MXPA97005723A - Transderm formulation - Google Patents

Abstract

The present invention provides a method for the treatment of Alzheimer's disease using a transdermal formulation of xanomelin. The invention provides transdermal formulations of xanomeline in the desired patch

Description

TRANSDERMAL FORMULATION FIELD OF THE INVENTION The present invention provides a novel transdermal formulation containing the pharmaceutically active compound 3- (4- (hexyloxy) -l, 2,5-thiadiazol-3-yl) -l, 2,5,6-tetrahydro- l -methylpyridine (xanomeline).

BACKGROUND OF THE INVENTION Xanomelin, described in U.S. Patent No. 5,043,345 ('345), is a compound having -muscarinic activity, which may be useful for the treatment of Alzheimer's disease. As set forth in the '345 patent, xanomelin can be prepared in solid form for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral use. A formulation for a characteristic tablet is provided; so, the patent does not suggest that it is possible or desirable to prepare a transdermal xanomeline formulation in patch.

Ref. 25249 DETAILED DESCRIPTION OF THE INVENTION Applicants have discovered that the cross-market xenomeline formulation of this invention provides surprising beneficial effects. The present invention provides a method for the treatment of Alzheimer's disease with fewer side effects that are typically associated with muscarinic agonists such as xanomelin. The transdermal formulation of this invention provides consistent dosages of the active ingredient, continuous applications of the pharmaceutically active agent in the concentration of the plasma, and stimulations in accordance with the patient. The present invention provides a transdermal xanomelin formulation in patch which comprises an effective amount of xanomelin, from 0.1 to 10 parts by weight of azone, from 30 to 69.8 parts of ethanol, 29 to 50 parts by weight of water, from 0 to 30 parts by weight of propylene glycol, and from 1 to 5 parts by weight of Klucel HF. In addition, it provides a transdermal formulation of patch xanomeline which comprises an effective amount of xanomeline and from about 70 to 99.8% adhesive acrylate. This provides a transdermal patch where the xanomeline is intimately distributed in a matrix. Additionally, it provides a transdermal formulation of patch xanomeline which comprises an effective amount of xanomelin, from 85 to 97 parts by weight of ethanol and from 2 to 14.9 parts of Klucel HF. Finally, it provides a method for the treatment of Alzheimer's disease, which comprises the administration of xanomelin transdermally using a patch formulation. As used herein, "xanomelin" will refer to the free base, a pharmaceutically acceptable salt or solvate thereof. The free base is preferred. The cross-sold xanomeline patch formulations of the present invention provide surprising beneficial properties. The xanomeline tablet was associated with undesirable parasympathomimetic effects when administered to humans. Applicants have discovered that the patch transdermal formulation can minimize such effects, while providing higher and continuous plasma levels of the pharmaceutically active agent. Although the patch transdermal formulations claimed herein are preferred for the transdermal distribution of -xanomeline, other transdermal formulations may be employed. Percutaneous or transdermal distribution of pharmacologically active agents has been feasible in recent years, due in large part to vehicles which allow an increase in the penetration of said agents on the surface of the body in which they are applied. Such agents, which may be useful for the preparation of a transdermal patch xanomeline formulation, include, but are not necessarily limited to, dimethylsulfoxide (Patent of US Patent No. 3,551,554); various 1-substituted azacycloalkan-2-ones such as azone (U.S. Patent Nos. 4,562,075, 4,405-616, 4,326,893 and 3,989,816); sugar esters in combination with phosphine oxide sulfoxide (U.S. Patent Nos. 4,130,667, 4,130,643, 4,046,886, 3,952,099 and 3,896,238); low alkyl amides (U.S. Patent No. 3,472,931) certain certain aliphatic sulfoxides (U.S. Patent No. 3,093,256); a composition containing glycerol monooleate, e-tanol and isopropyl myristate (U.S. Patent 4,335, 115); a binary mixture of l-dodecylazacycloheptan-2-one and a compound selected from a diol or a second