United States Patent [19]
`Hille et al. (cid:9)
`
`[54] TRANSDERMAL THERAPEUTIC SYSTEM
`AND A PROCESS FOR THE COMBINED
`TRANSDERMAL APPLICATION OF
`PHYSOSTIGMINE AND SCOPOLAMINE FOR
`THE PROPHYLAXIS AND PRETREATMENT
`OF A POISONING CAUSED BY HIGHLY
`TOXIC ORGANOPHOSPHORUS
`NEUROTOXINS IN PARTICULAR SOMAN
`
`[75] Inventors: Thomas Wile; Walter Muller, both of
`Neuwied; Bodo Asmussen, Ammersbek,
`all of Germany
`
`[73] Assignee: LTS Lohmann Therapie-Systeme
`GmbH, Neuwied, Germany
`
`[21] Appl. No.: (cid:9)
`
`08/656,208
`
`[22] PCT Filed: (cid:9)
`
`Dec. 6, 1994
`
`[86] PCT No.: (cid:9)
`
`PCT/EP94/04048
`
`§ 371 Date: (cid:9)
`
`Jul. 30, 1996
`
`§ 102(e) Date: Jul. 30, 1996
`
`[87] PCT Pub. No.: W095/15755
`
`PCT Pub. Date: Jun. 15, 1995
`
`[30] (cid:9)
`
`Foreign Application Priority Data
`
`Dec. 10, 1993 [DE] Germany (cid:9)
`
` P 43 42 174
`
`[51] Int. C1.6
`[52] U.S. Cl. (cid:9)
`[58] Field of Search (cid:9)
`
` A61F 13/00
` 424/449; 424/448
` 424/448, 449
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,742,951 7/1973 Zaffaroni (cid:9)
`3,797,494 3/1974 Zaffaroni (cid:9)
`3,996,934 12/1976 Zaffaroni (cid:9)
`4,031,894 6/1977 Urquhart et al. (cid:9)
`4,981,858 1/1991 Fisher (cid:9)
`5,089,267 2/1992 Hille (cid:9)
`
` 128/268
` 128/268
` 128/268
` 128/268
` 514/278
` 424/449
`
`11111111111111111111111111111111!19 t111111111111111111111111111111111
`
`[n] Patent Number: (cid:9)
`[45] Date of Patent: (cid:9)
`
`5,939,095
`Aug. 17, 1999
`
`4/1992 Fisher (cid:9)
`5,106,831
`5,364,629 11/1994 Kochinke (cid:9)
`5,391,375
`2/1995 Hille (cid:9)
`
`
`
`
`
`514/2
`424/449
`424/449
`
`FOREIGN PATENT DOCUMENTS
`
`3/1986 Germany .
`3 315 272
`2/1990 Germany .
`3 843 239
`4 115 558 11/1992 Germany .
`
`OTHER PUBLICATIONS
`
`Can. J. Physiol. and Pharmacol., Effects of subchronic
`pyridostigmine pretreatment on the toxicity of soman, J. D.
`Shiloff, et al. vol. 64, pp. 1047-1049, 1986.
`Gov. Rep. Announce Index, Comparing the Efficacy of
`Physostigmine pretreatment in combination with Scopola-
`mine versus Artane against Soman Challenge, R.P. Solana,
`et al, vol. 89, No. 15, abstract 942,440, 1989.
`Leadbetter, "When all else fails", Chemistry in Britain, Jul.
`1988 pp. 683-688.
`Fleisher et al., "Dealkylation As A Mechanism For Aging of
`Cholinesterase After Poisoning With Pinacolyl Meth-
`ylphosphonofluoridate"Biochemical Pharmacology, 1965,
`vol. 14, pp. 641-650.
`Berry et al., "The Use of Carbamates And Atropine In The
`Protection of Animals Against Poisoning By 1,2,2–Trimeth-
`ylpropyl Methylphosphonofluoridate"Biochemical Pharma-
`cology, vol. 19, pp. 927-934 (1990).
