Patch coated with a silicone gel containing capsaicin

Abstract

This invention relates to a patch having a silicone gel containing capsaicin coated on a substrate, wherein the amount of capsaicin delivered to the skin is from 0.01 to 0.145 g / m². 2 Preferably, the concentration is 0.02 to 0.13 g / m³. 2 More preferably 0.04 to 0.12 g / m 2 Skin area. This patch exhibits a balance of excellent silicone gel adhesion strength and skin comfort. Furthermore, the present invention relates to the use of capsaicin in patches for balancing silicone gel adhesion strength and skin comfort, and a method for preparing patches having a capsaicin-containing silicone gel.

Description

Technical Field

[0001] This invention relates to a patch coated with capsaicin-containing silicone gel and its preparation method. Background Technology

[0002] Many people suffer from neuropathic pain, and it has a devastating impact on their quality of life. The causes of neuropathic pain are highly diverse, including reactivation of latent viruses, direct nerve trauma, diabetes, and HIV infection and treatment.

[0003] Capsaicin, its derivatives, and analogues (or so-called "capsaicinoids") have long been known for their use in pain relief. Capsaicin (the irritant in chili peppers) activates vanillin receptors (TRPV1) expressed in sensory nerve fibers that sense nociception in the skin, resulting in a sharp burning sensation and subsequently prolonging the function of these nociceptors.

[0004] For example, US5762963 provides methods and compositions for oral delivery of temporarily increased concentrations of capsaicin or capsaicinoids. The compositions provided therein comprise one or more capsaicins dispersed in a solid carrier material such as a lollipop. While oral capsaicin formulations provide pain relief, unavoidable burning and nausea are generally associated with oral administration of capsaicin or capsaicinoids. Furthermore, oral delivery of capsaicin or capsaicinoids is limited and inconvenient.

[0005] Various other capsaicin delivery methods have been developed. One of the most commonly used capsaicin-loaded systems is based on a self-adhesive matrix of organosilicon PSA, rubber, or silicone gel. CN 105687125A discloses that capsaicin can be directly added to a mixture based on polydimethylsiloxane, which can be applied directly to the skin.

[0006] Considering patient compliance and convenience, therapeutic patches coated with capsaicin-loaded silicone gel are suitable. WO 2005102403 and WO 2008057155 provide silicone gels for adhering to transdermal drug delivery devices, which contain hydroxyl-functionalized siloxane resins to improve adhesive strength.

[0007] However, when capsaicin is used in patches primarily based on PSA, silicone gel, or natural rubber adhesive systems (typically solvent-based), the adhesive strength is often so high that it can damage the patient's skin or the object to be adhered to, causing pain upon removal. Additionally, they often exhibit cold flow at skin temperature, which leads to significant discomfort for the patient. Therefore, there is an ongoing need to improve PSA, silicone gel, or natural rubber, especially silicone gels, to address these shortcomings in patch applications. Invention Overview

[0009] The inventors of this application have surprisingly discovered that the dynamic process of capsaicin transdermal delivery from the patch to the skin, measured by the amount of capsaicin delivered, affects the adhesive strength of the silicone gel and the comfort on the skin. Therefore, the aforementioned objective can be achieved by controlling the amount of capsaicin delivered to the skin. More specifically, if the amount of capsaicin delivered in the patch can be controlled within 0.01 to 0.145 g / m², the effect is improved. 2 Within the skin area, a balance will be achieved between moderate adhesion strength and comfort on the skin.

[0010] The term "delivery amount" as used throughout this application refers to the transdermal amount of a pharmaceutically active substance (such as capsaicin as used herein) that enters the skin from the patch. Delivery amount can be defined as the amount of active substance added per unit area of ​​skin in contact with the patch. For example, the capsaicin delivery amount can be calculated using the following equation:

[0011] Capsaicin delivery rate (g / m 2 = Capsaicin content (%) * Coating weight (g / m²) 2 ) / 100.