N-substituted azacycloalkyl-2-one (U.S. Patent No. 4, 557, 934); and polyethylene glycol monolaurate (U.S. Patent No. 4,568,343). The patents of the? U. Nos. 3,551, 554, 4,562,075, 4,405,616, 4,326,893, 3,989,816, 4,130,667, 4.1 to 30.643, 4,046,886, 3,952,099, 3,896,238, 3,472,931, 3,903,256, 4,335,115, 4,557,934 and 4,568,343 are incorporated herein by reference in their entirety. It is considered that the transdermal-in-patch formulations of this invention will find utility in both humans and animals, i. e., will have both medical and veterinary applications to provide an increase in percutaneous absorption of the pharmaceutically active agent. As used herein, the term "percutaneous" refers to the passage of such agents through the skin. (typically intact) The transdermal formulations of the present invention can be administered using a variety of devices which have been described in the art. For example, such devices include, but not limited to this, those disclosed in U.S. Nos. 3,598,122, 3,598,123 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, and 4,292,303 each of which is incorporated herein by reference in its entirety. Dosage forms of the present invention may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. These include, but are not limited to, gelling agents, cream and ointment bases, and the like. Xanomeline will be present in the dosage forms demanded in an effective amount. The term "an effective amount" will refer to an amount calculated to achieve and maintain blood levels, which will result in approaching the desired therapeutic or beneficial effect over the desired period of time. These amounts vary Syran depending on the amount of agent pharmacologically ac tive required to achieve the desired beneficial or therapeutic effect, whether one or more patches will be administered simultaneously the specific formulation of the patch, the age and -with diting patient to be treated, and the analogues. Such conventional titration techniques for dosing, familiar to those skilled in the art, can be used to determine the amount of xanomelin present in the final pharmaceutical dosage form for any specific location. The pharmacologically active xanomelin is administered by known techniques, such as that of placing the patch which contains said agent and the transdermal formulation, on the surface of the body and maintaining said medium on the surface of said body in relation to the transmitting agent and transmitting composition to it. One of the transdermal xanomeline patch formulations uses ethanol, water, azone, and, optionally, glycol, to increase the penetration of pharmacologically active xanomelin. As noted above, azone is known to be useful for increasing transdermal penetration, and is chemically l-dodecylazacycloheptan-2-one. Azona can be prepared as described in U.S. Patent No. 4,316,893, incorporated herein by reference. The formulation of the demanded compositions can be carried out by conventional methods, such as, for example, the simple mixing of all the components carried out perfectly. Artisans will appreciate that compositions with have diols, other containing propylene glycol and alcohols and others containing ethanol (i.e., 2-propanol) may Encon strate utility in transdermal xanomeline compositions as a component of the formulation. To the extent that such formulation shows the characteristics of the present compositions, such formulations are considered to be within the scope of the present invention. The present invention provides a transdermal xanomelin formulation in patch which comprises an effective amount of xanomeline, from 0.1 to 10 parts by weight of azone, from 30 to 69.8 parts of ethanol, from 29 to 50 parts by weight of water, from 0 to 30 parts by weight of propylene glycol, and from 1 to 5 parts by weight of Klucel HF. Preferred ranges for the formulation include from 2 to 4 parts by weight of azone, from 30 to 55 parts by weight of ethanol, from 0 to 20 parts by weight of propylene glycol, from 35 to 45 parts by weight of water, and from 2.5 to 3.5 parts of Klucel HF. A preferred embodiment is to omit propylene glycol from the formulation. It provides a transdermal patch formulation wherein an effective amount of xanomelin is intimately distributed in a matrix. A preferred matrix is a pressure sensitive adhesive.