`
`Primary Examiner—a Gabrielle Brouillette
`Attorney, Agent, or Firm—Wenderoth, Lind & Ponack,
`L.L.P.
`
`[57] (cid:9)
`
`ABSTRACT
`
`A transdermal therapeutic system for the prophylaxis and
`pretreatment of a poisoning caused by highly toxic organo-
`phosphorus neurotoxins is characterized in that it has a
`pharmaceutical formulation with an active substance com-
`bination consisting of at least one parasympathomimetically
`active substance and at least one parasympatholytically
`active substance.
`
`6 Claims, 1 Drawing Sheet
`
`1
`
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`Noven v. Novartis and LTS Lohmann
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`(cid:9)
`(cid:9)
`(cid:9)
`

`

`U.S. Patent (cid:9)
`
`Aug. 17, 1999
`
`5,939,095
`
`FIG. 1
`
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`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
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`

`5,939,095
`
`1
`TRANSDERMAL THERAPEUTIC SYSTEM
`AND A PROCESS FOR THE COMBINED
`TRANSDERMAL APPLICATION OF
`PHYSOSTIGMINE AND SCOPOLAMINE FOR
`THE PROPHYLAXIS AND PRETREATMENT
`OF A POISONING CAUSED BY HIGHLY
`TOXIC ORGANOPHOSPHORUS
`NEUROTOXINS IN PARTICULAR SOMAN
`
`This application is a 371 of PCT/EP94/04048, filed Dec.
`6, 1994.
`The present invention relates to a transdermal therapeutic
`system and to a process for the combined transdermal
`application of physostigmine and scopolamine for the pro-
`phylaxis and preliminary treatment of poisoning caused by
`highly toxic organophosphorus cholinesterase inhibitors, in
`particular soman. In particular, the present invention is to
`provide pharmaceutical formulations releasing suitable
`active substances without detrimental side effects in a con-
`trolled manner for the prophylactic treatment of poisonings
`caused by organophosphorus cholinesterase inhibitors.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`The group of organophosphorus cholinesterase inhibitors
`include certain esters of phosphoric acid derivatives, e.g.,
`nitrostigmine (=diethyl-(4-nitrophenyl)-thiophosphate), bet-
`ter known under the names Parathion or E 605, but they also
`include tabun, as well as the phosphonic acid derivatives
`sarin, soman and VX.
`Among other things cholinesterase-inhibiting phosphoric
`esters are used as insecticides in agriculture. Since they have
`a toxic effect on human beings too, the staff working in
`agriculture is subject to a basic hazard to life and limb; this
`is true all the more since these organic phosphoric esters can
`also be absorbed via the skin. As compared to insecticides,
`the compounds tabun, sarin, soman and VX which belong to
`the group of the so-called nerve warfare agents are distin-
`guished by a particularly high toxicity. All of these com-
`pounds are more or less strong inhibitors of
`acetylcholinesterase, an enzyme which physiologically
`blocks the effect of the transmitter acetylcholine released at
`certain nerve endings. Most of the symptoms of poisoning
`caused by cholinesterase inhibitors are produced by an
`inundation with endogenic acetylcholine.
`The basic drug therapy of such a poisoning consists in the
`administration of the parasympatholytic atropine, blocking
`the exceeding muscarinic acetylcholine effects (e.g.,
`increase of secretion in the respiratory system,
`bronchospasm, inhibition of the central nervous respiratory
`drive). There is no suitable antagonist available to normalize
`the exceeding nicotinic acetylcholine actions (e.g., inhibi-
`tion of the impulse transmission at the synapses of motorial
`nerves to the respiratory musculature and to other skeletal
`muscles up to a complete peripheral motor paralysis). The
`peripherally caused myoparesis can only be compensated by
`oximes, e.g., pralidoxime (PAM) or obidoxime
`(Toxogonin®) whose mechanism of action consists in a
`reactivation of the inhibited acetylcholinesterase.