[0012] Therefore, the present invention relates to a patch having a silicone gel containing capsaicin coated on a substrate, wherein the amount of capsaicin delivered to the skin is between 0.01 and 0.145 g / m². 2 Within a certain range. In a preferred embodiment, the capsaicin-coated silicone gel is applied to the skin at a weight of 100 g / m². 2 Up to 500g / m 2 For example, 120 to 400 g / m 2 Or 150 to 220 g / m 2 .

[0013] On the other hand, the present invention relates to the use of capsaicin in patches for balancing the adhesive strength of silicone gel and comfort on the skin.

[0014] On the other hand, the present invention relates to a method for preparing a patch having a capsaicin-containing silicone gel. Invention Details

[0016] As described above, the present invention relates to a patch having a capsaicin-containing silicone gel coated on a substrate.

[0017] As used herein, the term "patch" refers to a medical device capable of delivering a drug or active substance transdermally, and generally refers to a piece of material commonly used in medicine to cover wounds or repair skin defects on human or animal skin, particularly topical patches or transdermal patches. They are typically prepared by coating, spreading, or distributing a pharmaceutically active substance or a carrier or medium loaded with such active substances onto a substrate. The carrier or medium loaded with the active substance has a consistency suitable for coating, spreading, or distribution. Substrates that can be used for patches are well known to those skilled in the art of medical devices, and they can generally be continuous, discontinuous, or porous. The substrate can be a backing layer of the patch. Useful examples of substrates include thermoplastic, foamed, or perforated plastic films, such as (foamed) polyurethane films, thermoplastic polyurethane films, or PET films, nonwoven fabrics, knitted fabrics, fiber webs, or kraft paper and cotton fabrics, etc.; nonwoven fabrics, polyurethane films, kraft paper, and cotton fabrics are preferred.

[0018] In addition to the substrate and the carrier or medium (e.g., silicone gel) coated thereon carrying the pharmaceutically active substance, the patch may also include a release film disposed on the surface of the carrier or medium (e.g., silicone gel) opposite the substrate to prevent contamination of, for example, the silicone gel during preparation, transportation, and storage. The release film is peeled off before application to the skin.

[0019] The capsaicin used in this application is well-known, referring not only to pure capsaicin powder but also to various forms of capsaicin and its derivatives and analogs (or capsaicin-like substances) and mixtures thereof. Capsaicin is also known as 8-methyl-N-vanillyl-trans-6-nonenamide or (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide and has the following chemical structure:

[0020]

[0021] Besides capsaicin, there are various capsaicin analogues and derivatives that can also be used in this invention and are included within the scope of "capsaicin" as used herein. Exemplary forms of capsaicin and its derivatives and analogues include, but are not limited to, N-vanillyl alkyldienamide, N-vanillyl-alkyldienyl, N-vanillyl-cis-monounsaturated alkylenamide, capsaicin, dihydrocapsaicin, norhydrocapsaicin, nordihydrocapsaicin, high capsaicin and high dihydrocapsaicin, as well as naturally extracted capsaicin oleoresins from Capsicum fruits, said naturally extracted capsaicin oleoresins having different capsaicin concentrations of 0.5% to 90% by weight, for example, 5% to 70% by weight, based on the total weight of the extract.

[0022] Therefore, the term "capsaicin-containing silicone gel" refers to silicone gels containing capsaicin, all forms of capsaicin analogues and their derivatives and / or mixtures thereof that may have pain-relieving functions.

[0023] The term "silicone gel" refers to an elastic, jelly-like solid material formed by slightly cross-linking a silicone polymer or precursor silicone composition, which does not exhibit flow when in a stable state. In contrast, silicone pressure-sensitive adhesives ("PSA") have low or no elasticity and are therefore different from silicone gels.

[0024] Silicon gels are typically formed from linear or branched organosilicones with reactive groups through a crosslinking reaction. Examples of crosslinking reactions include hydrosilylation, in which organosilicones or organopolysiloxanes with Si-H reactive groups react with organosilicones or organopolysiloxanes with alkenyl or vinyl (Si-alkenyl) groups, preferably in the presence of a hydrosilylation catalyst.

