EP1585514A1 - Method for the medicinal prophylaxis of cholinesterase inhibitor intoxication, and active substances and medicaments suitable therefor - Google Patents

Abstract

Disclosed are (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl-carbamate (1) or one or several active substances according to formula (2), which are used for the prophylactic protection of individuals from intoxication caused by cholinesterase inhibitors.

Description

Procedures for drug prophylaxis against poisoning by cholinesterase inhibitors, as well as suitable active ingredients and medicines.

The present invention relates to methods for drug prophylaxis against poisoning, which are caused by cholinesterase inhibitors, in particular those from the class of organophosphorus compounds. It also relates to active substances and medicaments which are suitable as prophylactic agents against such poisoning, in particular medicinal substances with active substances from the group of the phenyl carbamates. The invention further includes the use of the active substances mentioned for the prophylaxis against the poisonings mentioned.

Compounds with cholinesterase-inhibiting activity are used on the one hand as insecticides and fungicides in crop protection, on the other hand some of these compounds are suitable for use as warfare agents or combat gases in wars or in terrorist attacks. While the poisoning effect is intended in the latter case, the poisoning of people caused by insecticides or fungicides can be attributed to improper handling, in particular inadequate protective measures during transport or handling.

The risk of being exposed to a poison gas attack has recently increased again due to terrorist activities. In addition, some states produce or keep war gases and consider using such weapons to achieve their military objectives.

Not only soldiers in combat operations are at risk, but also increasingly the civilian population and especially rescue workers. Nerve warfare agents or nerve gases from the class of organic phosphoric acid esters and phosphonic acid esters are the most frequently used poisonous gases. The main representatives of these warfare agents are Tabun (GA), Sarin (GB), Soman (GD) and VX.

Examples of pesticidal or fungicidally active organophosphates which are used in agriculture or horticulture are parathion (diethyl (4-nitrophenyl) thionophosphate), dimethoate (diethyl1-S-meth 1-carbamoylmethyldithiophosphate) and Called Malathion.

The toxic effects of these warfare agents as well as that of the organophosphates and carbamates used as insecticides or fungicides are based on an inhibition of the choline esterase, which results in an excessive accumulation of the neurotransmitter acetylcholine on the cholinergic receptors. The excessive activation of peripheral and central receptors causes severe paralysis, with death mostly due to the onset

Respiratory paralysis is caused. Additional clinical symptoms such as excessive salivation, apnea and seizures appear within the first minutes after exposure to the warfare agent. If not treated adequately and immediately, they can lead to death or permanent damage, comparable to the consequences of irreversible brain damage.

For the treatment of acute organophosphate poisoning, atropine is usually administered parenterally in high doses as an antidote in order to antagonize the acetylcholine effect. This can be done with the help of so-called autoinjectors, which are intended to enable the persons concerned to administer the required dose of atropine themselves in an emergency. However, such treatment is only promising if it is within one Minute after the poison intake is made. Under the actual circumstances, this is rarely possible because the time available in an emergency (e.g. during combat operations or terrorist attacks) is too short. This is particularly true of the extremely toxic warfare agents Sarin (GB) and Soman (GD). Furthermore, the dose of atropine used for the treatment must be carefully selected depending on the severity of the poisoning, in order to avoid overdosing and atropine poisoning. Realistically, this is hardly possible in practice under operating conditions.

In some cases it is possible to treat organophosphate poisoning by administering oxime compounds (e.g. obidoxime, pralidoxime). However, oximes are only effective with certain alkyl phosphates (e.g. parathion), and treatment must be carried out as early as possible after exposure to the poison. Oximes are effective against most organophosphates, with the exception of e.g. B. Soman (GD).

There are insufficient preventive measures against the poisoning mentioned. Oral application of pyridostig in is known, for example, which was carried out in the second Gulf War as a measure to protect soldiers from exposure to poison gas. This treatment has since been abandoned because pyridostigmine is suspected of causing serious side effects that are partly responsible for the "Gulf War Syndrome". As such, the compound pyridostigmine has no independent protective effect. In the above case, pyridostigmine was only used as a pretreatment, but not as a prophylactic agent. This pretreatment is intended to improve the actual treatment with the second active ingredient, the antidote atropine. Another reason why pyridostigmine is no longer used is that there has not yet been a regular approval based on extensive clinical trials that have proven the safety of the drug.

Furthermore, the currently available antidote therapies do not offer adequate protection against seizures due to exposure to neurotoxins and the resulting long-term brain damage and cognitive disorders.

DE 43 42 173 A has proposed the use of a combination of physostigmine and scopolamine as a prophylactic measure or for pretreating organophosphate poisoning, this combination being administered by injection or skin patch.

It is disadvantageous, however, that physostigmine is also not approved as a drug. There are therefore reasonable concerns that physostigmine, due to its chemical similarity to pyridostigmine, could cause side effects similar to this.