`However, this post-exposure therapy is not sufficient to 60
`ensure survival after poisoning with the double LD„ of
`soman (LD„=dose which is lethal for 50% of the exposed
`subjects). The probability of survival after a soman poison-
`ing increases only when a pretreatment with a carbamate,
`e.g., pyridostigmine or physostigmine, has taken place prior
`to the poison exposure, and when additionally the conven-
`tional antidote-therapy with atropine and an oxime is started
`
`2
`immediately on occurrence of the first symptoms of the
`poisoning. The requirement with respect to the carbamate
`used in the pretreatment is that it should not have significant
`undesired effects at the highest possible, lasting protective
`action, in particular it must not impair reaction capacity.
`Some of the organophosphorus cholinesterase inhibitors
`are distinguished by the fact that they split off alkyl residues
`after accumulation to the acetylcholinesterase, thus stabiliz-
`ing the bond ("aging"). The aged esterase inhibitor complex
`cannot be reactivated by oximes. In case of poisonings
`caused by the nerve warfare agent soman, aging already
`occurs after 2 to 5 minutes. The therapy with atropine and
`oximes can considerably be improved by a preliminary
`treatment with indirect parasympathomimetics, e.g., car-
`bamic acid esters, such as pyridostigmine and physostig-
`mine.
`Carbamic acid esters inhibit the acetylcholinesterase in a
`manner similar to that of phosphoric acids. However, the
`bond is of a shorter duration and completely reversible. The
`fact that the carbamates inhibit part of the
`acetylcholinesterase, if dosed suitably, and thus remove it
`from the reach of the phosphoric esters and phosphonates
`having a stronger and prolonged inhibition may well be a
`decisive factor for their protective action, provided that the
`pretreatment started in time.
`Also, the treatment of poisoning caused by phosphoric
`insecticides requires prompt medical care in any case. Since
`medical care in case of harvesters cannot always be accom-
`plished promptly, there is a need for drugs prophylactically
`counteracting an intoxication. The use of carbamic acid
`esters for this purpose has already been described
`(Leadbeater, L. Chem. in Brit. 24, 683, 1988). The same
`applies to the effectiveness of carbamic acid esters in the
`pretreatment of a soman poisoning in animal experiments
`(Fleischer, J. H., Harris, L. W. Biochem. Pharmacol. 14, 641,
`1965; Berry, W. K., Davies, D. R. Biochem. Pharmacol. 19,
`927, 1970). The effective dosage of drugs to be applied
`prophylactically should not impair reactivity and functional
`capacity. However, carbamic acid esters have a low thera-
`peutic index. As compared to pyridostigmine, an increased
`protective action can be achieved by physostigmine,
`however, the side effects are more severe.
`On principle, undesired parasympathomimetic effects of
`the carbamates can be repressed by combinations with a
`parasympatholytic (e.g., atropine, scopolamine).
`DE-OS 41 15 558 describes a prophylactic antidote
`consisting of a combination of pyridostigmine or physos-
`tigmine and N-methyl-4-piperidyl-1-phenylcyclopentane
`carboxylate-hydrochloride or arpenal, sycotrol, carmiphene
`or benactyzine, and, as an additional compelling component,
`a tranquilizer, i.e., diazepam or clonazepam. The undesired
`effects of physostigmine or pyridostigmine can therefore not
`be suppressed by the mentioned parasympatholytics alone,
`for this reason tranquilizers are additionally administered,
`whose side effects are problematic too.
`Accordingly, it is necessary to allow the prophylactic
`administration of carbamic acid esters or other indirect
`parasympathomimetics at a dosage causing a sufficient pro-
`tection against organophosphorus cholinesterase inhibitors
`without undesired accompanying effects.
`
`50
`
`55
`
`DESCRIPTION OF THE INVENTION
`It is the object of the present invention to provide a special
`65 pharmaceutical formulation of active substances for the
`transdermal application as a skin patch for the prophylaxis
`and preliminary treatment of a poisoning caused by highly
`
`NOVARTIS EXHIBIT 2031
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 6
`
`

`

`5,939,095
`
`4
`The present invention will be illustrated in more detail by
`means of an example:
`
`EXAMPLE
`
`BRIEF DESCRIPTION OF DRAWING
`
`3
`toxic organophosphorus cholinesterase inhibitors, involving
`the lowest possible extent of side effects, with the following
`objectives:
`continuous and uniform release of the active substances
`over a period of 72 h, (cid:9)
`I. Active substance-free laminate
`the protective effect of the active substances shall be
`887.0 kg acidic polyacrylate solution (50%)
`higher than the protective effect of atropine and reac-
`10.1 kg basic methacrylate
`tivating oxime,
`undesired effects, e.g., impairment of functional capacity,
`50.4 kg triacetin
`shall not occur in the chosen dose.