[0025] When used on humans or animals, silicone gels should be soft and flexible enough to ensure user comfort. Therefore, silicone gels are typically characterized by penetration (or "penetration" or "cone penetration"). This is measured using a Petrotest penetration meter, PNR 12, according to standard NF ISO 2137, with the total weight of the rod and cone fixed at 62.5 g. The cone penetration of the silicone gel is determined at 25°C by measuring the depth to which the cone penetrates the sample, obtained by releasing the cone assembly of the penetration meter and allowing the cone to act for 5 seconds.

[0026] However, as described above, the inventors have discovered that the addition of capsaicin significantly affects the penetration of the silicone gel. The penetration after the addition of capsaicin is closely related to the adhesion properties of the patch. Penetration below 100 mm / 10 may result in poor adhesion, while penetration above 250 mm / 10 may result in poor cohesive properties, leading to gel residue on the skin. Therefore, the penetration of capsaicin-containing gels must be controlled within the range of 100-250 mm / 10, preferably 140-210 mm / 10.

[0027] In a preferred embodiment of the invention, the silicone gel is formed from a precursor composition via a hydrosilylation reaction, the precursor composition containing, in addition to capsaicin:

[0028] 1) At least one organopolysiloxane B, comprising:

[0029] (i) at least two silyloxy units of formula (B1)

[0030] (Y) a (Z) b SiO (4-(a+b)) / 2 (B1)

[0031] in

[0032] -Y represents a monovalent group containing 2 to 6 carbon atoms and having at least one alkenyl group;

[0033] -Z indicates a monovalent group containing 1 to 20 carbon atoms and not an alkenyl group;

[0034] -a and b represent integers, where a is 1, 2 or 3, b is 0, 1 or 2, and (a+b) is 1, 2 or 3;

[0035] (ii) and optionally other siloxy units of formula (B2).

[0036] (Z) c SiO (4-c) / 2 (B2)

[0037] in

[0038] -Z has the same meaning as described above, and

[0039] -c represents an integer of 0, 1, 2, or 3;

[0040] 2) At least one organopolysiloxane CE, which contains:

[0041] - Two silyloxy terminal units, which may be the same or different and have the formula (CE-1).

[0042] (H) p (R 1 ) q SiO 1 / 2 (CE-1)

[0043] in

[0044] - Symbol R 1 Corresponding to C1 to C8 alkyl or C6 to C10 aryl;

[0045] - and the symbol H represents a hydrogen atom, where p = 0 or 1, q = 2 or 3 and (p+q) = 3;

[0046] - At least one silyl group of formula (CE-2):

[0047] (H) n (R 2 ) m SiO 2 / 2 (CE-2)

[0048] Wherein group R 2 Corresponding to C1 to C8 alkyl groups or C6 to C 10An aryl group, with the symbol H representing a hydrogen atom, where n = 0 or 1, m = 1 or 2, and (n + m) = 2.

[0049] and

[0050] The condition is that each polymer of organopolysiloxane CE contains two hydrogen atoms, each hydrogen atom being bonded to a different silicon atom, and preferably, each polymer of organopolysiloxane CE contains two silanoxy units of formula (CE-1) where p=1 and at least one silanoxy unit of formula (CE-2) where n=0.

[0051] 3) At least one organopolysiloxane XL, comprising:

[0052] - At least three silyloxy units of formula (XL-1):

[0053] (H)(L) e SiO (3-e) / 2 (XL-1)

[0054] The symbol H represents a hydrogen atom, and the symbol L represents an alkyl group with 1 to 8 carbon atoms (including terminal values) or a C6 to C6 group. 10 Aryl group, and the symbol e equals 0, 1, or 2; and

[0055] -Optional other siloxy units of formula (XL-2):

[0056] (L) g SiO (4-g) / 2 (XL-2)

[0057] The symbol L represents an alkyl group having 1 to 8 carbon atoms (including the terminal value) or a C6 to C6 alkyl group. 10 Aryl, and the symbol g equals 0, 1, 2 or 3, and

[0058] The condition is that the organopolysiloxane XL contains 1.0% to 15.0% by weight of Si-H functional groups / polymer, preferably 1.5% to 15.0% by weight of Si-H functional groups / polymer, and even more preferably 1.5% to 12.5% ​​by weight of Si-H functional groups / polymer.

