Transdermal device including porous microparticles

Abstract

The present invention relates to a transdermal device including porous microparticles capable of containing an active principle, in particular nicotine, and to the use thereof as a drug, in particular for tobacco cessation. The present invention further relates to a method for preparing a transdermal device including porous microparticles filled with an active principle.

Claims

1. A self-adhesive transdermal device including the association of a support layer and a self-adhesive matrix layer and a detachable protective film, said self-adhesive matrix layer allowing the device to adhere to skin for at least 12 hours and said self-adhesive matrix layer including, in relation to the total weight of the self-adhesive matrix layer: a. 65 to 93% by weight of at least one self-adhesive polymer selected from the group comprising polymers of acrylic or acrylate, wherein the polymers of acrylic or acrylate comprise monomers selected from the group comprising vinyl acetate, 2-ethylhexyl acrylate, butyl acrylate, acrylic acid, methyl methacrylate, methyl acrylate, tert—octyl acrylamide, 2-hydroxy ethyl acrylate, glycidyl methacrylate, or mixtures; b. 2 to 15% by weight of at least one microporous solid polymer in the form of microparticles containing nicotine, said microporous solid polymer being comprised of monomer units selected from the group of monomers comprising lauryl methacrylate and glycol dimethacrylate, said microparticles having an average size comprised between 1 μm and 100 μm and said microparticles being distributed within the self-adhesive polymer mass; and c. 5 to 20% by weight of nicotine.

2. The device according to claim 1, wherein the monomers are selected from the group comprising acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, or mixtures thereof.

3. The device according to claim 1, wherein said microporous solid polymer is provided in the form of microparticles of average size comprised between 5 μm and 50 μm.

4. The device according to claim 1, wherein said microporous solid polymer is provided in the form of microparticles of average size comprised between 15 μm and 30 μm.

5. The device according to claim 1, wherein said microporous solid polymer has a total pore volume comprised between 0.5 ml/g and 3.0 ml/g.

6. The device according to claim 5, wherein said microporous solid polymer has a total pore volume comprised between 1 ml/g and 2 ml/g.

7. The device according to claim 1, wherein said microporous solid polymer has a granular pore volume comprised between 0.2 ml/g and 3.0 ml/g.

8. The device according to claim 7, wherein said microporous solid polymer has a granular pore volume comprised between 0.5 ml/g and 1.5 ml/g.

9. The device according to claim 1, wherein the microporous solid polymer is distributed homogeneously within the self-adhesive polymer mass.

10. The device according to claim 1, wherein the active principle is adsorbed homogeneously in the microporous solid polymer mass.

11. The device according to claim 1, wherein the basis weight of the self-adhesive matrix layer is comprised between 50 and 300 g/m.sup.2.

12. The device according to claim 11, wherein the basis weight of the self-adhesive matrix layer is comprised between 100 and 200 g/m.sup.2.

13. The device according to claim 1, wherein the self-adhesive matrix layer includes at least one antioxidant agent selected from the group comprising butylhydroxytoluene (BHT), butyl hydroxy anisole (BHA), ascorbyl palmitate, alpha tocopherol and esters thereof, citric acid, propyl gallate and mixtures thereof.

14. The device according to claim 13, wherein the antioxidant agent is present in said self-adhesive matrix layer, in relation to the total weight of said self-adhesive matrix layer, in a proportion comprised between 0.01 and 1% by weight.

15. The device according to claim 1, having an average nicotine delivery rate from the matrix layer comprised between 10 μg/cm.sup.2/h and 50 μg/cm.sup.2/h, during a time interval comprised between 1 and 24 hours.

16. A method for preparing a transdermal device according to claim 1, comprising the following steps: a. mixing the self-adhesive polymer, the microporous solid polymer, nicotine and optionally an oxidizing agent until a homogeneous mixture is obtained; b. coating the homogeneous mixture obtained in step a. on a detachable protective film; c. gradually drying the coated mixture; d. laminating the product obtained in step c. onto a support layer; and e. optionally, cutting the product obtained in step d. in such a way as to obtain transdermal devices or patches of the desired size.