`0.508 kg aluminum acetylacetonate
`According to the present invention this object is achieved
`and
`by a transdermal therapeutic therapy-system having an
`37.8 kg ethanol
`active substance combination of at least one parasympatho-
`are mixed, and a polyester film which has been rendered
`mimetically active substance and at least one parasym-
`removable by means of siliconization is coated with this
`patholytically active substance. This solution is surprising 15
`solution. After evaporation of the solvents the adhesive
`all the more, since the present invention shows that the
`coating weight amounts to 120 g/m2. The laminate is cov-
`parasympatholytically active substance not only contributes
`ered with a supporting fabric made of polyester and elastic
`to the protective action but also reliably suppresses the
`in the longitudinal and transverse direction (active
`undesired effects of the parasympathomimetically active
`substance-free laminate).
`substance. (cid:9)
`II. Scopolamine-Containing Laminate
`Administration forms, such as transdermal therapeutic
`918.75 kg acidic polyacrylate solution (50%)
`systems, releasing active substances in a controlled manner
`84.38 kg 1-dodecanol
`over extended periods of time are known in the art.
`In a formulation for the transdermal administration of
`3.68 kg acetylacetone
`compounds according to the present invention the pharma- 2
`3.38 kg aceylacetonate and
`5 (cid:9)
`ceutically active substances may be contained in a matrix
`18.0 kg scopolamine base
`from which they are released in the desired gradual, constant
`are mixed, and a polyester sheet which has been rendered
`and controlled manner. The permeability of the matrix
`removable by means of siliconization is coated with this
`during the release of the compound is based on diffusion.
`solution. After evaporation of the solvents the adhesive
`Such a system is described in German patent DE 33 15 272. 3
`0 coating weight amounts to 150 g/m2. The laminate is cov-
`This system consists of an impermeable cover layer, a
`ered with a polyester sheet having a thickness of 23 /inn.
`specially constructed, oversaturated active substance reser-
`III. Physostigmine-Containing Laminate
`voir connected therewith and made of a polymer matrix, a
`542.2 kg acidic polyacrylate solution (50%)
`pressure sensitive adhesive layer connected with the reser-
`125.8 kg 1-dodecanol
`voir and permeable to the active substance, and a protective 3
`5 (cid:9)
`layer which covers the pressure sensitive adhesive layer and
`83.3 kg physostigmine
`is removed prior to use. Also, systems are possible in which
`83.3 kg basic methacrylate
`the reservoir layer has a self-tackiness that is high enough
`16.6 kg aluminum acetylacetonate and
`for it to represent the pressure sensitive adhesive layer at the
`166.6 kg ethanol
`same time. German patent DE 38 43 239 describes such a 4
`are mixed, and a PE-sheet which has been rendered remov-
`system. In principle it is also possible to apply two separate
`able by means of siliconization is coated with this solution.
`TTS having one active substance each.
`After evaporation of the solvents the adhesive coating
`According to the present invention a patch system can be
`weight amounts to 240 g/m2. The following narrow rolls are
`constructed such that it comprises two separate reservoirs
`5 cut:
`for the parasympathomimetically active substance and the 4
`PE-sheet with siliconization: 87 mm in width (I)
`parasympatholytically active substance; this would mean a
`"Two-in-One-TTS". As an alternative, a TTS can be devel-
`Active substance-free laminate: 87 mm in width (II)
`oped that comprises two active substances in one reservoir.