[0059] 4) An effective amount of at least one hydrosilylation catalyst E,

[0060] 5) At least one inhibitor of hydrosilylation reaction D,

[0061] Wherein the molar ratio RHAlk = tH / tAlk < 1.0, preferably 0.4 to 0.9, more preferably 0.5 to 0.85; or > 3, preferably 3 to 24 and more preferably 3.5 to 20, wherein tH = the number of moles of hydrogen atoms directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition, and tAlk = the number of moles of alkenyl groups directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition.

[0062] According to a specific embodiment of the precursor composition of the silicone gel:

[0063] - The dynamic viscosity of organopolysiloxane B at 25°C ranges from 100 mPa·s to 120,000 mPa·s.

[0064] - The dynamic viscosity of organopolysiloxane CE at 25°C is from 1 mPa·s to 500 mPa·s, preferably from 5 to 200 mPa·s, and

[0065] - The dynamic viscosity of organopolysiloxane XL at 25°C is from 5 mPa·s to 2000 mPa·s, preferably from 5 to 500 mPa·s.

[0066] All viscosities considered in this specification correspond to “Newtonian” dynamic viscosity values ​​at 25°C, i.e., dynamic viscosities measured in a manner known per se using a Brookfield viscometer at sufficiently low shear rate gradients, such that the measured viscosity is independent of the rate gradient.

[0067] According to an advantageous embodiment, the properties and weights of organopolysiloxanes B, CE, and XL are selected such that the dynamic viscosity of the silicone gel precursor composition at 25°C is from 200 mPa·s to 100,000 mPa·s, preferably from 200 mPa·s to 80,000 mPa·s.

[0068] It is advantageous to adhere to the following two conditions:

[0069] The organopolysiloxane CE has at least 5 silicon atoms and a ratio between 0.05 and 0.40, and preferably between 0.08 and 0.35: (molar number of SiH groups) / (total number of silicon atoms).

[0070] - Organopolysiloxane XL has at least 5 silicon atoms and a ratio of (molar number of SiH groups) / (total number of silicon atoms) of 0.05-0.80, preferably 0.05-0.50.

[0071] According to the present invention, it is wise that, for the definition of organopolysiloxane B in formula (B1), the symbol a can preferably be equal to 1 or 2, even more preferably 1. Furthermore, in formulas (B1) and (B2), the symbol Z can preferably represent an alkyl group selected from 1 to 8 carbon atoms (optionally substituted with at least one halogen atom) and C6 to C6 atoms. 10 A monovalent group formed from the aryl group. Z can advantageously represent a monovalent group selected from the group consisting of methyl, ethyl, propyl, 3,3,3-trifluoropropyl, xylyl, tolyl, and phenyl. Furthermore, in formula (B1), the symbol Y can advantageously represent a group selected from the group consisting of vinyl, propenyl, 3-butenyl, and 5-hexenyl. Preferably, the symbol Y is vinyl and the symbol Z is methyl.

[0072] Organopolysiloxanes B can have linear, branched, cyclic, or network structures. When they are linear organopolysiloxanes, they can mainly consist of the following:

[0073] - Selected from formula (Y)2SiO 2 / 2 (Y)(Z)SiO 2 / 2 and (Z)2SiO 2 / 2 The silanoxy unit "D" of the unit; and

[0074] - Selected from formula (Y)3SiO 1 / 2 (Y)2(Z)SiO 1 / 2 (Y)(Z)2SiO 1 / 2 and (Z)3SiO 2 / 2 The silyloxy unit "M" of the unit.

[0075] - In the formula, the symbols Y and Z are as defined above.

[0076] As examples of unit "D", dimethylsiloxy, methylphenylsiloxy, methylvinylsiloxy, methylbutenylsiloxy, methylhexenylsiloxy, methyldecenylsiloxy, and methyldecadienylsiloxy can be mentioned.