17. A method for treating nicotine addiction comprising the application to a person in need thereof of a self-adhesive transdermal device according to claim 1.

18. A method for treating neurodegenerative diseases comprising the application to a person in need thereof of a self-adhesive transdermal device according to claim 1.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1 and 2: In vitro permeation kinetics showing the effect of the presence of microporous solid polymer (Microsponge®) in the composition according to the invention.

(2) FIG. 3: Adhesive monolayer compositions and permeation results according to the adhesive used.

(3) FIG. 4: In vitro permeation kinetics showing the equivalence of the effect of the presence of solid microporous polymer Microsponge® or Polytrap® in the composition according to the invention.

(4) The present invention thus relates to a self-adhesive transdermal device, characterized in that it includes the association of a support layer and a self-adhesive matrix layer, and a detachable protective film, said self-adhesive matrix layer including, in relation to the total weight of the self-adhesive matrix layer: a. 65 to 93% by weight of at least one self-adhesive polymer selected from the group comprising polymers of the acrylic or acrylate type, polymers of the silicone type, polymers of the vinyl acetate type, natural or synthetic gums, copolymers thereof and mixtures thereof; b. 2 to 15% by weight of at least one microporous solid polymer capable of containing an active principle, said polymer being comprised of monomer units selected from the group of monomers comprising styrene, divinylbenzene, methyl methacrylate, ethylene glycol dimethacrylate, 4-vinylpyridine, lauryl methacrylate, allyl methacrylate, glycol dimethacrylate and mixtures thereof; and c. 5 to 20% by weight of active principle.

(5) By “association” is meant that the layers of the device according to the invention are directly in contact with each other and that once assembled they form a whole which cannot come apart easily and in particular which cannot come apart without human will and intervention.

(6) Preferentially, the patch according to the invention will be of the adhesive monolayer type.

(7) By “support layer according to the invention” is meant any support layer typically used in the field of patches. Preferentially, the support layer is a multilayer film at least one layer of which is a polyester layer and at least one other layer is a polyethylene-based or vinyl acetate ethylene-based layer. Preferentially, the support layer is transparent.

(8) By “detachable protective film” is meant all detachable protective films capable of protecting the device's matrix before the device is used. These films typically used in the field of transdermal devices are well-known to the person skilled in the art. Preferentially, this film is made of siliconized polyester.

(9) The matrix layer according to the invention is self-adhesive. By “self-adhesive” is meant that the matrix layer is able to keep the device according to the invention bound to a support, for example the skin, in a stable manner, with no need for the use of other means of bonding. Preferentially, by “self-adhesive” is meant that the matrix layer allows the device to adhere to the skin for at least 12 hours, preferentially for about 12 to 48 hours, more preferentially for about 24 hours.

(10) The matrix layer according to the invention includes from 65 to 93%, preferentially between 75 and 85% by weight of at least one self-adhesive polymer selected from the group comprising polymers of the acrylic or acrylate type, polymers of the silicone type, polymers of the vinyl acetate type, natural or synthetic gums, copolymers thereof and mixtures thereof.

(11) By “synthetic gum” is meant in particular in the context of the present invention gums selected from the family of elastomers, for example styrene, styrene-isoprene-styrene (SIS), polystyrene-butadiene-styrene (SBS) or styrene-ethylene/butylene-styrene (SEBS). By “natural gum” is meant all types of natural gums such as carrageenan gum or guar gum, for example.

(12) Preferentially, the matrix layer includes at least one polymer of the acrylic or acrylate type.

(13) The polymer of the acrylic or acrylate type according to the invention will preferentially be comprised of monomers selected from the group comprising or consisting of vinyl acetate, 2-ethylhexyl acrylate, butyl acrylate, acrylic acid, methyl methacrylate, methyl acrylate, tert-octyl acrylamide, 2-hydroxy ethyl acrylate, glycidyl methacrylate, or mixtures thereof, more preferentially from the group comprising or consisting of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, and mixtures thereof.