`Scopolamine-containing laminate: 15 mm in width (III)
`When the active substances are absorbed through the skin,
`Physostigmine-containing laminate: 50 mm in width (IV)
`the person to be treated thus receives a controlled and 50
`The removable siliconized PE-sheets are removed from
`predetermined flow of active substances.
`the scopolamine and physostigmine-containing laminates (II
`Other suitable transdermal formulations are described in
`and III), and the adhesive side of rectangles having a size of
`U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,
`15x50 mm2 and 50x50 mm2 are transferred on the middle of
`894. These formulations basically consist of a back face
`and parallel to the edges of the PE-film (I).
`representing one of the surfaces, an adhesive layer which is 55
`Then, the removable PE-sheet I is removed from the
`permeable to the active substance and represents the other
`active substance-free laminate (II), and the adhesive side of
`surface, and finally a reservoir comprising the active sub-
`the laminate (II) is laminated along the edges over the web
`stance between the layers forming the surfaces.
`(I) provided with the rectangles. The systems are separated
`Alternatively, the active substance may be comprised in a
`by means of an oval punching tool.
`plurality of microcapsules which are distributed within a 60
`permeable adhesive layer. In any case, the active substances
`are continuously released from the reservoir or microcap-
`sules through a membrane into the adhesive layer which is
`permeable to the active substances and which is in contact
`with the skin or mucosa of the person to be treated. In the
`case of microcapsules, the material of the capsule may also
`act as a membrane.
`
`FIG. 1 shows the top view of the systems after removal of
`the protective layer.
`1. represents a reservoir portion with scopolamine
`2. represents a reservoir portion with physostigmine
`3. represents an active substance-free adhesive edge.
`
`5
`
`0 (cid:9)
`
`20
`
`65 (cid:9)
`
`NOVARTIS EXHIBIT 2031
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`
`

`

`5
`The controlled release of the active substances both into
`physiological saline and through excized rodent skin are
`shown in Tables 1 and 2.
`
`TABLE 1
`
`Accumulated release after
`
`Scopolamine [mg/cm2]
`Physostigmine [mg/cm2]
`
`2h (cid:9)
`
`0.1
`0.5
`
`0.14
`0.69
`
`0.20
`1.02
`
`0.33
`1.71
`
`Table 1:
`In-vitro-liberation of scopolamine and physostigmine
`Release apparatus: rotating cylinder acc. to US PXXII
`Release medium: physiological saline solution
`Content determination by means of HPLC
`
`5,939,095
`
`6
`
`TABLE 3
`
`Protective action of different kinds of preliminary treatments in
`guinea pigs against a load of 1.5 LD50 soman IM, without an addi-
`tional post-exposure therapy
`
`5
`
`4h (cid:9)
`
`8h (cid:9)
`
`24h
`
`Pretreatment
`
`Lethality rate (24 h)
`
`no
`pyridostigmine transdermally (3 cm2/kg)
`pyridostigmine transdermally (1.5 cm2/kg)
`+ Alzet 3-scopolamine 10 ng/kg-111-1
`pyridostigmine transdermally (1.5 cm2/kg)
`pyridostigmine transdermally (1.5 cm2/kg)
`+ Alzet 3-scopolamine 9 ng kg 1h-1
`physostigmine transdermally (1.5 cm2/kg)
`+ Scopoderm 3-TTS
`
`10 (cid:9)
`
`15 (cid:9)
`
`10/10
`6/6
`5/6
`
`6/20
`0/10
`
`1/10
`
`TABLE 2
`
`TABLE 4
`
`Accumulated release after
`
`8 h
`
`24 h
`
`48 h
`
`72 h
`
`20 (cid:9)
`
`Scopolamine [ug/2.54 cm2]
`Physostigmine [ug/2.54 cm2]
`
`5.6
`95
`
`67.6
`850
`
`200
`2160
`
`3430
`
`Efficacy of a physostigmine or combined physostigmine-scopolamine-
`pretreatment in guinea pigs against a soman load and additional
`post-exposure therapy with atropine sulfate and obidoxime chloride
`(in each case 10 mg/kg body weight IM, 1 min. after soman).