[0077] Examples of unit “M” include trimethylsilyloxy, dimethylphenylsilyloxy, dimethylvinylsilyloxy, and dimethylhexenylsilyloxy.

[0078] Organopolysiloxane B, especially when it is linear, can be a silicone oil with a dynamic viscosity of 50 mPa·s to 120,000 mPa·s, preferably 100 mPa·s to 120,000 mPa·s, at 25°C.

[0079] When the organopolysiloxane B is cyclic, it can be selected from the formula Y₂SiO₃. 2 / 2 YZSiO2 / 2 and Z2SiO 2 / 2 The unit is composed of silanoxy units "D". Examples of such units "D" are as described above. The dynamic viscosity of this cyclic organopolysiloxane at 25°C can be between 1 mPa·s and 5000 mPa·s.

[0080] As a useful example of organopolysiloxane B, the following can be mentioned:

[0081] - Polydimethylsiloxane containing dimethylvinylsilyl end groups;

[0082] - Poly(methylphenylsiloxane-co-dimethylsiloxane) containing dimethylvinylsilyl end groups;

[0083] - Poly(vinylmethylsiloxane-co-dimethylsiloxane) containing dimethylvinylsilyl end groups;

[0084] - Poly(dimethylsiloxane-co-vinylmethylsiloxane) containing trimethylsilyl end groups;

[0085] - and cyclic polymethylvinylsiloxane.

[0086] Particularly advantageous is an organopolysiloxane B, which is a polydimethylsiloxane containing a dimethylvinylsilyl end group, having a dynamic viscosity at 25°C of 50 mPa·s to 120,000 mPa·s, preferably 100 mPa·s to 120,000 mPa·s. The particularly advantageous organopolysiloxane B includes formula M... Vi D x M Vi Those, among them:

[0087] -M Vi =The silanoxy unit in the following formula: (vinyl)(CH3)2SiO 1 / 2

[0088] -D = the silyloxy group of the following formula: (CH3)2SiO 2 / 2 ,and

[0089] -x is a number from 1 to 1000, preferably a number from 5 to 1000.

[0090] In some embodiments, the precursor composition of the silicone gel may optionally contain an organopolysiloxane B' comprising only one vinyl or alkenyl group, located at one or one terminal silanoxy unit (e.g., an alkenyl group present only at one terminal silanoxy unit, such as "unit M"), and in an amount of 1-40%, preferably 1.5-30%, more preferably 2.5-20%, for example 2.5-10%, based on the total weight of the precursor composition.

[0091] In one possible implementation, the organopolysiloxane B' contains formula M Vi D x Those of M as organopolysiloxanes having an alkenyl group only at a terminal silanoxy unit, wherein:

[0092] -M Vi =The silanoxy unit in the following formula: (vinyl)(Z)2SiO 1 / 2 Preferred (vinyl)(CH3)2SiO 1 / 2

[0093] -M = the silyloxy group of the following formula: (Z)3SiO 1 / 2 (CH3)3SiO is preferred. 1 / 2

[0094] -D = the silyloxy group of the following formula: (Z)2SiO 2 / 2 (CH3)2SiO is preferred. 2 / 2 and

[0095] -x is a number from 1 to 1000, preferably from 50 to 800, and more preferably from 100 to 800.

[0096] Particularly advantageous are organopolysiloxanes B' containing a vinyl or alkenyl group only at one terminal silanoxy unit, such as M Vi D x The M-type molecules have a dynamic viscosity of 100 mPa·s to 10000 mPa·s, preferably 100 mPa·s to 8000 mPa·s, and more preferably 100 mPa·s to 5000 mPa·s at 25°C.

[0097] In a preferred embodiment, the organopolysiloxane in the precursor composition contains formula M Vi D x M Vi organopolysiloxanes B and M Vi D x M is an organopolysiloxane B' or is composed of it, wherein M is an organopolysiloxane. Vi D x The amount of organopolysiloxane B' of M is 1 to 40% by weight of the total weight of the silicone gel-based precursor composition, preferably 1.5 to 30%, more preferably 2.5 to 20%, for example 2.5 to 10%.