(14) In an embodiment, the self-adhesive polymer according to the invention is an acrylate-vinyl acetate copolymer.

(15) The matrix layer according to the invention further includes from 2 to 15%, preferentially from 5 to 12% by weight in relation to the total weight of the self-adhesive matrix layer of at least one microporous solid polymer capable of containing an active principle.

(16) By “capable of containing an active principle” according to the invention is meant that the microporous solid polymer may be loaded with active principle by adsorption, the active principle is thus associated with the polymer. Preferentially, the microporous solid polymer according to the invention may be loaded with 15% to more than 400%, preferentially more than 50%, for example between 50 and 150%, even for example around 100% or around 140% by weight of active principle in relation to the weight of free microporous solid polymer. The microporous solid polymers according to the invention are preferentially loaded by simple contact (adsorption) with the active principle via mixing.

(17) The microporous solid polymer capable of containing an active principle according to the invention will be preferentially solid porous microparticles of the polymer type or the cross-linked copolymer type (microporous solid polymer).

(18) Preferentially, said microporous solid polymer is comprised of monomer units selected from the group of monomers comprising or consisting of styrene, divinylbenzene, methyl methacrylate, ethylene glycol dimethacrylate, 4-vinylpyridine, lauryl methacrylate, allyl methacrylate, glycol dimethacrylate and mixtures thereof.

(19) Preferentially, the microporous solid polymer is comprised of monomer units of methyl methacrylate and ethylene glycol dimethacrylate. One such polymer may in particular be obtained commercially under the Microsponge® brand. Alternatively, the microporous solid polymer is comprised of monomer units of lauryl methacrylate and glycol dimethyl methacrylate. One such polymer may in particular be obtained commercially under the Polytrap® brand. Preferentially, the self-adhesive transdermal device according to the invention does not contain a microporous solid polymer other than the microporous solid polymer comprised of monomer units of methyl methacrylate and ethylene glycol dimethacrylate or the microporous solid polymer comprised of monomer units of lauryl methacrylate and glycol dimethyl methacrylate.

(20) Preferentially, the microporous solid polymer according to the invention is provided in the form of microparticles of average size comprised between 1 μm and 100 μm, preferentially between 5 μm and 50 μm, more preferentially between 15 μm and 30 μm. The average size may in particular be measured by an apparatus of the laser particle-size analyzer type, for example the Malvern Mastersizer 2000 which, in particular, measures particles ranging from 0.2 μm to 2000 μm in a dry system.

(21) In an embodiment of the invention, the microporous solid polymer according to the invention has a total pore volume comprised between 0.5 and 3 ml/g, preferentially between 1 and 2 ml/g.

(22) In another embodiment, said microporous polymer has a granular pore volume comprised between 0.2 and 3 ml/g, preferentially between 0.5 and 1.5 ml/g, more preferentially between 0.7 and 1.0 ml/g.

(23) Total pore volume and granular pore volume may in particular be measured by a mercury porosimeter, for example the Autopore IV (Micromeritics). These porosimeters make it possible in particular to carry out an intrusion of mercury at constant pressure and thus to be able to determine the total pore volume and granular pore volume of microporous solid polymers. At low pressure (3.45 kPa to 186 kPa, for example), the intrusion volumes obtained correspond to packed powder and total porosity (intergranular and granular). At high pressure (186 kPa to 20.7 MPa, for example), the mercury intrusion values observed correspond to granular porosity.

(24) According to an advantageous characteristic of the present invention, the microporous solid polymer, which is advantageously provided in the form of microparticles, is distributed homogeneously within the self-adhesive polymer mass. According to another characteristic of the invention, the active principle is adsorbed homogeneously in the microporous solid polymer mass. The result is thus regular distribution within the self-adhesive matrix layer of the device of the invention and, therefore, regular release of the active principle.

(25) Preferentially, the device according to the invention is characterized in that the basis weight of the self-adhesive matrix layer is comprised between 50 and 300 g/m.sup.2, preferentially between 100 and 200 g/m.sup.2.

