-PAM, optionally water-soluble hydrochloride), and abiscvartemia pyridinaldoximes (e.g., 1,3-) bis (4-hydroxyiminomethylpyridinium) propane chloride, TMB-4), or HLO-7- (2,4-bishydroxyiminomethylpyridinium) -3 (4-carbamoylpyridinium) -2-oxapropane dichloride or dimethanesulfonate

So far, the most effective antidote, which is effective not only in the treatment of poisoning with sarin, tabun, VX-substance, but also with soman, which causes the worst treatable intoxication, is the bisquartine pyridinaldoxime substance, namely 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride, optionally in the form of dimethanesulfonate and other salts (bromide, acetate, etc.) known under the designation HI-6 (Hagedom, I., Gundell, WH, Hoose, J., Jenter, C., Arzneim. Forsch., 1976, 26, 2055; Rousseaux, CG, Dua, AK, Can. J. Physiol. Pharmacol., 67, 1989, p. 1183).

For the administration of cholinesterase reactivators as antidotes for OFI poisoning, medical treatments primarily used for the intramuscular or slow intravenous administration of these substances, mainly in combination with cholinolytics, are used in the treatment. For use in the military field, injectable preparations are designed as specially designed, compact autoinjectors (automatic syringes) for intramuscular administration. For a poorly stable HI-6 reactivator, a special auto-injector has been constructed in which HI-6 is placed in a separate compartment in a lyophilized or micronized form separately from the liquid hydrophilic injection vehicle. In this way, the low stability of HI-6 is solved. However, injections of these antidotes cannot be considered prophylactically usable due to their complexity and generally low compliance. Preventive administration of cholinesterase reactivators has been shown to be essential for the prognosis of subsequent OFI poisoning therapy (Vachek, J., et al., In: Proceedings of VLA JEP. Vol. 116. VLA JEP, Hradec Králové, 1993. p. 67). ).

Oral administration of cholinesterase reactivators, due to the low bioavailability of these substances from the gastrointestinal tract (11.38 ± 3.37%) and the short half-life (Tl / 2 <60 min), has not been successfully resolved (Baggot, JD, et al. (Biophannaceutics & Drug Disposition, 14, 1993, p. 93). Only oral preparations containing cholinolytics or a reversible cholinesterase inhibitor are available, but these are only partial solutions to the problem of OFI poisoning.

It has now been found that the most effective of cholinesterase reactivators can be unexpectedly well used for the manufacture of a pharmaceutical composition for the prophylactic and therapeutic transdermal application of cholinesterase reactivators, either as individual cholinesterase reactivators alone or in admixture or as a mixture of at least one choliesterase reactivators with at least one of a group of synergistic cholinolytics. It has been shown that by using the pharmaceutical composition according to the invention a sufficiently high rate of penetration of cholinesterase reactivators through the skin and sufficiently high blood levels of these substances in various species of experimental animals can be achieved, which has not been published by anyone.

Transdermal application (TDA) of substances for systemic therapy, prevention or alleviation of diseases is currently well accepted. Transdermal preparations (TDPs) have been and are being developed to provide, with the possibility of self-administration by the patient, the continuous administration of therapeutically active agents to the systemic body circulation (Michaels, AS, Chandrasekaran, SK, Shaw, J. E, Amer. Inst. Chem. Eng. Heilmann, K .. In: Therapeutic Systems Pattem-Specific Drug Delivery: Concept and Development, Thieme, Stuttgart 1978, p. 52; Chien, YW, Drug Dev. Ind. Pharm., 9, 1983, 449). Its advantages can be defined as follows (Barry, B.W., Dermatological Formulations. Percutaneous Absorption. Marcel Dekker, New York, Basel, 1982. p. 181): easy application with the ability to move the patient freely; the absorption of the active substance is not primarily influenced by the patient's daily regimen (amount and composition of the food, the intervals of its intake and a number of other common activities); first pass liver effect is bypassed; substances with a low therapeutic index are not at risk of adverse side effects of the drug associated with an initial peak in its central body compartment shortly after administration; the risk of overdose is minimized; if necessary, the application can be interrupted easily and quickly.

The disadvantages of TDP include (Boddé, HE, et al., CRC Drug Carrier Systems 6, 1989, p. 87): the possibility of adverse skin reactions as a direct result of physical effects at the application site (occlusion, friction, pressure) or chemical stimuli local and systemic irritant and allergic reactions. The disadvantages based in principle on the natural barrier properties of the skin include the limited molecular weight, the delayed onset of systemic erothermic effect and the relatively limited amount of substances applicable in this way.