It was therefore the task of specifying methods for preventing poisoning by cholinesterase inhibitors and medicaments suitable therefor, the aforementioned disadvantages of known methods and medicaments being avoided or reduced.

Surprisingly, it has been found in animal experiments (see example) that this task can be achieved by using (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate ("Compound (1)" ) is solved as a prophylactic agent. Connection (1)

The solution according to the invention therefore comprises methods for the prophylactic treatment against poisoning by cholinesterase inhibitors, the methods being based on the administration of (S) -N-ethyl-N-methyl-3- [1- (dimethylaminojethyl] phenylcarbamate or one of these The invention further relates to the use of (S) -N-ethyl-N-methyl-3- [l- (dimethylamino) ethyl] phenylcarbamate, or for prophylaxis against poisoning by cholinesterase inhibitors the invention further comprises pharmaceutical compositions which contain the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate in combination with at least one further pharmaceutical active ingredient.

Compound (1) is a carbamic acid ester which inhibits the cholinesterase enzyme by carbamylation. This inhibition is reversible with a half-life of a few minutes. Because of these properties, this active ingredient is used for the therapy of Alzheimer's disease, in which case the acetylcholine deficit caused by the destruction of cholinergic neurons should be compensated for. Compound (1) is approved as a drug for treating Alzheimer's disease and is on the market; it does at least in some patients Improve memory performance. The drug is considered safe; serious side effects are not known. It is also advantageous that (S) -N-ethyl-N-methyl-3- [l- (dimethylamino) ethyl] phenyl carbamate is well absorbed from the gastrointestinal tract and easily crosses the blood-brain barrier.

The use of (S) -N-ethyl-N-methyl-3- [1- (dimethylaminoethyl) phenyl carbamate as a safe prophylactic for the prevention of poisoning by cholinesterase inhibitors, in particular organophosphate poisoning, has not hitherto been known Surprisingly, specific, particularly good suitability has been found in animal experiments, and it has been found particularly advantageously that a significantly lower dose is obviously required than in the regular therapy of Alzheimer's diseases.

The pharmaceuticals according to the invention for the prophylactic treatment against organophosphate poisoning contain the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate as the free base or in the form of a pharmaceutically acceptable acid addition salt. Particularly suitable salts are: salicylate, hydrogen tartrate, hydrobromide, hydrochloride. The hydrogen tartrate salt of the active ingredient (empirical formula C14H22N2O2 • C4H5O6) is particularly suitable, the tartaric acid preferably being in the configuration (2R, 3R).

The free active ingredient base or its acid addition salts can be used as racemic mixtures; the (-)-

However, enantiomers of (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate and its acid addition salts are preferred because of their higher selectivity. If the active ingredient is in the form of an acid addition salt, the direction of rotation can be (+) or (-). The free base (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate can be obtained by amidating α-m-hydroxyphenylethyl dimethylamine with a corresponding carbamoyl halide. The racemates can be separated and acid addition salts can be prepared by known processes. The racemic mixture of the hydrochloride form of compound (1) is known from EP-A-0 193 926 (referred to there as "RA7HCI"). The (-) - enantiomer of compound (1) and its acid addition salts have been described in DE 38 05 744 AI.

Compounds with the following general structural formula (2) are also suitable as active substances which can be used according to the present invention for the prophylactic treatment against poisoning by cholinesterase inhibitors:

Formula (2)

In this formula, the R ^ radical is selected from the group consisting of hydrogen, unbranched and branched lower alkyl radicals (1 to 5 C atoms), cyclohexyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen, methyl, ethyl and propyl; the rest R3 is selected from the group consisting of hydrogen as well includes unbranched and branched Nißderalkylreste (1 to 5 carbon atoms); the radicals R and R5 are selected from the group of unbranched and branched lower alkyl radicals (1 to 5 carbon atoms), where R4 and R5 can be identical or different; the dialkylaminoalkyl group with the radicals R3, R4 and R5 can optionally be in the ortho, meta or para position.

The active compound compounds according to formula (2) can be used as free bases or in the form of their pharmaceutically acceptable acid addition salts. The salts mentioned in connection with compound (1) are particularly suitable, in particular the hydrogen tartrate and the hydrochloride.

Compounds of formula (2) and their preparation are disclosed in EP-A-0 193 926.

According to a preferred embodiment of the invention, the compound (1) or one of the compounds of the formula (2), in each case optionally in the form of a pharmaceutically acceptable salt, is administered as a sole active ingredient for the prophylaxis against poisoning by cholinesterase inhibitors to a person at risk. This is a prophylactic measure that is sufficient in itself and does not require any further treatment measures or active ingredients.

According to a further preferred embodiment, the compound (1) or one of the compounds of the formula (2), in each case optionally in the form of a pharmaceutically acceptable salt, in combination (ie simultaneously or in succession) with one or more additional active ingredient (s) (s) administered to the person to be treated. The active substance (s) mentioned is / are selected from the group of the parasympatholytic agents, preferably from the group of the tropane alkaloids, with scopolamine is particularly preferred. Other suitable active ingredients from this group are: atropine, butylscopolamine, benzatropine. These active ingredients can also be in the form of their pharmaceutically acceptable salts.