(26) By “active principle” according to the invention is meant any active principle or any mixture of active principles that may be administered by a device according to the invention. In an embodiment the active principle may be in liquid form, preferentially in the form of an oily liquid. For example, the active principle according to the invention may be selected from the group comprising or consisting of nicotine, nicotinic agonists in particular such as varenicline or cytisine, nitroglycerin, tolbuterol, propanolol, bupranolol, hormones in particular such as estrogens including testosterone, fentanyl, selegiline or lidocaine. In an embodiment the active principle is selected from the group comprising or consisting of nicotine, selegiline, nitroglycerin, tolbuterol, propanolol and bupranolol. The active principle according to the invention is advantageously an active principle the release of which must be slowed or controlled such as, for example, nicotine or selegiline. Preferentially, the active principle according to the invention is nicotine, more preferentially the device according to the invention does not include an active principle other than nicotine.

(27) The active principle may be loaded into the microporous solid polymer in liquid form. The active principle, in particular nicotine, will be preferentially loaded in base form or in the form of a solution of a salt thereof, more preferentially in base form. The quantity of active principle loaded in the particles will depend in particular on the desired quantity of active principle released by the transdermal device according to the invention and on the desired release time. For example, the device according to the invention including nicotine may include between 10 and 100 mg of nicotine, preferentially between 15 and 90 mg of nicotine, for example 15, 30, 45 or 90 mg of nicotine.

(28) The inventors noted that the release of nicotine was particularly well controlled when the microporous solid polymer is as defined in the present invention, preferentially, a methyl methacrylate and ethylene glycol dimethacrylate copolymer, and that the adhesive matrix has a basis weight between 50 and 300 g/m.sup.2, preferentially between 100 and 200 g/m.sup.2.

(29) The rate of nicotine released by the microporous solid polymers will depend in particular on the nature of the polymer and on pore size. Preferentially, the devices according to the invention allow the release of nicotine from the matrix layer by an average delivery rate comprised between 5 and 100 μg/cm.sup.2/h, in an embodiment between 10 μg/cm.sup.2/h and 50 μg/cm.sup.2/h, for a time interval comprised between 1 and 24 hours. The release rate may be measured by any permeation technique known to the person skilled in the art, in particular via permeation kinetics, for example on abdominal skin of nude mouse arranged on the surface of a glass (Franz) cell, such as in particular described in Example 3.

(30) The matrix layer according to the invention may further include other excipients or components such as antioxidants, for example. In an embodiment, the self-adhesive matrix layer includes at least one antioxidant agent in particular selected from the group comprising or consisting of butyl hydroxy toluene (BHT), butyl hydroxy anisole (BHA), ascorbyl palmitate, alpha tocopherol and esters thereof, citric acid, propyl gallate and mixtures thereof, preferentially BHT. The antioxidant agent is then preferentially present in said self-adhesive matrix layer in a proportion comprised between 0.01 and 1% by weight in relation to the total weight of said self-adhesive matrix layer.

(31) In another embodiment, the self-adhesive transdermal device according to the invention is characterized in that it consists of the association of a support layer and a self-adhesive matrix layer, and a detachable protective film, said self-adhesive matrix layer consisting of, in relation to the total weight of the self-adhesive matrix layer: a. 65 to 93% by weight of at least one self-adhesive polymer selected from the group comprising polymers of the acrylic type, polymers of the silicone type, polymers of the vinyl acetate type, natural or synthetic gums, copolymers thereof and mixtures thereof; b. 2 to 15% by weight of at least one microporous solid polymer capable of containing an active principle, said polymer being comprised of monomer units selected from the group of monomers comprising styrene, divinylbenzene, methyl methacrylate, ethylene glycol dimethacrylate, 4-vinylpyridine, lauryl methacrylate, allyl methacrylate, glycol dimethacrylate and mixtures thereof; c. 5 to 20% by weight of nicotine as active principle; d. optionally from 0.1 to 1% of an antioxidant agent; and

(32) Preferably, the patch according to the invention will be transparent.