In view of the above-mentioned advantages of TDA therapeutics, considerable research attention has been devoted to this application method over the past approximately twenty years, which has led to the practical extension of the therapeutic palette to a number of therapeutically and commercially successful pharmaceutical formulations. Considering its limits, TDA is considered highly promising (Guy, R., J. Contr. Rel., 4, 1987, p. 237; Knepp, VM, Hadgraft, I, Guy, RH, CRC Crit. Rev. Ther. Drug Carrier Syst., 4, 1987, p. 13; Chien, YW, Drug Dev. Ind. Pharm., 20, 1994, p. 417).

Said TDPs are realized in different embodiments in terms of composition and technology of production, they also differ in different mechanisms of drug release. At present, TDP can be divided into the following four groups (Cleary, G. W .: Transdermal Controlled Release Systems. In: Langer, R. S. Wise, D. L. .: Medical Applications of Controlled Release. Vol. 1. CRC Press, Boča Raton 1984. p. 203):

A. Semi-solid preparations of ointment, cream or gel type. They are applied by spreading on the skin (sometimes followed by occlusive dressing). Defining the absorption area and defining the kinetics of the passage of such applied substances through the skin are very problematic in these TDPs. In general, the release parameters of therapeutically active agents from formulations of this type can be solved by optimizing the polarity and adjusting the viscosity of the vehicle.

B. Peripherally adhesive matrix formulations in which the substance is dispersed in a hydrophilic or lipophilic polymer matrix of the shape of a disc of defined dimensions (thickness, area). The disc containing the therapeutically active agent is disposed on an impermeable occlusive carrier membrane. The fixation of the preparation at the site of application is realized by an adhesive layer applied on the upper carrier membrane, so that at the same time it anchors the matrix containing the active substance and in the form of a ring around this matrix adheres to the skin.

C. Preparations with a liquid reservoir and a modulating membrane, the liquid reservoir compartment of which is encapsulated with a carrier film impermeable to the therapeutically active substance and a non-porous or microporous membrane which serves to limit the liberation of the active substance by stabilizing partition equilibrium or by appropriately selected porosity of the membrane . Contact of the modulating membrane to the skin is provided by a polymer which is selected so as not to have a significant effect on the release of the active substance.

D. Elastic laminated formulations employing in principle at least two layered surfaces, one of which is a carrier and the other has a controlling function in the release of the active ingredient from the pharmaceutical formulation and, in a simpler case, provides the necessary adhesion. However, multilayer laminated formulations are more common.

Until now, an optimal TDP is considered to be a formulation that, while meeting conventional requirements, permits the long-term administration of therapeutically active agents to the systemic systemic circulation at a rate determined only by a constant release rate of the active agent from the formulation optimally by zero order kinetics. The available literature, however, points out that most of the currently manufactured TDPs do not fully meet this idea (Chien, YW, Drug Dev. Ind Pharm., 13, 1987, p. 589). In fact, human skin, with its highly variable barrier properties, remains the driving factor for absorption rates in the TDP range. This is particularly true for type A and type B TDPs. It is known that at various stages of research and development there are also TDA formulations of a number of other therapeutically active substances. However, pharmaceutical preparations for TDA cholinesterase reactivators have not been described.

The above-mentioned drawbacks of the hitherto used methods of systemic application of cholinesterase reactivators are solved by the pharmaceutical preparation according to the invention.

SUMMARY OF THE INVENTION

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SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition for the prophylactic and therapeutic transdermal application of cholinesterase reactivators comprising a compound or a mixture of 1- (2-hydroxy-aminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane (a compound).

HI-6), pralidoxime, methoxime, obidoxime, trimedoxime or a mixture of at least one of these cholinesterase reactivators with at least one cholinolytic agent selected from the group consisting of atropine, homatropin, scopolamine, benactyzine, biperidene.

The present invention further provides a pharmaceutical composition comprising an impermeable cover film provided with an adhesive layer delimiting the application area circumferentially and an ointment or cream or hydrogel or foam containing 1.0% to 30.0% by weight of cholinesterase reactivators or their and 0.01% to 1.0% by weight of a cholinolytic or a mixture of the aforementioned cholinolytics, in an anhydrous hydrophobic ointment, or oleocreme, or hydrocream or hydrophobic foam base, or a hydrogel.