The combination of compound (1) or an active ingredient according to formula (2) with at least one active ingredient from the group of the parasympatholytics, in particular from the group of the tropane alkaloids, is particularly preferred because these active ingredients are competitive antagonists against released substances

Acetylcholine and thereby reduce the undesirable effects caused by the cholinesterase inhibitory effect of the compound (1).

The present invention also extends to medicaments which have a content of compound (1) or of an active compound of the formula (2), optionally in the form of a pharmaceutically acceptable salt. Medicaments according to the invention which contain such a phenyl carbamate active substance as the sole active substance component are particularly preferred.

As described above, the medicament used for prophylaxis can contain one or more additional active substance (s), this active substance (s) being selected from the group of the parasympatholytic agents.

The medicaments according to the invention, which contain compound (1) or at least one compound according to formula (2), can be prepared in various dosage forms using known excipients. In the prophylactic methods according to the invention, pharmaceutical forms are preferably used for enteral or parenteral, in particular transdermal, administration. In the former case, the active ingredient (s) is / are in an oral enteral dosage form (e.g. tablet, coated tablet, Chewable tablet, lozenge, capsule, powder, suspension, solution) or in a rectal dosage form (e.g. suppository). Suitable formulation auxiliaries are known to the person skilled in the art. Parenteral oral delivery forms, such as lozenges, sublingual tablets, sheet-like adhesive systems which are applied to the oral mucosa, sheet-like systems which dissolve on the tongue or the oral cavity and which adhere to the oral mucosa, also come into consideration Apply the active ingredient.

Furthermore, devices for administering medicaments to mucosal tissue, as described in DE 0069030095 T2 and DE 0069032982 T2, are also suitable. These devices can be used like a lollipop and essentially comprise a carrier device which is supported on a total mass.

Application with the aid of the “Methods and devices for using regulated heat for regulating transdermal administration” described in US Pat. No. 2001037104 (Zhang Jie et al.) Is also possible.

However, the medicaments according to the invention can also be formulated as injection solutions and, for example, contained in a disposable syringe. Depot dosage forms or therapeutic systems which enable delayed and / or controlled release of active ingredient are particularly suitable.

It is particularly advantageous to add one or more antioxidants, preferably selected from the group consisting of tocopherol and its derivatives (in particular esters, acetate), ascorbic acid and its derivatives (for example ascorbyl palmitate), butylated hydroxyanisole, butylated hydroxytoluene and Propyl gallate comprises, with tocopherol and Asσorbylpalmi- are particularly preferred. These substances are preferably added in a concentration of 0.01 to approximately 1.0% by weight, preferably 0.05 to 0.5% by weight, in each case based on the entire pharmaceutical preparation.

The medicaments according to the invention preferably contain 0.1 to 100 mg, particularly preferably 0.5 to 20 mg of the compound (1) (or an active ingredient according to formula (2)). In the case of oral single dose forms, the active substance content is preferably in the range from 0.1 to 10 mg, in the case of depot pharmaceutical forms or therapeutic systems it is preferably in the range from 1.0 to 100 mg. The content of the further active ingredient (s) (preferably tropane alkaloids) mentioned is preferably in the range from 0.1 to 100 mg, in particular 0.5 to 50 mg. The percentage of active ingredient, based on an individual pharmaceutical preparation, is preferably in the range from 0.1 to 50% by weight, in particular in the range from 5 to 40% by weight. The maximum daily dose (based on compound (1)) is approx. 2 6 mg daily (oral) or approx. 24 mg daily (transdermal).

According to a preferred embodiment, the active ingredient is (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (“compound (1)”), particularly preferably in combination with at least one further active ingredient (especially scopolamine), contained in a flat, film-shaped oral dosage form. These dosage forms, which are also known as "wafers", are intended for application in the oral cavity. The medicinal product with its active and ineffective components acquires a gel-like consistency through the entry of saliva - or other liquid - and thus adheres to the mucous membrane. There is the Release of the active ingredients and subsequent absorption through the oral mucosa. During the release, the wafer remains in the oral cavity, virtually dissolves and releases the active ingredient in a very short time. In another preferred dosage form, the wafer is provided with an adhesive layer, so that it adheres to the oral mucosa for a controlled period of time.

Wafers essentially contain one or more polymers as basic substances, as well as one or more active ingredient (s) dissolved or dispersed therein. Polymers that are particularly suitable are water-soluble or swellable or decomposable polymers in aqueous media. Polymers selected from the group below are particularly suitable: cellulose derivatives (in particular hydroxypropyl methyl cellulose, carboxy ethyl cellulose, hydroxypropyl cellulose and methyl cellulose); water-soluble polysaccharides that are of vegetable or microbial origin (in particular pullulan, xanthan, alginates, dextrans, pectins, starch); Polyvinyl alcohols, polyacrylates, polyvinyl pyrrolidones; Proteins (preferably gelatin or other gel-forming proteins).