[0098] As an example of an organopolysiloxane CE with "chain extender" function, polydimethylsiloxane containing dimethylhydrosilyl end groups can be mentioned, whose dynamic viscosity at 25°C is between 1 mPa·s and 500 mPa·s, preferably between 5 mPa·s and 200 mPa·s, and even more preferably between 1 and 30 mPa·s. A particularly advantageous organopolysiloxane CE is of formula M... H D x’ M H The poly(dimethylsiloxy)α,ω(dimethylhydrosiloxy) group, wherein:

[0099] -M H =The silyloxy group in the following formula: (H)(CH3)2SiO 1 / 2

[0100] -D = the silyloxy group of the following formula: (CH3)2SiO 2 / 2 ,and

[0101] -x' is an integer between 1 and 200, preferably between 1 and 150, and even more preferably between 3 and 120.

[0102] Organopolysiloxanes (CEs) are described as "chain extenders" because they are intended to increase the mesh size of the network during crosslinking. When the SiH reactive functional group is at the chain end, the term "teleclaw" is sometimes preferred over "chain extender".

[0103] As an organopolysiloxane XL having crosslinking function and used according to the present invention, formula M can be mentioned. H D x” D w H M H M H D x” D y H M and MD x” D z H Those of M, where the formula is:

[0104] -M H =The silyloxy group in the following formula: (H)(CH3)2SiO 1 / 2

[0105] -D H =The silanoxy unit in the following formula: (H)(CH3)SiO 2 / 2

[0106] -D = the silyloxy group of the following formula: (CH3)2SiO 2 / 2 ,and

[0107] -M = the silyloxy group of the following formula: (CH3)3SiO 1 / 2 ,

[0108] -in:

[0109] "x" is a number from 0 to 500, preferably from 2 to 250, or even more preferably from 5 to 80;

[0110] • w is a number between 1 and 500, preferably between 1 and 250, or between 1 and 100, and even more preferably between 1 and 70;

[0111] •y is a number from 2 to 500, preferably from 3 to 250, or from 2 to 100, or even more preferably from 2 to 70; and

[0112] • z is a number from 3 to 500, preferably from 3 to 250, or from 3 to 100, and even more preferably from 3 to 70, and

[0113] Each polymer contains 2.5% to 15.0% by weight of Si-H functional groups, preferably 3.0% to 15.0% by weight of Si-H functional groups, and even more preferably 3.5% to 12.5% ​​by weight of Si-H functional groups.

[0114] As a useful hydrosilylation catalyst E according to the present invention, compounds of platinum group metals known to those skilled in the art may be mentioned. Platinum group metals are those referred to as platinum classes, a name that includes ruthenium, rhodium, palladium, osmium, and iridium in addition to platinum. Compounds of platinum and rhodium are preferred. In particular, complexes of platinum and organic products described in patents US-A-3 159 601, US-A-3 159602, and US-A-3 220 972, and European patents EP-A-0 057 459, EP-A-0 188 978, and EP-A-0 190 530, and complexes of platinum and vinyl organosiloxanes described in patent US-A-3 419 593 may be used. Platinum is generally the preferred catalyst. Examples include black platinum, chloroplatinic acid, alcohol-modified chloroplatinic acid, and complexes of chloroplatinic acid with olefins, aldehydes, vinyl siloxanes, or alkynyl alcohols. Karstedt solutions or complexes as described in patent US-A-3 775 452, chloroplatinic acid hexahydrate, or platinum catalysts containing carbene ligands are preferred.

[0115] As a useful inhibitor of hydrosilylation reaction D according to the present invention, one selected from α-alkynols, α-α′-alkynyl diesters, ene-alkynyl conjugated compounds, α-alkynones, acrylonitriles, maleates, fumarates, and mixtures thereof may be mentioned. These compounds capable of functioning as inhibitors of hydrosilylation are well known to those skilled in the art. They can be used alone or as mixtures.

