USOO5939.095A United States Patent (19) 11 Patent Number: 5,939,095 Hille et al. (45) Date of Patent: Aug. 17, 1999 54) TRANSDERMAL THERAPEUTIC SYSTEM 5,106,831 4/1992 Fisher .......................................... 514/2 AND A PROCESS FOR THE COMBINED 5,364,629 11/1994 Kochinke ... 424/449 TRANSIDERMAL APPLICATION OF 5,391,375 2/1995 Hille ........................................ 424/449 PHYSOSTIGMINE AND SCOPOLAMINE FOR FOREIGN PATENT DOCUMENTS THE PROPHYLAXIS AND PRETREATMENT OF A POSONING CAUSED BY HIGHLY 3 315 272 3/1986 Germany. TOXC ORGANOPHOSPHORUS 3 843 239 2/1990 Germany. NEUROTOXINS IN PARTICULAR SOMAN 4 115 558 11/1992 Germany. OTHER PUBLICATIONS 75 Inventors: Thomas Hille; Walter Miller, both of Neuwied; Bodo Asmussen, Ammersbek, Can. J. Physiol. and Pharmacol., Effects of subchronic all of Germany pyridostigmine pretreatment on the toxicity of Soman, J. D. Shiloff, et al. vol. 64, pp. 1047-1049, 1986. 73 Assignee: LTS Lohmann Therapie-Systeme Gov. Rep. Announce Index, Comparing the Efficacy of GmbH, Neuwied, Germany PhySoStigmine pretreatment in combination with Scopola 21 Appl. No.: 08/656,208 mine verSuS Artane against Soman Challenge, R.P. Solana, et al, vol. 89, No. 15, abstract 942,440, 1989. 22 PCT Filed: Dec. 6, 1994 Leadbetter, “When all else fails”, Chemistry in Britain, Jul. 1988 pp. 683–688. 86 PCT No.: PCT/EP94/04.048 Fleisher et al., “Dealkylation ASA Mechanism For Aging of S371 Date: Jul. 30, 1996 Cholinesterase After Poisoning With Pinacolyl Meth ylphosphonofluoridate” Biochemical Pharmacology, 1965, S 102(e) Date: Jul. 30, 1996 vol. 14, pp. 641-650. 87 PCT Pub. No.: WO95/15755 Berry et al., “The Use of Carbamates And Atropine In The Protection of Animals Against Poisoning By 1.2.2-Trimeth PCT Pub. Date:Jun. 15, 1995 ylpropyl Methylphosphonofluoridate” Biochemical Pharma 30 Foreign Application Priority Data cology, vol. 19, pp. 927–934 (1990). Dec. 10, 1993 DEI Germany .......................... P 4342 174 Primary Examiner D. Gabrielle Brouillette Attorney, Agent, or Firm Wenderoth, Lind & Ponack, (51 Int. Cl. ................................................ A61F 13/00 LLP. 52 U.S. Cl. .................. ... 424/449; 424/448 58 Field of Search ...................................... 424/448, 449 57 ABSTRACT A transdermal therapeutic System for the prophylaxis and 56) References Cited pretreatment of a poisoning caused by highly toxic organo U.S. PATENT DOCUMENTS phosphorus neurotoxins is characterized in that it has a pharmaceutical formulation with an active Substance com 3,742,951 7/1973 Zaffaroni ................................. 128/268 bination consisting of at least one parasympathomimetically 3,797,494 3/1974 Zaffaroni ...... ... 128/268 active Substance and at least one parasympatholytically 3.996,934 12/1976 Zaffaroni .......... ... 128/268 active Substance. 4,031,894 6/1977 Urquhart et al. ... 128/268 4,981,858 1/1991 Fisher ... ... 514/278 5,089,267 2/1992 Hille ........................................ 424/449 6 Claims, 1 Drawing Sheet 2 5,939,095 1 2 TRANSIDERMAL THERAPEUTIC SYSTEM immediately on occurrence of the first Symptoms of the AND A PROCESS FOR THE COMBINED poisoning. The requirement with respect to the carbamate TRANSIDERMAL APPLICATION OF used in the pretreatment is that it should not have significant PHYSOSTIGMINE AND SCOPOLAMINE FOR undesired effects at the highest possible, lasting protective THE PROPHYLAXIS AND PRETREATMENT action, in particular it must not impair reaction capacity. OF A POSONING CAUSED BY HIGHLY Some of the organophosphorus cholinesterase inhibitors TOXC ORGANOPHOSPHORUS are distinguished by the fact that they split off alkyl residues NEUROTOXINS IN PARTICULAR SOMAN after accumulation to the acetylcholinesterase, thus Stabiliz ing the bond (“aging”). The aged esterase inhibitor complex This application is a 371 of PCT/EP94/04048, filed Dec. cannot be reactivated by Oximes. In case of poisonings 6, 1994. caused by the nerve warfare agent Soman, aging already The present invention relates to a transdermal therapeutic occurs after 2 to 5 minutes. The therapy with atropine and System and to a proceSS for the combined transdermal Oximes can considerably be improved by a preliminary application of phySoStigmine and Scopolamine for the pro treatment with indirect parasympathomimetics, e.g., car phylaxis and preliminary treatment of poisoning caused by 15 bamic acid esters, Such as pyridostigmine and phySoStig highly toxic organophosphorus cholinesterase inhibitors, in C. particular Soman. In particular, the present invention is to Carbamic acid esters inhibit the acetylcholinesterase in a provide pharmaceutical formulations releasing Suitable manner Similar to that of phosphoric acids. However, the active Substances without detrimental side