Furthermore, the wafers mentioned can contain one or more additives selected from the group of

Plasticizers, dyes and pigments, antioxidants, decay promoters, wetting agents, substances that promote absorption or permeation, pH regulators, fillers, flavors and aromas and sweeteners. Suitable pharmaceutically compatible substances for this purpose are known to the person skilled in the art, as are processes for the production of such wafers (see, for example, DE-A-196 52 268; DE-A-100 32 456; WO-A-98 26 763). In the production, a dispersion or solution of the constituents (polymer (s), active ingredient (s), additive (s)) is generally first prepared and this then coated on a flat, inert support and dried.

The thickness of these film-like dosage forms is preferably between 0.1 to 5 mm, particularly preferably between 0.5 to 1 mm.

In a further preferred embodiment of the invention it is provided that the active ingredient or, particularly preferably, an active ingredient combination as described above is contained in a transdermal therapeutic system (TTS). Since the skin permeability of the compound (1) (as a free base or as an acid addition salt), as well as that z. B. of scopolamine, these substances are suitable for the transdermal route of administration.

Transdermal dosage forms are particularly advantageous for the prophylactic use of phenyl carbamate active substances according to the present invention, since they allow precise control of the active substance release over a longer period (up to 72 h), with the result that the dosage interval can be extended. In this way, a plasma concentration sufficient for the desired prophylactic effect can be maintained without unfavorable plasma peak values or fluctuations in the plasma concentration occurring. Therefore, transdermal administration is also much cheaper in terms of side effects; when compound (1) is administered orally, nausea may occur in the treated persons in individual cases. The risk of an overdose is largely excluded at TTS; In addition, an improved acceptance among the people to be treated can be expected.

The construction and manufacture of transdermal therapeutic systems (TTS) are fundamentally known to the person skilled in the art. These systems include a drug reservoir, which can either be a membrane-enclosed, bag-shaped reservoir or a polymer-based reservoir ("matrix system"); the latter type is preferred. The reservoir is usually with a carrier layer (for example plastic film, such as

PETP, PE; z. B. 10-15 μ thickness) connected, which serves as a backing layer during application and covers the active substance-containing reservoir to the outside. The surface of the drug reservoir facing the skin (delivery side) can be covered with a removable protective film (e.g. P z or PETP film, siliconized or fluorosiliconized; e.g. 50-250 μm thick) before application.

Polymers from the following groups are particularly suitable as polymers for producing the active substance reservoir:

Polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, especially methyl and ethyl celluloses, isobutylene, ethylene-vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene -Block copolymers, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, silicone pressure sensitive adhesive and hot melt adhesive. Suitable pressure sensitive adhesives are known to the person skilled in the art (e.g. amine-resistant

Silicone pressure sensitive adhesives such as B. BIO-PSA® pressure sensitive adhesive, especially 7-4302; Dow Corning). Suitable mixtures of the polymers mentioned can also advantageously be used.

The term "hot melt adhesive" includes all adhesives that are not liquefied by solvents but by melting at elevated temperatures, for example in the range of 60-200 ° C. As hot melt adhesive z. B. Mixtures of esters of hydrogenated rosin with cellulose derivatives. The active substance reservoir of the TTS according to the invention can also contain various auxiliaries or additives, for example from the group of solubilizers, solvents, plasticizers, tackifiers, permeation improvers, pH regulators, antioxidants and preservatives.

The polymer matrix of the active substance reservoir can have one or more layers; it preferably has pressure-sensitive adhesive properties, as a result of which permanent contact of the active substance-dispensing side of the reservoir with the skin is made possible. Alternatively, a separate active substance-free pressure-sensitive adhesive layer or a pressure-sensitive adhesive zone can be provided if the active substance reservoir has no or insufficient pressure-sensitive adhesive properties.

The typical structure of a TTS according to a preferred embodiment comprises: a backing layer; (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (as base or as hydrogen tartra) in an acrylate copolymer as the drug reservoir; Silicone pressure sensitive adhesive layer (BIO-PSA® Q7- 4302); removable protective layer.

Substances from the following group are preferably considered as plasticizers: skin-compatible surfactants; Polyoxyethylene fatty alcohol ether, preferably with Ci2 ~ ^c 18 ~

Alcohol, particularly preferably polyoxyethylene (10) oleyl ether, in particular Brij® 97 (Atlas Chemie); Polyoxyethylene sorbitol fatty acid esters, preferably with particularly preferred polyoxyethylene (20) sorbitan monooleate (e.g. Tween® 80; Atlas Chemie); Polyoxyethylene- (5-40) -

Stearic acid esters (e.g. Myrj®; Atlas Chemie); Polyoxyethylene glycol fatty alcohol ether, e.g. B. polyethylene glycol (6-25) cetyl ether, glycerin polyethylene ricinoleate; glycerol Polyethylene glycol stearate (Cre ophor®; BASF); Polyoxyethylene glycols in the molecular weight range from 200 to 600

Dalton; Cetiol® HE (from Henkel); Lower alkyl esters of adipic acid, especially di-n-butyl adipate, diisopropyl adipate; Glyerine polyethylene glycol ricinoleate (e.g. Cremophor EL, BASF®); Triacetin- (1,2,3); Fatty acids, fatty alcohols, preferably C12-C18.