`
`25
`
`30
`
`Pretreatment
`
`physostigmine transdermally (1.5 cm2/kg)
`
`pyridostigmine transdermally (1.5 cm2/kg) +
`Alzet 3-scopolamine 4.5 ng kg 1h-1
`
`Efficacy index*)
`(fiduciary limits)
`
`3.45
`(3.00; 3.95)
`3.70
`(3.65; 4.50)
`
`*) efficacy index =
`
`LD 50 with treatment
`
`LD 50 without treatment
`
`Table 2:
`Penetration rate of scopolamine and physostigmine
`Release apparatus: Franz-Cell (type of skin: guinea pig)
`Release medium: physiological saline solution
`Determination of content by means of HPLC.
`The results shown in Table 2 prove the functional perfor-
`mance of the transdermal therapeutic system according to
`the present invention over a period of two and three full
`days, respectively.
`Potency test based on animal experiments:
`The protective effect of pyridostigmine and physostig-
`mine alone and combined with scopolamine was tested on
`the basis of a soman poisoning in guinea pigs. 24 hours
`before the soman load, 6 to 10 animals received a pyri-
`dostigmine (3 cm2/kg) or physostigmine (1.5 cm2/kg) skin
`patch. After a 24-hour application of the physostigmine skin
`patch, plasma concentrations of 0.9±0.3 ng/ml (average
`value ±SEM; n=4) were measured. When the larger pyri-
`dostigmine skin patch was applied, the cholinesterase activ-
`ity in the total blood was inhibited by 38±4%, in case of the
`smaller physostigmine skin patch by 48±10%. In order to
`test the additional protective action of scopolamine either a
`commercial transdermal therapeutic system (Scopoderm®
`TTS) was used, or osmotic minipumps (Alzet®) having a
`release rate of 9 to 10 ng scopolamine hydrobromide per kg
`of body weight and hour were implanted subcutaneously
`into the animals. The results obtained after application of the
`pyridostigmine and physostigmine skin patches and a soman
`load of 1.5 LD„ intramuscular are shown in Table 3.
`The physostigmine pretreatment is not only effective in
`case of a poisoning by soman but also in case of a sarin
`poisoning: after a transdermal pretreatment with
`physostigmine-Scopoderm®-TTS and a load of 1.5 LD„
`sarin, 9 out of 10 guinea pigs survived without an additional
`post-exposure therapy.
`The efficacy of the physostigmine pretreatment with and
`without scopolamine against soman was determined in an
`additional test series on guinea pigs, wherein an additional
`post-exposure therapy was applied using atropine sulfate
`and obidoxime chloride, based on the efficacy index 65
`(protective ratio=quotient of LD„ with treatment and LD„
`without treatment) (Table 4).
`
`35
`
`In test series using two different physostigmine
`formulations, the combined pretreatment with transdermal
`physostigmine and Scopoderm®-TTS without post-
`exposure therapy resulted in efficacy indices of 2.11 (1.71;
`2.60) and 2.27 (1.86; 2.79), respectively.
`The pharmocokinetics of transdermally administered phy-
`40 sostigmine and scopolamine was tested on pigs. Within a
`period of 5 to 6 h, the plasma concentration rose to a level
`which lasted for 72 h. In order to examine the effectiveness
`against an intravenous soman load in pigs, physostigmine
`skin patches (0.5 cm2/kg) were used which resulted in
`plasma concentrations of 1.1±0.1 ng/ml (16±3% inhibition
`of the cholinesterase activity in the total blood) after 48 h.
`The Scopoderm®-TTS caused scopolamine concentrations
`in the plasma of 0.18±0.06 ng/ml (n=9) after 24 h. The
`following results (Table 5) were obtained for a load of 2.5
`LD„ soman without additional post-exposure therapy:
`
`45
`
`50
`
`55
`
`TABLE 5
`
`Protective action of the physostigmine and physostigmine-sco-
`polamine pretreatment in pigs against a load of 2.5 LD50 soman
`IV, without additional post-exposure therapy
`
`Pretreatment
`
`Lethality rate (cid:9)
`
`Mean recovery time
`*) (min.)