(33) By “transparent” is meant that it makes it possible to sufficiently observe the skin through the patch in order to rapidly identify any possible skin intolerance.

(34) The present invention further relates to a method for preparing a transdermal device according to the invention, characterized in that it comprises or consists of the following steps: a. Mixing the self-adhesive polymer, the microporous solid polymer, the active principle, preferentially nicotine, and optionally the oxidizing agent, until a homogeneous mixture is obtained; b. Coating the homogeneous mixture obtained in step a. on a detachable protective film; c. Gradually drying the coated mixture; d. Laminating the product obtained in step c. onto a support layer; and e. Optionally, cutting the product obtained in step d. in such a way as to obtain transdermal devices or patches of the desired size.

(35) By mixing the self-adhesive polymer and the microporous solid polymer according to the invention “until a homogeneous mixture is obtained according to the present invention” is meant that the microporous solid polymer must be distributed uniformly in the self-adhesive polymer. This distribution may in particular be evaluated by visual observation (absence of aggregates).

(36) Nicotine may or may not be mixed with the microporous support according to the invention before step a. In a preferred embodiment, nicotine is not mixed with the microporous support prior to step a., the nicotine, the microporous support and the self-adhesive polymer thus being brought into contact independently and concomitantly in step a.

(37) Preferentially, the coating step b. is carried out at a temperature comprised between 30° C. and 50° C.

(38) By “gradually drying” is meant the creation of a temperature gradient. It is preferable that drying occurs gradually in order to avoid crusting. For example, the temperature gradient may be a gradient of 5 to 20° C. in a temperature range from 30° C. to 80° C., preferentially from 40 to 60° C.

(39) After coating and drying, the product obtained in step c. is laminated onto a support layer according to the invention. The lamination operation may be carried out by all methods well-known to the person skilled in the art.

(40) The coated support layer obtained in step d. of the method according to the invention may then optionally be cut to the desired size. For example, the support layer may be cut into transdermal devices or patches (or units) of between 5 cm.sup.2 and 80 cm.sup.2, for example 10 cm.sup.2, 20 cm.sup.2, 30 cm.sup.2 or 60 cm.sup.2.

(41) The transdermal device according to the invention may be packaged in a packaging under a protective (inert) atmosphere, preferentially under nitrogen, in particular when the patch according to the invention does not contain an antioxidant agent. The preparation of inert packaging for patches is well-known to the person skilled in the art and may be carried out by all known methods.

(42) The present invention further relates to a self-adhesive transdermal device according to the invention for use as a drug.

(43) In particular, the present invention relates to a self-adhesive transdermal device according to the invention, preferentially a transdermal device according to the invention containing nicotine, for use in the treatment of nicotine addiction, in particular in order to facilitate smoking cessation.

(44) In another embodiment, the present invention relates to a self-adhesive transdermal device, preferentially a transdermal device according to the invention containing nicotine, for use in the treatment of neurodegenerative diseases such as in particular Parkinson's disease or Alzheimer's disease.

(45) The present invention is illustrated by the examples below which do not limit its scope.

EXAMPLES

Example 1: Characterization of Adsorption Supports

Example 1A: Adsorption Capacity Tests (Table 1)

(46) Comparative tests for measuring the adsorption capacity of nicotine by various microporous solids were carried out. The tests consisted in determining the maximum quantity of nicotine that could be adsorbed on the microporous supports according to the following procedure: weighing the microporous support, between 0.3 and 2.0 g depending on its density, to have an identical volume, adding nicotine in an iterative manner by weighing out about 0.1 g, impregnating the support with nicotine using a spatula after each addition of nicotine; the appearance of the mixture is then noted.

(47) The maximum adsorption capacity is thus determined: it is the quantity of nicotine adsorbed by the microporous support expressed in grams of nicotine per gram of support, with nicotine seepage not observed.