Azon (l-dodecylazacycloheptan-2-one) or / and DEΞT (N, N-diethyl-m-toluamide) are preferably used as permeation improvers (enhancers).

The total proportion of plasticizers and permeation-improving substances can be up to approximately 50% by weight, based on the active substance-containing polymer preparation (active substance reservoir). A content of less than 1% by weight or the complete absence of such additives is particularly preferred.

The preparation of the TTS according to the invention can be carried out in such a way that compound (1) and / or an active compound of the formula (2), and optionally further active compounds, are / are coarsely, colloidally or molecularly dispersed in a solution of matrix base polymers and the mixture on a suitable base, for example a plastic film provided with a silicone layer. As a solvent, for. B. acetone, ethyl acetate or hexane, or solvent mixture β can be used. After the solvent components have been dried and evaporated, the active substance-containing matrix layer is covered with a further film which represents the later back layer of the TTS. By punching flat structures in the desired geometric shape and size, individual TTSs are produced from such a laminate. Alternatively, the production of the active substance-containing polymer matrix take place starting from a polymer melt, the active substance-containing molten polymer mass being extruded onto a film-shaped carrier in a thin layer. The thickness of the active substance-containing layer is preferably 10 μm to 2 mm, preferably 50 μm to 0.5 mm. The skin contact area of a TTS can optionally be approximately 1 to 80 cm ² , preferably approximately 2 to 20 cm ² .

If a TTS, as provided for in a particularly preferred embodiment, the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate (“compound (1)”) in combination with at least one further active ingredient (preferably from the group of the tropane alkali ide, in particular scopolamine), use can additionally be made of the measure that the TTS is composed of several layers, surface areas, sections or compartments, the individual Distinguish layers, surface areas, sections or compartments by the type and / or concentration of the active ingredient contained.

For example, a TTS according to a preferred embodiment of the invention can comprise two compartments, each as a reservoir for the phenylcarbama active ingredient

(Compound (1) and / and compound of formula (2)) or for scopolamine. These two reservoirs are connected to a common backing layer and protective layer. The relative area expansions of the two compartments (and / or the relative amounts or concentrations of the active ingredients) can be adjusted accordingly in order to adjust the permeation rate for each of the active ingredients. For example, the first compartment (containing compound (1), e.g. 60 mg) can have an area of 25 have cm ² ; in this case the second compartment (with scopolamine; e.g. 4 mg) has an area of 7.5 cm ² .

As mentioned above, the present invention also encompasses TTS designed as bag-shaped systems. In this case, the active ingredient (s) is / are contained in a liquid or semi-liquid (e.g. gel-like or viscous) composition which is enclosed in a bag-shaped container. The active ingredient is released via an adhesive-coated membrane in the container, which comes into contact with the skin of the person to be treated. Suitable materials and processes for producing such systems are known in principle to the person skilled in the art.

Transdermal systems which are particularly advantageous for the prophylactic administration of compound (1) or active compounds of the formula (2), optionally in combination with at least one further active compound, are disclosed in WO-A-99 34782. The pharmaceutical compositions and components described there are therefore discussed in

In connection with the present invention expressly referred.

In accordance with WO-A-99 34782, the active ingredient (s) is / are dissolved in one or more matrix polymers, with hydrophilic polymers being preferred. These polymers are preferably selected from the group of polyacrylates and poly ethacrylates; their average molecular weight is preferably in the range from about 50,000 to about 300,000 daltons. In particular, these are polymers with film-forming properties.

Preferred acrylate copolymers, e.g. B. copolymers of butyl acrylate, ethylhexyl acrylate and vinyl acetate, into consideration. That is also particularly advantageous Use of crosslinked polymers of the type mentioned. Examples of particularly suitable polymers are Durotak 87-2353, Durotak 387-2051 and Durotak 387-2052 (available from: National Starch and Chemical Company). The proportion of these polymers can be up to 90% by weight, preferably up to 70% by weight, in each case based on the total weight of the preparation containing the active ingredient.

Particularly suitable as hydrophilic polymers are polyacrylamide and its copolymers, polyvinylpyrrolidones, polyvinyl alcohol and derivatives thereof, vinyl acetate-vinyl alcohol copolymers, ethyl cellulose and other cellulose and starch derivatives. Hydrophilic polyacrylates are most preferred; the polyacrylate may be substituted (e.g. a methacrylate), or some or all of the acid groups may be esterified, e.g. B. with AlkyKCi- to C Q) groups, especially with methyl or ethyl groups. Examples of commercially available polymers of this type are: Plastoid® B (Röhm, Darmstadt); Eudragit® RS 100 and RL 100 (from Röhm); Eudragit® E 100 (from Röhm).