effects in a con bond is of a shorter duration and completely reversible. The trolled manner for the prophylactic treatment of poisonings fact that the carb amates inhibit part of the caused by organophosphorus cholinesterase inhibitors. acetylcholinesterase, if dosed Suitably, and thus remove it from the reach of the phosphoric esters and phosphonates BACKGROUND OF THE INVENTION having a stronger and prolonged inhibition may well be a The group of organophosphorus cholinesterase inhibitors decisive factor for their protective action, provided that the include certain esters of phosphoric acid derivatives, e.g., 25 pretreatment started in time. nitrostigmine (=diethyl-(4-nitrophenyl)-thiophosphate), bet Also, the treatment of poisoning caused by phosphoric ter known under the names Parathion or E 605, but they also insecticides requires prompt medical care in any case. Since include tabun, as well as the phosphonic acid derivatives medical care in case of harvesters cannot always be accom Sarin, Soman and VX. plished promptly, there is a need for drugs prophylactically Among other things cholinesterase-inhibiting phosphoric counteracting an intoxication. The use of carbamic acid esters are used as insecticides in agriculture. Since they have esters for this purpose has already been described a toxic effect on human beings too, the Staff working in (Leadbeater, L. Chem. in Brit. 24, 683, 1988). The same agriculture is Subject to a basic hazard to life and limb; this applies to the effectiveness of carbamic acid esters in the pretreatment of a Soman poisoning in animal experiments is true all the more since these organic phosphoric esters can 35 also be absorbed via the skin. AS compared to insecticides, (Fleischer, J. H., Harris, L. W. Biochem. Pharmacol. 14,641, the compounds tabun, Sarin, Soman and VX which belong to 1965; Berry, W. K., Davies, D. R. Biochem. Pharmacol. 19, the group of the So-called nerve warfare agents are distin 927, 1970). The effective dosage of drugs to be applied guished by a particularly high toxicity. All of these com prophylactically should not impair reactivity and functional pounds are more or le SS Strong inhibitors of capacity. However, carbamic acid esters have a low thera acetylcholinesterase, an enzyme which physiologically 40 peutic index. AS compared to pyridoStigmine, an increased blocks the effect of the transmitter acetylcholine released at protective action can be achieved by physostigmine, certain nerve endings. Most of the Symptoms of poisoning however, the Side effects are more Severe. caused by cholinesterase inhibitors are produced by an On principle, undesired parasympathomimetic effects of inundation with endogenic acetylcholine. 45 the carbamates can be repressed by combinations with a The basic drug therapy of Such a poisoning consists in the parasympatholytic (e.g., atropine, Scopolamine). administration of the parasympatholytic atropine, blocking DE-OS 41 15 558 describes a prophylactic antidote the exceeding muscarinic acetylcholine effects (e.g., consisting of a combination of pyridoStigmine or phySOS increase of Secretion in the respiratory System, tigmine and N-methyl-4-piperidyl-1-phenylcyclopentane bronchoSpasm, inhibition of the central nervous respiratory 50 carboxylate-hydrochloride or arpenal, Sycotrol, carmiphene drive). There is no Suitable antagonist available to normalize orbenactyzine, and, as an additional compelling component, the exceeding nicotinic acetylcholine actions (e.g., inhibi a tranquilizer, i.e., diazepam or clonazepam. The undesired tion of the impulse transmission at the Synapses of motorial effects of phySoStigmine or pyridoStigmine can therefore not nerves to the respiratory musculature and to other skeletal be Suppressed by the mentioned parasympatholytics alone, muscles up to a complete peripheral motor paralysis). The 55 for this reason tranquilizers are additionally administered, peripherally caused myoparesis can only be compensated by whose side effects are problematic too. Oximes, e.g., pralidoxime (PAM) or obido Xime Accordingly, it is necessary to allow the prophylactic (Toxogonine) whose mechanism of action consists in a administration of carbamic acid esters or other indirect reactivation of the inhibited acetylcholinesterase. parasympathomimetics at a dosage causing a Sufficient pro However, this post-exposure therapy is not Sufficient to 60 tection against organophosphorus cholinesterase inhibitors ensure Survival after poisoning with the double LDs of without undesired accompanying effects. Soman (LDso=dose which is lethal for 50% of the exposed Subjects). The probability of Survival after a Soman poison DESCRIPTION OF THE INVENTION ing increases only when a pretreatment with a carbamate, It is the object of the present