(48) The following results were obtained:

(49) TABLE-US-00001 TABLE 1 Adsorption capacity (quantity of nicotine in grams/1 gram of Support type Trade name support) Comments - Visual appearance Cross-linked Microsponge ® 1.40 Significant swelling of MMA/GDMA particles; light yellow color polymer maintained Silica Silica shells 2.70 Very small particles forming clusters once impregnated Silica MSS-500/3H4 ® 3.00 Difficult homogenization with formation of lumps Densified Aerosil ®V200 2.75 Nicotine penetrates but is not fumed silica spread out; particles form irregular heaps Polyurethane/silica BPD 800 ® 1.05 Significant swelling of microspheres particles; light yellow color maintained Crospovidone Polyplasdone ® 0.15 Nicotine penetrates but is not XL-10 spread out; significant yellowing Silicone resin/POE DC 9506 ® 0.60 Powders that wet well, but lauryl ether 98/2 tendency to ooze

(50) As may be noted, the majority of the supports tested combined with nicotine have a large number of disadvantages that make them unusable: spreading is impossible; seepage; formation of aggregates, clusters or lumps.

(51) The cross-linked MMA/CDMA polymers (cross-linked polymer of methyl methacrylate and ethylene glycol dimethacrylate) allow good adsorption of nicotine and have after adsorption a suitable appearance.

Example 1B: Adsorption Support Release Capacity Test (Table 2)

(52) The adsorption supports are loaded with nicotine at 50% or 80% of their maximum adsorption capacity determined beforehand (see preceding Table 1). A wash test is then carried out in order to determine their release capacity expressed in % of nicotine released in relation to the quantity of nicotine added.

(53) The following results were obtained:

(54) TABLE-US-00002 TABLE 2 Support type Load (%) Part in the wash (%) Silica (Silica shells) 80% 90 50% 96 Cross-linked MMA/GDMA 80% 79 polymer (Microsponge ®) 50% 69 Polyurethane/silica 80% 91 (BPD800 ® microspheres) 50% 84 Crospovidone 80% 99 (Polyplasdone ® XL-10) 50% 89 Silicone resin/POE 80% 72 lauryl ether 98/2 (DC9506 ®) 50% 69

(55) The wash test is carried out on 200 mg of loaded microparticles, with rinsing carried out with 1 ml of water for a period of 10 seconds with shaking, followed by filtration.

(56) These results show that the cross-linked MMA/GDMA polymers and DC9506® silicone resin retain more nicotine via better adsorption than the other supports.

Example 1C: Adsorption Support Dispersion Tests

(57) Tests of dispersion of the microporous supports are carried out in solvents constituting the majority phase of the adhesive mixtures before coating. These dispersion tests make it possible to verify the technical feasibility of the adhesive mixtures.

(58) These tests are carried out according to the following procedure: In a 9 ml glass vial, weigh the microporous support, between 0.2 and 1.25 g depending on its density, add solvent (ethyl acetate or heptane) so as to have a mass ratio of solvent to microporous support equal to about 3, mix with a spatula and immediately observe the mixture; the mixture is also observed after resting for 48 hours.

(59) The results are presented in Table 3:

(60) TABLE-US-00003 TABLE 3 Observations with Observations with Support type ethyl acetate heptane Polyurethane/silica Liquid suspension Liquid suspension (BPD800 ® microspheres) Crospovidone Liquid suspension Liquid suspension (Polyplasdone ® XL-10) Cross-linked MMA/ Pasty suspension Liquid suspension GDMA polymer (Microsponge ®) Silica (Silica Support remains dry Support remains dry shells) Densified fumed Support changes Support remains dry silica (Aerosil ® appearance: presence 200VV) of translucent agglomerates Silica Support changes Support changes (MSS-500/3H4 ®) appearance: presence appearance: formation of translucent of a gel agglomerates Silicone resin/POE Support changes Support changes lauryl ether 98/2 appearance: formation appearance: formation (DC9506 ®) of a kind of of a kind of gum translucent gel

(61) The supports of greatest interest at the conclusion of these dispersion tests in solvent are the supports that remain in suspension in either liquid or pasty form: cross-linked MMA/GDMA polymers (Microsponge®), BPD800 or Polyplasdone XL10.