In addition, hydrophobic polymers can be included, in particular one or more synthetic resins, optionally in combination with modifying substances such as. B. resin acids, glyceryl and phthalate esters of resin acids.

TTS whose active ingredient reservoir contains a pharmaceutical preparation of the following composition are particularly preferred: 20 to 40% by weight (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (as free base or as a salt, especially as a hydrogen tartrate); 10 to 30% by weight polymethacrylate; 40 to 60% by weight of an acrylate copolymer; 0.05 to

0.3 wt. Sδ α-tocopherol (total 100 wt.%). The medicaments according to the invention containing compound (1) and / or at least one active substance according to formula (2) are advantageously suitable for the preventive treatment against poisonings caused by cholinesterase inhibitors, in particular toxins of the type mentioned at the outset. Among cholinesterase inhibitors are generally understood to be compounds which are able to chemically modify the active center of the enzyme, in particular by reaction with hydroxyl groups in the active center. These are primarily organophosphorus compounds, such as organic phosphoric acid esters and organic phosphonic acid esters, and their derivatives in each case. In addition, in connection with the present invention, cholinesterase inhibitors from other classes of substance also come into consideration, e.g. B. carbamates, especially those used as crop protection agents (z. B. Carbaryl _* 1-naphthyl-N-methy carbamate).

The preventive agents according to the invention can be used in agriculture or in horticulture in order to protect employees who have to deal with organophosphorus insecticides or fungicides or can come into contact with them from possible poisoning. These prophylactic drugs are also suitable for protecting people who are used for decommissioning weapons or for decontamination. The invention further includes the use of (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate, or a compound according to formula (2), for the prophylactic treatment of soldiers, police officers and civilians for protection against the named warfare agents or nerve gases.

The protective effect brings about a reduction in toxicity and an improvement in the chances of survival after one Toxin exposure. It also increases the chances of success of post-exposure therapy with an atropine-oxime combination.

The present invention further relates to methods for the prophylactic treatment or pretreatment of persons in order to protect them from poisoning which are caused by the action of organophosphorus cholinesterase inhibitors. These processes are characterized in that they comprise at least one step in which a medicament which is (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate or / and an active ingredient according to formula (2) contains (in each case optionally in the form of a pharmaceutically acceptable salt), is administered to a person. Drugs containing active ingredients, as described above, are preferably used here.

The prophylactic administration of medicaments which contain at least one of the above-mentioned phenylcarbamate active ingredients is preferably carried out at least one day, possibly only at least (2) h before the expected exposure to toxins, provided that it is a predictable event (e.g. handling of insecticides, decontamination work, start of a combat operation). The protective effect can be maintained over a period of several (1 to 7) days to a few weeks by administration of a plurality of successive single doses, preferably by application of depot pharmaceuticals or therapeutic systems (particularly preferably TTS). Depending on the active substance content and the release rate, the application is repeated daily, for example, or at intervals of up to 7 days.

According to a particularly preferred embodiment, at least one drug is used in the prophylactic method administered, which contains (S) -N-ethyl-N-methyl-1-3- [1- (dimethylamino) ethyl] phenyl carbamate or a pharmaceutically acceptable salt of this compound as the sole active ingredient.

According to a further preferred embodiment of the prophylactic method, it is provided that one or more further active substances from the group of the parasympatholytics are / are additionally administered to the person to be treated, preferably active substance (s) from the group of the tropane alkaloids, scopolamine being particularly preferred becomes. This combined administration can take place either by application of a medicament which contains the active substances mentioned in combination, or by the simultaneous or successive application of individual medicaments which each contain only one active substance of the active substance combination. For example, a person can be treated prophylactically in such a way that a TTS containing the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate is applied to the skin (e.g. on Upper arm) is applied and during this

Application time a second drug, which preferably contains scopolamine, is administered orally to this person. Alternatively, the treatment can be carried out in such a way that a TTS, which is a combination of at least two active ingredients (e.g. (S) -N-ethyl-N-methyl-1-3- [1- (dimethylamino) ethyl] phenyl carbamate and scopolamine ) contains, is applied to the skin. The transdermal or oral administration of (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate with the parenteral administration of at least one further active ingredient, preferably from the group of the parasympatholytics, is also provided , to combine.

In the case of transdermal administration of the active ingredients (as described above), the protective effect occurs at the earliest after about 4 hours. This delay can occur under certain May be critical, e.g. B. in the event of a terrorist attack, if immediate intervention by soldiers or police is required. In order to achieve a faster onset of the protective action, the present invention includes a method for prophylactic treatment, the transdermal administration being combined with the oral administration of the above-mentioned active ingredients. Preferably, in a first step (S) - N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (or preferably a combination of this active ingredient and scopolamine) is administered orally to a person in whom a rapid onset of the protective effect is necessary. In this way, it is possible within a short time (approx. 1/2 hour) to produce therapeutic plasma levels that provide protection against warfare agents. This enables the treated person to enter a contaminated environment immediately after an emergency order.