`
`Scopoderm 3-TTS (cid:9)
`Physostigmine transdermally (cid:9)
`60 (0.5 cm2/1(g)
`Physostigmine transdermally (cid:9)
`(0.5 cm2/kg)
`+ Scopoderm 3-TTS
`
`4/4
`1/4 (cid:9)
`
`2/5 (cid:9)
`
`146
`
`29
`
`*) Recovery time = period until the surviving animals are able to stand and
`walk.
`
`When the pigs were not subjected to 2.5 LD„ but to 4
`LD„ soman IV after the transdermal physostigmine-
`
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`

`5,939,095
`
`8
`7
`scopolamine-pretreatment, and when a post-exposure (cid:9)
`which comprises the transdermal therapeutic application of
`therapy was carried out 20 s later (0.5 mg atropine sulfate (cid:9)
`a patch to a patient in need thereof of an effective amount of
`an active substance combination of at least one parasym-
`and 3 mg obidoxime chloride/kg body weight, IM), 3 out of
`5 animals survived, with the surviving animals having (cid:9)
`pathomimetically active substance and at least one parasym-
`higher physostigmine and scopolamine concentrations than 5 patholytically active substance, at least one of said active
`the dead ones. When the post-exposure therapy additionally (cid:9)
`substances being in a form acting as a depot.
`comprised loprazolam (0.2 mg/kg, IM) all of the 5 animals
`2. A method according to claim 1 wherein the parasym-
`survived, however, recovery of 2 animals was insufficient, (cid:9)
`patholytically active substance is selected from the group
`exemplifying the disadvantages of the benzodiazepine (cid:9)
`consisting of the tropane alkaloids, a pharmaceutically
`administration. (cid:9)
`10 acceptable salt thereof and a racemic mixture thereof.
`Clinical Tolerance Studies
`3. A method according to claim 1 wherein the parasym-
`The tolerance of physostigmine skin patches was tested
`pathomimetically active substance is an indirect parasym-
`with 11 voluntary test persons (age 29±2 years) under (cid:9)
`pathomimetic.
`double-blind-conditions as against placebo and additional
`4. A method according to claim 3 wherein the parasym-
`use of Scopoderm® TTS. With the physostigmine concen- 15 pathomimetically active substance is an acetylcholine-
`trations in the plasma amounting to 0.3±0.1 ng/ml after 48
`sterase inhibitor selected from the group consisting of
`h, and the scopolamine concentrations amounting to (cid:9)
`physostigmine, heptylphysostigmine, neostigmine,
`0.07±0.01 ng/ml, scopolamine proved to be effective in (cid:9)
`pyridostigmine, galanthamine, tetrahydroacridine,
`suppressing the undesired effects caused by physostigmine, (cid:9)
`velnacridine, their pharmaceutically acceptable salts and
`in particular nausea and vomiting. Statistically significant 20 racemic mixtures.
`changes in behavior and performance could not be detected
`5. A method according to claim 1 wherein separate areas
`in case of the combined physostigmine-scopolamine- (cid:9)
`of matrix or reservoir portions for the parasympathomimeti-
`treatment. Accordingly, the object according to the present (cid:9)
`cally active substance and for the parasympatholytically
`invention is achieved, i.e., to develop an administration form (cid:9)
`active substance in a therapeutic patch are used.
`comprising at least one parasympathomimetically active 25 (cid:9)
`6. A method according to claim 1 wherein physostigmine
`substance and at least one parasympatholytically active (cid:9)
`and/or a pharmaceutically acceptable salt thereof is used as
`substance, without occurrence of the side effects typical for (cid:9)
`parasympathomimetically active substance and that scopo-
`these substances. (cid:9)
`lamine and/or a pharmaceutically acceptable salt thereof is
`We claim: (cid:9)
`used as parasympatholytically active substance.
`1. A method for the prophylaxis or pretreatment of poi- 30
`soning caused by toxic organophosphorus neurotoxins,
`
`NOVARTIS EXHIBIT 2031
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 6 of 6
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