In addition, it provides a transdermal formulation of patch xanomeline which comprises an effective amount of xanomelin and about 50 to 99.9% by weight of adhesive -acrylic. A preferred range of adhesive acrylic -consists of around 65 to about 99.8% by weight of a-cylindrical adhesive. Another preferred range of acrylic adhesive - from around 70 to about 98% by weight of acrylic adhesive. Another preferred range for the adhesive acrylate is from about 80 to 98 parts by weight. Adhesive acrylate is commercially available, and can be purchased, e.g., from National Starch and Chemical Corporation, Bridgewater New Jersey 08807, catalog number 80-1054. The adhesive acrylate typically contains 48% solids in 33% ethyl acetate / 28% heptane / 34% isopropanol / 5% toluene by weight. Additionally, this invention provides a transdermal patch xanomeline formulation which comprises an effective amount of xanomelin, from 85 to 97 parts by weight of ethanol and from 2 to 14.9 parts of Klucel HF. -Klucel HF is a commercially available gelling agent. For example, the Klucel HF can be purchased by Aqualon. Other suitable gelling agents can be selected by skilled artisans. Preferred ranges for the formulation are: from 92 to 96 parts by weight of ethanol and from -2.5 to 3.5 parts of Klucel HF or other suitable gelling agent. Another preferred range for such formulations comprises: from about 93 to about 95 parts by weight of ethanol and about 3 to about 3.5 parts of the gelling agent. The xanomelin compound can be prepared as described in U.S. Patent No. 5,043,345 Sauerberg et. to the. ('345) which is incorporated herein for reference in its entirety. As disclosed in the '345 patent, xanomelin may be useful for the treatment of Alzheimer's disease, for severe conditions of pain, for glaucoma, and for the stimulation of cognitive function of the anterior and hippocampal brain. mammals The formulation for the xanomelin tablet has been administered to patients with mildly and moderately severe Alzheimer's disease. Such a formulation for the xanomelin tablet is associated with parasympathomimetic-undesirable effects when administered to a group of subjects. Surprisingly, transdermal xanomelin formulations - now demanded - can minimize or eliminate such effects - while maintaining a desirable plasma concentration consistent with the pharmacologically active agent. This invention provides a method for the treatment of a condition associated with the modulation of a muscarinic receptor with minimal effects or with nonpara-sympathomimetic effects, which comprises the transdermal administration of xanomelin. Examples of such associated conditions-with the modulation of a muscarinic receptor include, but not limited to, diminishing perception, Alzheimer's disease, and severe pain conditions. Preferred transdermal patch formulations include, but are not limited to, a patch formulation containing an effective amount of xanomelin, azone, ethanol, water, optionally pro-pill glycol and Klucel HF; an effective amount of xanomelin intimately distributed in a matrix; an effective amount of xanomeline and an acrylic adhesive; an effective amount - of xanomeline, ethanol, and Klucel HF; all of them described here. As reported here, plasma levels were determined using gas chromatography methods familiar to skilled artisans. The artisan can establish the appropriate conditions for gas chromatographic analysis; so that a set of suggested conditions include the following: A capillary column of 30 cm X 0.25 m (J &W Scientific for example); hydrogen flow rate of 3.2 ml / min, helium flow rate of 14.3 ml / min, and air flow rate of 115.0 ml / min. The temperature gradient of the column is suggested to be 90 to 270 ° C, the detector to 250 ° C, and the injector to 250 ° C. One type of detection suggested is nitrogen-phosphorus. The artisan will recognize that other -conditions will also be effective; so, the present conditions are provided as a guide to assist the craftsman in the choice of the most desired parameters for these conditions. Suitable additives may additionally be alcohols such as 1,2-propane diol, 1,3-butylene glycol, 1-he-xadecanol, 2-hydroxy fatty alcohols, 2-octyldodecanol, 2-propa-nol, benzyl alcohol, cetylstearyl alcohol, diethylene glycol, dipropylene glycol, dodecanol, ethanol, glycerol, hexane-diol, octanol, oleyl alcohol, panthenol, phenyloctanol, polyethylene glycols, or polypropylene glycols, or fatty acids such as capric acid, linoleic acid, lauric acid, acid -ristic, n-valerianic acid, pelargonic acid, also other physiologically acceptable low molecular weight acids such as eg, 3-phenylpropionic acid, acetic acid, adipic acid, benzoic acid, salicyclic acid or its salts compatible with the skin. Similarly, sulfates and sulfonates of fatty acids, such as cetylstearyl sodium sulfate and lauryl sodium sulfate, can be used advantageously. Esters of the formula (CH3"(CH2") mC00) nR, wherein m is an integer from 8 to 16, preferably from 8 to 12; n is 1 or 2, preferably 1 and R is a lower alkyl (C to C residue) but also-compounds such as 1,3-diacetin, capric / caprylic triglyceride, diisopropyl adipate, ethyl oleate, (di-) stearate ethylene glycol, ethylene glycol monostearate, glycerol hydroxystearate, glycerol monostearate, hydrogenated castor oil, oleic acid esters, triacetin, alsof-thalate esters such as diethyl phthalate or, di- (2-ethylhexyl) -phthalate they can be added to the composition. Other compounds with an advantageous action on the flow of the drug substance in the skin, include sulfoxides, e.g. dimethyl sulfoxide or dodecyl methyl sulfoxide, amides such as diethyl-m-taluamide, dimethyl formamide, fatty acid diethanolamide, N-dimethyl acetamide, amines such as diethanolamine or triethanolamine, ethylene glycol derivatives as ethoxylated castoreum oil, oleyl alcohol / PEG-5- ether, glycerol ethers with polyethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, terpenes and terpenoids such as menthol, thiol, -cineol, isobornyl acetate, limonene and finally other compounds not belonging to a specific chemically defined group but which are known for those skilled in the art and used for that purpose, eg dimeticon, scalene, dimethyl isosorbide, lecithin, glycofurol, urea, N-methyl pyrrolidone.