In a second step, the same person is administered a transdermal system (as described above) in order to produce a lasting protective effect (for example up to 24 hours). The TTS can be administered at the same time as the administration of the oral drug; however, it can also be carried out after a delay, preferably within 12 hours after oral administration. This second step can be repeated at certain intervals (e.g. 6 to 24 h) to extend the duration of the protective effect. According to this method, oral administration is only required to bring about a rapid onset of the protective effect; the maintenance of the protective effect is made possible by administration of one or more transdermal therapeutic systems. This method is particularly simple and safe to use; it enables the rapid build-up of a prophylactic protective effect for those to be protected persons without being exposed to an unacceptable burden of side effects.

Preferred oral dosage forms for use in the method described above are tablets and particularly preferably "wafers" (film-like or wafer-shaped dosage forms; as described above). According to a preferred embodiment of the method, a wafer containing the compound (1) and scopolamine is applied into a person's oral cavity. The active ingredients are released from the wafer and absorbed through the oral mucosa. A therapeutic, prophylactic plasma level that ensures a protective effect is reached quickly (e.g. within 30 min).

The prophylactic agents and methods according to the invention are advantageously suitable for pretreating people who are at risk of exposure to toxins.

Example:

In order to demonstrate the prophylactic properties of the combination of (S) - N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate (compound (1)) and scopolamine against neurotoxins, the protective effect was investigated Piglets examined as an animal model. The plasma levels of the two active substances were set in the animals in a range which corresponds to that which is to be used in humans.

In a preliminary experiment, 6 mg (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate hydrogen tartrate in the form of capsules were orally administered to piglets (12 kg each). This caused a 20-40% inhibition of the enzyme cholinesterase in the blood two hours after the administration causes. This area corresponds to the inhibition that is sought and should be achieved in humans. It should be noted that a lower dose is required in humans due to the better absorption of the active ingredient. Based on those measured in humans

Blood cholinesterase inhibition can be assumed that treatment with 3 mg BID (i.e. twice a day) is sufficient to ensure the required protective effect. This dose is therefore considerably lower than the dose used to treat Alzheimer's patients (12 mg daily; Culter NR et al.: Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease. Acta Neurol. Scand., 1998, 97 , 244-250).

Another preliminary experiment has shown that an intravenous infusion of scopolamine at a rate of 0.8 mg / kg / h leads to an equilibrium concentration of approximately 150 pg / ml in the piglet blood; here, too, this value corresponds to the concentration that is expected to be achieved in humans.

In the protective effect experiments, the piglets were exposed to a dose of the nerve agent sarin, which corresponds to twice the LDsQ dose (40 μg / kg); this was done using an intravenous cannula in the piglet's ear.

Untreated piglets (controls) died within 4-6 minutes after exposure to combat substances. Treated piglets (approx. 12 kg each) received a 6 mg capsule (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate hydrogen tartrate; the piglets were also infused with scopolamine 2 h before exposure (0.8 mg / kg / h). Before the drug treatment and immediately before exposure, blood samples were taken from the subclavian vein to determine scopolamine and to assess cholinesterase inhibition. As can be seen from the table below, all five piglets treated survived. In addition, the average recovery time, with the piglets standing firmly on their feet, was extremely short (17 min); and this despite the relatively high dose of the nerve agent.

Table:

Protection of pigs against sarin (2 x LD50) by prophylactic treatment with (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] -phenylcarbamate hydrogen tartrate (oral) and scopolamine (infusion).

ChE = cholinesterase.