The invention further provides a pharmaceutical composition comprising an impermeable backing film provided with an adhesive layer and an anhydrous hydrophilic macroporous matrix of 0.1 mm to 5.0 mm thickness incorporated by the cholinesterase reactivator or mixtures thereof in an amount of 150 pg / cm ² to 15 mg / cm ² matrix or a mixture of at least one cholinesterase reactivator in an amount of 150 pg / cm ² to 15 mg / cm ² matrix with at least one cholinolytic agent in an amount of 10 pg / cm ² to 100 pg / cm matrix and a removable protective anti-adhesive film for removal, the matrix is impregnated with a liquid solvent in an amount of 35 µl / cm ² to 250 µl / cm ^{2 of} matrix and the composition is adhered to the skin.

The pharmaceutical composition according to the invention is also characterized in that it consists of an impermeable backing film provided with an adhesive layer, an anhydrous hydrophilic macroporous matrix of 0.1 mm to 5.0 mm thickness and a removable antiadhesive film, after removal of which the matrix is impregnated with cholinesterase reactivators or mixtures thereof having a concentration of 1% to 35% by weight, or a solution of cholinesterase reactivators or a mixture thereof, of a concentration of 1% to 35% by weight and a 0.01% to 1.0% by weight solution of cholinolytics or a mixture thereof, in an amount of 3.5pl / cm ² to 250 μΐ / cm ^{2 of} matrix and product adhered to the skin.

Determination of the skin permeation rate of cholinesterase reactivators after administration of the pharmaceutical transdermal preparations of the invention was performed in vitro using human skin placed in a permeation cell according to Franz (Franz, TJ, J. Invest. Dermatol., 64, 1975, p. 190). the amount of permeating active ingredient in the acceptor compartment over time. The results obtained in these experiments can be documented, for example, with the following data.

Average HI-6 fluxes between the first and eighth hours after application were measured in the range of 20.1 to 35.8 [pg / cm .li] for different Type A formulations; 108.9 to 252.1 [gg / cm ^2. ^ ¹ ]

Confirmation and augmentation of the credibility of the in vitro transdermal penetration levels of cholinesterase reactivators provide results obtained in vivo in laboratory animals.

Results of HPLC determination of HI-6 blood levels after administration of type B preparation with a 4 cm ² exposure area in mice showed that between 2 and 5 hours after administration, average HI-6 concentrations reached more than 10 µg / ml blood, with peaks at 5 hour of the experiment with a value of 13.8 μg / ml of blood. In analogous experiments on mini-pigs weighing approximately 25 kg, with an exposure area of 50 cm ^{2 of the} preparation according to the invention, the HI-6 concentration values found were between 4 and 6 hours after administration higher than 4 μg / ml, peaking at 5 hours at level 7. , 0 μg / ml blood.

In connection with these results, it is significant that the concentration level of HI-6 required for the effective prophylaxis of OFI poisoning was determined in rats in the range of 0.3 pg / ml to 5.4 pg / ml plasma, with the pharmacokinetic characteristics of HI -6 in mice, rats, dogs (Beagle), sheep, monkeys (Rhesus macaque) and humans are very similar (Baggot, JD, et al., Biopharmaceutics & Drug Disposition, 14, 1993, p. 93).

The final confirmation of the functionality of the transdermal formulations of the invention is evidenced by in vivo bio-toxicological experiments using laboratory animals in which selected chemical noxa is applied in a defined manner at a certain time from the application of the transdermal formulation. The results obtained in these experiments can be illustrated, for example, by the following data.

In experiments in mice, when prophylactic administration of HI-6 via a type B preparation, under the same application conditions as in the above-mentioned pharmacokinetic experiments, it was found, inter alia, that:

(a) 4-hour transdermal premedication of animals, with concomitant addition of benactyzinium chloride treatment, increased the mean dark LD ₅₀ values following intramuscular administration of VX-agent by approximately 12-fold while benactyl chloride chloride alone was only 3-fold;

b) after analogue transdermal prophylaxis with HI-6, supplemented with oral prophylactic treatment, increased the LD50 by about 25-fold, compared to only a 3-fold increase in this parameter by prophylaxis of oral poisoning alone.

c) prophylaxis of experimental VX poisoning with type B and a special oral formulation increased the effect of treatment with a combination of HI-6 and benactyzinium chloride from nearly 20-fold to more than 55-fold the LD ₅₀ .

Also, another experimental evaluation of the efficacy of transdermal administration of cholinesterase reactivators has documented that the compositions of the invention provide good prophylaxis against OFI poisoning, including V-substances and soman.