Acrylic copolymers Acrylic copolymers are more specifically understood to be copolymers prepared from esters of acrylic acid and methacrylic acid with alcohols of C to C, dimethylamino or methanol or other suitable alcoholic components, vinyl acetate, vinyl pyrrolidone, styrene, butadiene, acrylic nitrile or other suitable compounds with a vinyl group.

The following examples are provided to further illustrate the invention claimed herein. The examples are provided for illustrative purposes only, and are not intended to limit the scope of the invention in any way.

EXAMPLE 1 Transdermal Free Base Formulation A sample of 0.5 g of free base xanomeline is dissolved in 9.25 g of ethanol (graduation 200). A sample of 0.75 g of azone and an aliquot of 5.0 g of propylene glycol are added to the ethanol mixture with stirring. A sample of 10 g of water is added to the mixture. The mixture is a cloudy suspension. Finally, 0.75 g of Klucel is added to the mixture and this is stirred until the Klucel disperses. The mixture is allowed to remain for 24 hours. A 2.0 g sample of the formulation prepared as described herein is administered by syringe in a transdermal reservoir-type adhesive system.

TIME CONCENTRATION IN DOGS hours after application ng / ml Plasma 1 2 3 Media + SEM 0 0 0 0 0 + 0 3 19 11 10 10.7 + 6.0 6 27 16 16 19.7 + 4.5 9 26 17 15 19.3 + 4.2 12 16 13 14 14.3 + 1.1 12 10 12 11.3 + 0.8 24 7 8 10 8.3 + 1.1 28 6 8 9 7.7 + 1.1 32 4 7 8 6.3 + 1.5 48 3 6 8 5.7 + 1.8 54 0 4 5 3.0 + 1.8 72 0 0 0 0 + 0 EXAMPLE 2 Transdermal Formulation without Polyethylene Glycol A sample of 0.5 g of free base xanomeline is dissolved in 13.0 g of ethanol (graduation 200). A sample of 0.75 g of azone is added to the ethanol mixture with stirring. A sample of 11.25 g of water is added to the mixture. The mixture is a clear solution. Finally, 0.75 g of Klucel is added to the mixture, and this is stirred until the Klucel disperses. It is allowed to mix - stay for 24 hours. A 2.0 g sample of the formulation prepared as described above, is administered in a transdermal, reservoir-by-syringe adhesive system.