Claims

Expectations 1. Use of (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (1) or a medicament containing this compound (1) for the preventive protection of persons against poisoning caused by cholinesterase inhibitors. 2. Use of one or more active substances according to the following formula (2) or a medicinal product containing at least one such active ingredient for the preventive protection of people against poisoning caused by cholinesterase inhibitors; in which R ^ is selected from the group consisting of hydrogen, unbranched and branched lower alkyl radicals (1 to 5 C- Atoms), cyclohexyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen, methyl, ethyl and propyl; R3 is selected from the group consisting of hydrogen and unbranched and branched lower alkyl radicals (1 to 5 C- Atoms); the radicals R4 and R5 are selected from the group of the unbranched and branched lower alkyl radicals (1 to 5 carbon atoms), it being possible for R4 and R5 to be identical or different; and wherein the dialkylaminoalkyl group with the radicals R3, R4 and R5 is optionally in the ortho, meta or para position. 3. Use according to claim 1 or 2, characterized in that compound (1) or at least one active ingredient according to formula (2) is present as a free base. 4. Use according to claim 1 or 2, characterized in that compound (1) or at least one active ingredient of the formula (2) is present as an acid addition salt, preferably as a hydrogen tartrate or as a hydrochloride, the hydrogen tartrate being particularly preferred. 5. Use according to one of claims 1 to 4, characterized in that the poisonings mentioned are those which are caused by the inclusion of one or more of the following substances: organophosphorus compounds, in particular organic phosphoric acid esters or organic phosphonic acid esters ; Derivatives of organic phosphoric acid esters, derivatives of organic phosphonic acid esters; Carbamates. 6. Use according to any one of claims 1 to 5, characterized in that compound (1) or at least one active ingredient according to formula (2), or a medicament containing compound (1) or said active ingredient (2), as a prophylactic agent is used to protect against poisoning caused by pesticides. 7. Use according to one of claims 1 to 5, characterized in that compound (1) or at least one Active ingredient according to formula (2), or a medicament containing compound (1) or a named active ingredient (2), is used as a prophylactic agent for protection against poisoning caused by warfare agents or nerve gases. 8. Use according to one of claims 1 to 7, characterized in that compound (1) or an active ingredient according to formula (2) is used as the sole active ingredient for prophylaxis. 9. Use according to one of claims 1 to 7, characterized in that compound (1) or an active ingredient according to formula (2) is in each case used in combination with at least one further active ingredient, preferably from the group of the parasympatholytics, particularly preferably from the Group of the tropane alkaloids, with scopolamine being the most preferred. 10. Medicament for the prophylaxis of poisoning by cholinesterase inhibitors, characterized in that it contains the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (1) as the free base or in the form of a pharmaceutically acceptable salt, and additionally contains one or more further active compounds from the group of the parasympatholytics, preferably from the group of the Tropan alkaloids, with scopolamine being particularly preferred. 11. Medicament for the prophylaxis of poisoning by cholinesterase inhibitors, characterized in that it contains at least one active substance according to formula (2) as a free base or in the form of a pharmaceutically acceptable salt, and additionally one or more further active substances from the group of the parasympatholytics, preferably from the group of the tropane alkaloids, with scopolamine being particularly preferred. 12. Medicament according to claim 10 or 11, characterized in that the compound (1) and / or at least one active compound of the formula (2) is present as an acid addition salt, preferably as the hydrochloride form or the hydrogen tartrate form, the latter form being most preferred becomes. 13. Medicament according to one of claims 1 to 3, characterized in that it is present as an oral, rectal or transdermal dosage form or as an injection liquid, preferably as a transdermal therapeutic system or as a film-shaped oral dosage form. 14. Medicament according to one of the preceding claims, characterized in that it contains 0.1 to 100 mg, preferably 0.5 to 20 mg of phenylcarbamate active ingredient (s) according to formula (1) or formula (2). 15. A method for the prophylactic treatment of people for the purpose of protection against poisoning caused by the action of cholinesterase inhibitors, in particular organophosphorus inhibitors, characterized in that the method comprises at least one step in which a person to be protected is given a medicament - agent containing the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenyl carbamate (1) as a free base or in the form of a pharmaceutically acceptable salt. 16. A method for the prophylactic treatment of people for the purpose of protection against poisoning caused by the action of cholinesterase inhibitors, in particular organophosphorus inhibitors, characterized in that the method comprises at least one step in which a person to be protected is a medicament , which contains at least one active ingredient according to formula (2) as a free base or in the form of a pharmaceutically acceptable salt. 17. The method according to claim 15, characterized in that said medicament contains the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate (1) as the sole active ingredient. 18. The method according to claim 15 or 16, characterized in that one or more other active substances from the group of the parasympatholytic agent is / are administered to the person to be treated, preferably active substance (s) from the group of the tropane alkaloids, scopolamine in particular is preferred. 19. The method according to claim 18, characterized in that the said active substances are administered by means of a combination preparation which contains at least one active substance of the formula (1) or (2) and at least one active substance from the group of the parasympatholytics. 20. The method according to any one of claims 15 to 19, characterized in that at least one of the active ingredients is administered orally or transdermally. 21. The method according to claim 20, characterized. that - In a first treatment step, a film-like oral dosage form (wafer) is introduced into the oral cavity of a person or a tablet, pill, capsule or coated tablet is administered to this person; - And in at least one further treatment step, a transdermal therapeutic system is applied to the skin of this person. wherein said medicaments contain the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate (1) and / or at least one active ingredient according to formula (2), and wherein the / the active ingredient (s) are present as a free base or in the form of a pharmaceutically acceptable salt. 22. The method according to claim 21, characterized in that at least one or preferably all of the medicaments administered to the person additionally contain one or more active substances from the group of the parasympatholytics, preferably active substance (s) from the group of the tropane alkaloids, where Scopolamine is particularly preferred. 23. The method according to any one of claims 15 to 22, characterized in that one or different medicaments according to claims 10 to 14 are used for the administration of the active ingredient (s). 24. Use of the active ingredient (S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] phenylcarbamate (1) and / or at least one active ingredient according to formula (2) for the manufacture of a medicament for prophylactic treatment by people to protect against poisoning caused by choline esterase inhibitors.