(62) Surprisingly, only the cross-linked MMA/GDMA microporous support provides advantageous characteristics in all 3 characterization tests performed. Cross-linked MMA/GDMA microporous polymers are thus, unexpectedly, a support particularly well suited for nicotine (load, release, compatibility).

Example 2: Method for Preparing a Monolayer Transdermal Composition Containing Nicotine and a Microsponge®-Type Microporous Polymer

(63) The preparations according to the invention are prepared in the following way:

(64) The adhesive, then nicotine, microporous polymer and optionally BHT are added into a mixing vessel. The stirring parameters (time and speed) are set so as to avoid the formation of lumps and to obtain a homogeneous mixture, and depend in particular on the size of the vessel. After resting for 24 hours, the adhesive mass is coated onto a silicone film in a proportion of 150±5 g/m.sup.2 before proceeding to drying at 45° C., which is intended to evaporate the adhesive's solvents, followed by transfer of the matrix onto a transparent polyester support. The product thus obtained is cut into the desired sizes.

Example 3: Permeation Tests (FIGS. 1 and 2)

(65) The following compositions A and B are obtained according to the process of Example 2:

(66) TABLE-US-00004 TABLE 4 KG209 KG243 Composition A B Nicotine base 11.2% 11.2% Polymethyl methacrylate/ethylene glycol 8.1% dimethacrylate copolymer (Microsponge ®) Silicone adhesive 9.0% 8.1% Acrylate-vinyl acetate copolymer 79.8% 72.6%

(67) In vitro permeation kinetics were carried out on abdominal skin of nude mouse arranged on the surface of a glass (Franz) cell. The results obtained express the comparative cumulative quantities (CQ) from 0 to 48 hours in μg/cm.sup.2 between a preparation not containing microporous polymer (formula A) and the reference product (Nicotinell®) (FIG. 1).

(68) TABLE-US-00005 CQ 1 3 6 9 12 16 20 24 48 KG209 140.47 399.50 687.86 876.30 1018.01 1176.65 1235.77 1302.11 1504.50 Nicotinell 67.47 249.09 514.86 737.75 933.88 1156.95 1310.09 1449.56 1908.67

(69) The same preparation is then prepared but containing a quantity of microporous polymer of the cross-linked MMA/GDMA polymer (Microsponge®) type according to the invention (formula B). In vitro permeation kinetics are then carried out on abdominal skin of nude mouse arranged on the surface of a glass (Franz) cell. The results obtained express comparative cumulative quantities (CQ) from 0 to 48 hours in μg/cm.sup.2 between this preparation according to the invention (formula B) and the reference product (Nicotinell® comprised of a gelled nicotine depot on an adhesive layer) (FIG. 2).

(70) TABLE-US-00006 CQ 1 3 6 9 12 16 20 24 48 KG243 106.06 347.84 614.78 854.52 1024.88 1143.59 1268.95 1313.79 1515.68 Nicotinell 171.45 540.27 869.15 1166.56 1382.27 1567.33 1690.11 1849.09 2242.83

(71) These results show how the presence of a microporous support of the cross-linked MMA/GDMA polymer (Microsponge®) type is able to control the permeation kinetics of nicotine from the matrix patch according to the invention. In particular, the presence of microspheres makes it possible to reduce the quantity of nicotine released in the first 12 hours (“burst” effect observed in FIG. 1 for composition KG209, the curve which crosses that of Nicotinell®), not observed in FIG. 2 for the composition according to the invention. Reduction of the “burst” effect is very important in the case of nicotine in order to avoid a too rapid release of a too large amount of nicotine, an event which may prove to be irritating or toxic.

(72) The experiment was repeated with a formula C differing from formula B wherein the 8.1% of cross-linked MMA/GDMA polymer (Microsponge®) was replaced with 8.1% of lauryl methacrylate/glycol dimethyl methacrylate crosspolymer (Polytrap®). The permeation kinetics results obtained with this formula C were compared with those of formula B and those of Nicotinell obtained during the same experiment so that the results could be directly compared.