TIME CONCENTRATION IN DOGS hours after application ng / ml Plasma 1 2 3 Media + SEM 0 0 0 0 0 + 0 3 19 12 4 11.7 + 5.3 6 24 17 6 15.7 + 6.4 9 18 11 4 11.0 + 4.9 12 12 9 5 8.7 + 2. 5 9 8 3 6.7 + 2.3 24 6 5 3 4.7 + 1. 1 28 9 4 0 4. 3 + 3. 2 32 7 3 0 3.3 + 2. 5 48 3 0 3 2.0 + 1.2 54 0 0 0 0 + 0 72 0 0 0 0 + 0 TIME CONCENTRATION IN MONOS hours after application ng / ml Plasma 1 2 3 Media + SEM 0 0 0 0 0 + 0 3 50 59 65 58 + 5.3 6 44 50 59 51 + 5.3 8 39 45 45 43 + 2.5 12 25 42 41 36 + 6.7 25 34 37 22 + 11.8 24 14 13 16 14.3 + 1.1 28 12 8 8 9.3 + 1.6 32 9 7 7 7.7 + 0.8 48 5 5 4 4.7 + 0.4 54 2 2 2 2 + 0 72 0 0 0 0 + 0 The patches were applied to the shaved chest of each Macaco monkey in India.

EXAMPLE 3 Transdermal Xanomeline in Gel A sample of 1.0 g of free base xanomeline is dissolved in 47.5 g of ethanol (graduation 200). Then about 1.5 g of a sample of the Klucel gelling agent is added to the solution, and it is stirred until it disperses. The gel is allowed to remain for 24 hours. A 2.0 g sample of the formulation prepared above is administered by syringe in a transdermal deposit type adhesive system. The patches prepared as indicated here, are applied to rats. The rats are sacrificed in pairs at various time points after application, and the brains of the rats are removed and frozen. The link between the antagonist ligand MI, H-pirenzepine and the muscarinic receptors in the brain is determined. The decrease in the -linkage is indicative of the drug or active metabolite present in the brain. The effect of the drug after oral administration lasts less than 6 hours. The percentage of ex vivo control linked to pirenzepine at 6 hours was 33%, at 12 hours 15%, at 24 hours 26%, and at 48 hours 53%. The average concentration of plasma using this patch formulation was as follows: MEDIUM PLASMA CONCENTRATION TIME (ng / ml) + SEM 6 109.8 + 35.53 12 152.4 + 30.18 24 115.9 + 43.02 48 28.07 + 5.995 EXAMPLE 4 Transdermal Xanomeline in Acrylic Adhesive A 600 mg sample of free base xanomeline is dissolved in 41.6 g of pressure-sensitive acrylic adhesive (catalog number 80-1054, National Starch and Chemical Corporation, Bridgewater, New Jersey 08807). The mixture is stirred for 2 hours in a three-roll mill. The mixture is covered along a length of about 3,000 linear thicknesses using a knife coater that provides about 20,000 gaps. The 20 thousand gaps provide an effective 20 mil thick envelope of the formulation over the linear release. The sample is allowed to dry to air for 24 hours. The sample is laminated on a polyester support. Patches prepared as indicated above, are applied to rats. The rats are sacrificed in pairs at various time points after application, and the rats are removed and frozen. The link between the antagonist ligand MI, H-pirenzepine, and the muscarinic receptors in the brain is determined. The decrease in the link is indicative of the drug or active metabolite present in the brain. The effect of the drug after oral administration lasts less than 6 hours .. The percentage of ex vivo control linked to ^ pirenzepine at 6 hours - it was 101%, at 12 hours 89%, at 24 hours 75% , and at 48 hours 105%. A transdermal formulation of xanomelin "in patch in acrylic adhesive is prepared substantially as described above, so that the patch formulation comprises 2 10.8 g of xanomeline per m (18% by weight) and 60 g of 2-sided adhesive. Acrylic per m (82% by weight) Individual patches 2 of 25 cm are prepared to provide 27.2 mg of free base xanomeline per patch.The patches are applied to the a-fated abdomen of the rats and the shaved chest of monkeys. ches are removed at 24 hours.

MEDIUM CONCENTRATION OF PLASMA IN RATS Time (ng / ml) + SEM N- 1. 00 4.635 + 1.750 3 2.00 7.198 + 0.986 3 4.00 11.211 + 0.883 3 6.00 10.398 + 1.251 3 8.00 8.261 + 1.193 3 10.00 9.576 + 0.000 1 15.00 12.284 + 3.107 3 18.00 9.435 + 1.540 3 24.00 10.870 + 0.319 3 30.00 0. 522 + 0.268 3 Two such adhesive patches are applied to the shaved chest of each monkey. The patches are removed at 24-hours.