In the present context, it is irrelevant that the pharmaceutical transdermal formulations of the invention are not, by their very nature, one of the so-called therapeutic systems in which the maximum level of transdermal absorption of the active substances is predetermined by the composition and design of the formulation. This principle of controlled release is fully justified for the administration of active substances which are therapeutically effective even in small doses, at low concentration levels in the systemic circulation and at the same time have a small therapeutic width, which means that they can easily exceed therapeutic levels and achieve toxic levels . This risk is associated with cholinesterase reactivators, particularly in connection with the transdermal absorption of HI-6 due to its toxicological parameters (Levine, BS, Tomlinson, MJ, J. Amer. Coll. Toxicol., 12, 1993, p. 185; Jovanovič) , D., et al., Vojnosanit. Pregl., 50, 1993, p. 27), very small. For example, a single dose of 2-PAM, intramuscularly administered as an antidote for OFI poisoning, is about 7 mg / kg of human or animal weight, with an LD ₅ of 2-PAM (laundrated doxime) of about 200 mg / kg of weight. Analogous dosage values are about 4 mg / kg for IMB-4 and 15 mg / kg for HI-6, respectively, while the LD50 values for TMB-4 are about 150 mg / kg and about 700 mg / kg for HI-6, respectively. In volunteer tests, no significant toxic effects of HI-6 were found at the therapeutic doses considered (Clement, JG, et al., Biopharmaceutics & Drug Disposition, 16, 1995, p. 415).

The pharmaceutical composition of the present invention permits transdermal administration of cholinesterase reactivators, optionally in admixture with cholinolytics, for at least 8 hours, to the extent necessary to achieve a prophylactic effect against cholinesterase inhibitor poisoning and subsequent treatment of such poisoning. stability of some cholinesterase reactivators. The technical solution according to the invention uses for this purpose a combination of general principles known in the field of dosage form technology.

The invention is further elucidated by means of exemplary embodiments, but the scope thereof is not limited or exhaustive.

DETAILED DESCRIPTION OF THE INVENTION

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The anhydrous form of 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane methanesulfonate (salts of HI-6) with a particle size of up to 5 µm is dispersed in 1.0 g in a mixture of 1.9 g of isopropyl myristate and 0. 1 gram of diethylene glycol monoethyl ether, and the resulting suspension is subsequently triturated with 2.0 grams of molten white petrolatum. After thorough dispersion, the obtained anhydrous suspension ointment is adjusted into a tube and ready to be applied to the skin under a delimiting occlusive frame film of suitable shape and area of about 100 cm.

Example 2

To the heated oil phase composed of 2.0 grams of glyceryl sorbitanoleostearate, 2.0 grams of sorbitan isostearate, 11.0 grams of liquid paraffin and 5.0 grams of isopropyl stearate, an aqueous phase consisting of a solution of 74.8 grams of 2-hydroxyiminomethyl-1 is added gradually, with stirring. -methylpyridinium hydrochloride (2-PAM salt; pralidoxime) and 0.3 grams of biperidene lactate and 0.7 grams of magnesium sulfate in a mixture of 200.0 grams of acetate buffer pH 4.5 and 3.8 grams of propylene glycol and mixed on a suitable homogenizer mixer to cool. The resulting cream, after adjustment into tubes of 5 grams, is ready to be applied to the skin under a delimiting occlusive frame foil of suitable shape and area of about 100 cm ² .

Example 3

0.0625 grams of polyacrylamide-C13-14-isoparaffin-laureth7 gelling agent is mixed with 0.0625 grams of bis (4-hydroxyiminomonomethylpyridinium) -2-oxapropane dichloride (Obidoxime salt), 0.2 grams of 2-hydroxyiminomethyl-1-methylpyridinium iodide (2PAM salt) and 0.008 grams of benactyzinium chloride and adjusted to a plastic vial. Addition of 5.0 ml of Acetate Buffer pH 5.0 to the contents of the vial results in a brief vigorous shaking of the hydrogel ready for immediate application to the skin under a delimiting occlusive frame foil of suitable shape and area of about 100 cm ² .

Example 4

- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride (HI-6 salt) is dissolved in water to a 25% solution, which is applied by pressure to a rectangular 1.5 mm non-woven fabric matrix molded viscose staple, pre-positioned on a peripherally well-extending, drug-impermeable, flexible, drug-resistant backing polyester backing, pre-coated with a polybutadiene adhesive polymer membrane, whereupon the aqueous matrix vehicle is vaporized and the dried matrix containing HI- 6, the adhesive backing film is overlaid with a pre-prepared removable anti-adhesive

The second component of the formulation is made by dissolving 0.4% methylcellulose in citrate buffer pH 5.5 containing 2% by weight sodium pyrrolidone carboxylic acid and adjusting 15 ml of this solution into a polyethylene bottle with a stopper cap.