(73) TABLE-US-00007 Time (hours) 0.5 1 1.5 3 6 POLYTRAP 7.6 32.7 63.9 156.5 293.5 MICROSPONGE 6.2 28.3 55.8 139 266.4 12 18 24 461.8 547.3 599.3 438.9 530.5 587.6

(74) As may be noted in the table above and in appended FIG. 4, the results obtained are comparable when Microsponge® or Polytrap® is used.

(75) The following examples illustrate the influence of the microporous support on the adhesive and cohesive properties of the adhesive matrix containing nicotine.

(76) The following adhesive monolayer compositions C, D and E were obtained following the protocol of Example 2:

(77) TABLE-US-00008 TABLE 5 SME416 SME417 SME418 Composition C D E Nicotine base    0% 5.0% 5.0% Polymethyl methacrylate/ 4.1% ethylene glycol dimethacrylate copolymer (Microsponge ®) Butylhydroxytoluene 0.1% 0.1% Acrylate-vinyl acetate copolymer 100.0% 90.8% 94.9%

(78) These compositions are then characterized by adhesion tests, respectively a shear test and a tack test. The shear test consists in measuring the capacity of an adhesive or a self-adhesive formulation such as a patch to resist a static force applied in the same plane. The criterion measured is that of the time required to separate by sliding the material tested from a standard surface such as a steel plate. The longer this time is, the stronger the cohesion. The tack test consists in measuring the force required to unstick, at a given rate, an adhesive or a self-adhesive formulation such as a patch from a standard surface with which it was brought into contact under the effect of low pressure (by setting-up a loop in contact with a probe). The criterion measured is force expressed in Newton. The greater this force is, the greater the tack.

(79) The following results were obtained (Table 4):

(80) TABLE-US-00009 TABLE 6 Maximum tack force (Newton) Shear time Composition C 19.2 More than 168 hours Composition D 16.6 112 hours Composition E 23.1  86 hours

(81) It is thus shown that the addition of nicotine, by a plasticizing effect, within an adhesive decreases the cohesion of the system (reduction in shear time) and increases its tack (compared between compositions C and E). The addition of porous microparticles of the cross-linked MMA/GDMA polymer (Microsponge®) type improves the cohesion of the system and reduces tack strength (compared between compositions D and E). The addition of porous microparticles of the cross-linked MMA/GDMA polymer (Microsponge®) type thus unexpectedly reduces the plasticizing effect of nicotine.

Example 5: Influence of Adhesive on Nicotine Release

(82) The following examples illustrate, for the preparations of compositions according to the invention, the influence of the adhesive on nicotine release.

(83) The following adhesive monolayer compositions were obtained following the protocol of Example 2:

(84) TABLE-US-00010 TABLE 7 KG427 KG428 KG429 Nicotine base 10.0% 10.0% 10% Polymethyl methacrylate/ethylene 8.3% 8.3% 8.3% glycol dimethacrylate copolymer Butylhydroxytoluene 0.1% 0.1% 0.1% Self-cross-linking acrylate-vinyl 81.6% acetate adhesive (Duro-Tak ® 2052) Non-cross-linked acrylic adhesive 81.6% (Duro-Tak ® 9088) Self-cross-linking acrylate-vinyl 81.6% acetate adhesive (Duro-Tak ® 2196)

(85) The in vitro permeation test was performed according to the description provided in preceding Example 3 and the results obtained are those of FIG. 3.

(86) TABLE-US-00011 CQ 1 3 6 9 12 16 20 24 KG427 90 294 547 735 860 983 1076 1137 KG428 118 319 501 613 687 776 842 888 KG429 87 271 493 639 749 847 924 982

(87) The use of porous microparticles of the cross-linked MMA/GDMA polymer (Microsponge®) type makes it possible to obtain for a patch a similar in vitro kinetics profile whatever adhesive is used.