MEDIUM CONCENTRATION OF PLASMA IN MONKEYS Time (ng / ml) + SEM N 1. 50 25.750 + 2.160 3 3.00 35.467 + 1.840 3 6.00 31.070 + 2.352 3 9.00 31.300 + 1.578 3 12.00 30.230 + 3.413 3 24.00 27.037 + 1.868 3 28.00 8.917 + 3.301 3 32.00 4.867 + 2.622 3 48.00 1.080 + 0.571 3 One such adhesive patch is applied to the shaved chest of each monkey. The patches are removed at 24 hours.

MEDIUM CONCENTRATION OF PLASMA IN MONKEYS Time (ng / ml) + SEM N 1. 50 6.940 + 0.205 3 3.00 9.897 + 1.642 3 6.00 9.757 + 0.802 3 9.00 9.433 + 1.140 3 12.00 9.760 + 1.160 3 24.00 9.330 + 0.589 3 28.00 1.793 + 0.101 3 32.00 0.800 + 0.055 3 48.00 0.123 + 0.072 3 EXAMPLE 5 Transdepane Xanomeline in Acrylic Adhesive 9. 0 g of free base xanomelin are dissolved in 91 g of an acrylic adhesive solution (solid content 50.0% catalog number 901-1052, National Starch &Chemical, Zut-phen, The Netherlands). The mixture is stirred for at least 0.5 hours and is covered by the linear release of 4 mil of siliconized polyethylene terephthalate to provide a cover layer-2 of 60 g / m (based on dry substance). The wet layer is dried for 30 minutes at room temperature, and then for 10 minutes at 50 ° C. The sample is laminated onto a support layer (1 mil) of polyethylene terephthalate. 2 The test samples of approximately 5 cm are perforated for in vitro skin penetration experiments on the thick skin of the ear of pigs (Franz type diffusion cell, at 37 ° C, phosphate regulator pH 4.4 as receiving fluid ). An accumulated average amount (n = 3) that penetrated 46 g of xanomeline was found after 24 hours.

EXAMPLE 6 Trandéraic Xanomelina in Acrylic Adhesive 14. 3 g of free base xanomelin are dissolved in 85.7 g of an acrylic adhesive solution (50.0% solids content, catalog number 901-1052, National Starch &Chemical, Zutphen, The Netherlands). The mixture is stirred for at least 0.5 hours and is covered by the linear release of 4 mil of siliconized polyethylene terephthalate to provide a coated layer of 2 60 g / m (based on dry substance). The wet layer 4 dry for 30 minutes at room temperature, and then for -10 minutes at 50 ° C. The sample is laminated on a support layer (1 mil) of polyethylene terephthalate. 2 The test samples of approximately 5 cm are perforated for in vitro skin penetration experiments on the thick skin of the ear of pigs (Franz type diffusion cell, at 37 ° C, pH 5.5 phosphate regulator as receiving fluid ). An accumulated average amount (n = 3) that penetrated 102 g of xanomeline was found after 24-hours.

EXAMPLE 7 Transdermal Xanomeline in Acrylic Adhesive 18. 0 g of free base xanomelin are dissolved in 82 g of an acrylic adhesive solution (50.0% solids content catalog number 901-1052, National Starch &Chemical, Zutphen, The Netherlands). The mixture is stirred for at least 0.5 hours and is covered by the linear release of 4 mil of siliconized polyethylene terephthalate to provide a coated layer of 2 60 g / m. (based on the dry substance). The wet layer is dried for 30 minutes at room temperature, and then for -10 minutes at 50 ° C. The sample is laminated on a support layer (1 mil) of polymethacrylic copolymer. 2 The test samples of approximately 5 cm are perforated for in vitro skin penetration experiments on the thick skin of the ear of pigs (Franz type diffusion cell at 37 ° C, pH 5.5 phosphate regulator as the receiving fluid) . An accumulated average amount (n = 2) that penetrated 332 g of xanomeline was found after 24-hours. Examples 5 to 7 illustrate the dependence of the index of penetration of xanomeline on the concentration of the drug. According to Fick's law, one would expect a linear increase in the diffusion index (and penetration) with an increase in the concentration of the drug. So, the following results, based on the examples, show an unexpected increase.