If necessary, after removing the anti-adhesive film from the medicated patch and saturating its matrix with the above solution, the patch is ready for application.

Example 5

Using a procedure similar to Example 4, the first part of the formulation is a textile matrix patch of cellulose / cotton fiber 1: 1, fixed to a protective carrier film of unplasticized polyvinyl chloride with an adhesive layer of styrene-butadiene-styrene block copolymer overlaid with removable siliconized aluminum foil. . The second part of the formulation is a solution of 20% 1,3-bis (4-hydroxyiminomethylpyridimum) propane dichloride (TMB-4) in citrate-lactate buffer pH 4.8 with 0.6% hydroxyethylcellulose added.

Industrial applicability

The pharmaceutical composition of the invention may be used as an antidote prophylactic agent or a composition for enhancing the efficacy of subsequent treatment of cholinesterase inhibitor poisoning in human and veterinary medicine. It is easy to manufacture, easy to store and, due to its construction, has the stability parameters usually required for mass-produced medicines.

Claims (7)

PATENT CLAIMS A pharmaceutical composition for prophylactic and / or therapeutic transdermal administration and characterized in that it comprises a substance or mixture of substances from the group of »cholinesterase reactivators comprising 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane, pralidoxime, methoxime, obidoxime, trimedoxime or a mixture of at least one of these with at least one cholinolytic agent selected from the group consisting of atropine, homatropin, scopolamine, benactyzine, biperiden. Pharmaceutical preparation according to claim 1, characterized in that it consists of an impermeable covering film provided with an adhesive layer around its periphery and an ointment containing from 1.0% to 30.0% by weight of cholinesterase reactivators or mixtures thereof and from 0.01% to 1.0 % by weight of a cholinolytic or a mixture of cholinolytic in an anhydrous hydrophobic ointment base. Pharmaceutical preparation according to claim 1, characterized in that it consists of an impermeable covering film and a cream containing from 1.0% to 30.0% by weight of cholinesterase reactivators or a mixture thereof and from 0.01% to 1.0% by weight of a cholinolytic or mixture cholinolytic in a water-in-oil or oil-in-water cream base. Pharmaceutical preparation according to claim 1, characterized in that it consists of an impermeable covering film provided with an adhesive layer around the periphery and a foam containing from 1.0% to 30.0% by weight of cholinesterase reactivators or mixtures thereof and from 0.01% to 1% by weight. 0% by weight of a cholinolytic or a mixture of cholinolytic in an anhydrous hydrophobic foam base. Pharmaceutical preparation according to claim 1, characterized in that it consists of an impermeable covering film provided with an adhesive layer circumferentially and of a hydrogel containing 1.0% to 30.0% by weight of cholinesterase reactivators or a mixture thereof and 0.01% to 1.0 % by weight of a cholinolytic or a mixture of cholinolytic. Pharmaceutical preparation according to claim 1, characterized in that it consists of an impermeable carrier film provided with an adhesive layer and an anhydrous hydrophilic macroporous matrix of a thickness of 0.1 mm to 5.0 mm incorporated by the reactivator Λ Λ cholinesterases or mixtures thereof in an amount of 150 pg / cm to 15 mg / cm or a mixture of at least one cholinesterase reactivator in an amount of 150 pg / cm ² to 15 mg / cm ² matrix with at least one cholinolytic substance in an amount of 10 pg / cm to 100 pg / cm matrix and a removable protective anti-adhesive film, after which the matrix is impregnated with a liquid solvent in an amount of 3.5 μΐ / cm to 250 pl / cm matrix. 7. A pharmaceutical composition according to claim 1, comprising an impermeable backing film provided with an adhesive layer, an anhydrous hydrophilic macroporous matrix of 0.1 mm to 5.0 mm thickness, and a removable antiadhesive film, after which the matrix is impregnated with a solution of reactivators cholinesterases or mixtures thereof at a concentration of 1% to 35% by weight or a solution of reactivators or mixtures thereof at a concentration of 1% to 35% by weight and a 0.01% to 1.0% by weight solution of cholinolytics or mixtures of cholinolytics, in an amount of 3.5 μΐ / cm to 250 µl / cm matrix.