Concentration of xanomelin in a Penetration after 24 2 dry adhesive matrix (% w / w) hours pg / cm 18 46 (Example 5) 28. 5 102 (Example 6) 36 332 (Example 7) Values have been derived from clear solutions of the drug in the adhesive. Unfortunately, the saturation limit of about 23-28% (w / w) in this polymer limits the use of this unexpected advantage of favorably enriched xanomelin preparations. It is concluded from these unexpected results, that an optimal formulation must contain a slightly sub-saturated, saturated or even supersaturated amount of xanomeline for a better performance.

It is noted that in relation to this date, the best method known by the applicant to bring to practice the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, it is -claimed as property contained in the following.

Claims (20)

1. A transdermal formulation of xanomeline in which it comprises, as an active ingredient, an effective amount of xanomelin, about 0.1 to 10 parts by weight of azone, about 30 to 69.8 parts of ethanol, about 29 to 50 parts by weight. water weight, of; about 30 parts by weight of propylene glycol, and about 1 to 5 parts by weight of a gelling agent.

2. A transdermal formulation of xanomeline in accordance with claim 1, characterized in that the formulation contains 0 parts by weight of propylene glycol.

3. A transdermal formulation of xanomeline in par che according to claims 1 to 2, characterized in that the gelling agent is Klucel HF.

4. A transdermal formulation of xanomeline in which it comprises, as an active ingredient, an effective amount of xanomelin and about 88 to 99.8% acrylate -adhesive.

5. A transdermal formulation of xanomeline in par che according to claim 4, characterized in that the formulation contains about 80-98% acrylic adhesive.

6. A transdermal formulation of xanomeline in which it comprises, as an active ingredient, an effective amount of xanomelin, about 80 to 97 parts by weight of ethanol and about 2 to 20 parts of the gelling agent.

7. A transdermal formulation of xanomelin in par che according to claim 6, characterized in that the weight of ethanol is about 85 to 97 parts and the weight of the gelling agent is about 2 to 15 parts.

8. A transdermal formulation of xanomeline in par che according to claims 6 to 7, characterized in that the gelling agent is Klucel HF.

9. A transdermal xanomelin using a patch formulation according to any one of claims 1 to 8, characterized by its use in the treatment of a condition associated with the modulation of a musk rinic receptor.

10. A formulation according to claim 9, characterized in that the condition is a decrease in perception.

11. A formulation according to claim 9, characterized in that the condition is Alzheimer's disease.

12. A transdermal patch formulation which comprises, as an active ingredient, an effective amount of xanomelin.

13. A patch formulation according to claim 12, characterized in that xanomelin is distributed in a matrix.

14. A patch formulation according to claims 12 to 13, characterized in that the matrix consists of a pressure sensitive adhesive.

15. A patch formulation according to claim 12 to 14, characterized in that the pressure sensitive adhesive comprises an acrylic adhesive.

16. A patch formulation according to claims 12 to 14, characterized in that the matrix comprises a pressure sensitive adhesive selected from the group consisting of polymers and copolymers of alkyl esters of acrylic acid and methacrylic acid, the alkyl group has from 1 to 18 carbon atoms, ethylene copolymers of vinyl acetate with ethylene or with any of the aforementioned methacrylic and acrylic esters, polyvinyl pyrrolidone and vinyl pyrro-lidone copolymers, vinyl or with any of the methacrylic and acrylic esters mentioned above.

17. A transdermal patch formulation according to claims 12 to 16, characterized in that it additionally contains a penetration enhancer.

18. A transdermal patch formulation in accordance with claim 17, characterized in that the enhancer is present in an amount of 0.1 to 10 parts-by weight based on the total amount of the matrix, of xylene-meline and other constituents, excluding the enhancer , from the matrix.

19. A transdermal formulation according to claims 17 to 18, characterized in that the increment of the penetration is azone.

20. A transdermal patch formulation according to claims 12 to 19, characterized in that xanomelin is present in an amount of about 0.1 to 35% based on the total weight of the matrix.