[0116] α-Alynyl alcohol inhibitor D can be selected from compounds of formula (D1):

[0117] (R 1 (R) 2 C(OH)-C≡CH(D1)

[0118] in:

[0119] -Group R 1 Indicates alkyl, cycloalkyl, (cycloalkyl)alkyl, C6 to C6 10 Aryl or C7 to C 18 Arylalkyl,

[0120] -Group R 2 Indicates hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, C6 to C 10 Aryl or C7 to C 18 Arylalkyl,

[0121] -or R 1 and R 2 Together with the carbon atoms they are bonded to, they form 5, 6, 7, or 8-membered aliphatic rings that are optionally substituted once or multiple times.

[0122] According to formula (D1):

[0123] - The term "alkyl" refers to a saturated hydrocarbon chain containing 1-20 carbon atoms, preferably 1-8 carbon atoms. Alkyl groups may be selected from methyl, ethyl, isopropyl, n-propyl, tert-butyl, isobutyl, n-butyl, n-pentyl, isopentyl, and 1,1-dimethylpropyl.

[0124] According to the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group containing 3-20 carbon atoms, preferably 5-8 carbon atoms, and more preferably monocyclic or bicyclic alkyl groups. When the cycloalkyl group is polycyclic, multiple ring cores can be connected to each other by covalent bonds and / or by spirocyclic atoms and / or can be fused together. The cycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantane, and norbornene;

[0125] -According to the present invention, the term "(cycloalkyl)alkyl" is intended to refer to a cycloalkyl group as defined above that is bonded to an alkyl group as defined above;

[0126] According to the present invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group containing 6-10 carbon atoms. The aryl group may be selected from phenyl, naphthyl, and anthracene.

[0127] According to the present invention, the term "arylalkyl" is intended to refer to an aryl group as defined above that is bonded to an alkyl group as also defined above.

[0128] According to a preferred embodiment, in equation (D1), R 1 and R 2 Together with the carbon atoms they are bonded to, they form unsubstituted 5-, 6-, 7-, or 8-membered aliphatic rings. According to another preferred embodiment, R... 1 and R 2 They can be the same or different, and can be represented independently of each other, representing C1-C. 12 Preferably, C1-C6 monovalent alkyl groups.

[0129] The inhibitor D, useful as an α-alkynol according to the present invention, may be selected from the following compounds: 1-ethynyl-1-cyclopentanol; 1-ethynyl-1-cyclohexanol (also known as ECH); 1-ethynyl-1-cycloheptanol; 1-ethynyl-1-cyclooctanol; 3-methyl-1-butyn-3-ol (also known as MBT); 3-methyl-1-pentyn-3-ol; 3-methyl-1-hexyn-3-ol; 3-methyl-1-heptyyn-3-ol; 3-methyl-1-octyyn-3-ol; 3-methyl-1-nonyn-3-ol; 3-methyl-1-decyn-3-ol; 3-methyl-1-dodecyn-3-ol; 3-methyl-1-pentadenyyn-3-ol; 3-ethyl-1-pentyn-3-ol; 3-ethyl -1-Hexyn-3-ol; 3-Ethyl-1-heptyyn-3-ol; 3,5-Dimethyl-1-hexyn-3-ol; 3-Isobutyl-5-methyl-1-hexyn-3-ol; 3,4,4-Trimethyl-1-pentyn-3-ol; 3-Ethyl-5-methyl-1-heptyyn-3-ol; 3,6-Diethyl-1-nonyn-3-ol; 3,7,11-Trimethyl-1-dodecyn-3-ol (also known as TMDDO); 1,1-Diphenyl-2-propyn-1-ol; 3-Butyn-2-ol; 1-Pentyn-3-ol; 1-Hexyn-3-ol; 1-Hepyn-3-ol; 5-Methyl-1-hexyn-3-ol; 4-Ethyl-1-octyyn-3-ol and 9-ethynyl-9-fluorenol.

[0130] Inhibitor D of the α,α'-acetylacetyl diester type can be selected from compounds of the following formula (D2):

[0131]

[0132] Wherein group R 3 and R 4They can be the same or different, and can be independently represented as alkyl, cycloalkyl, (cycloalkyl)alkyl, C6 to C6. 10 Aryl, C7 to C 18 Arylalkyl or silylalkyl.

[0133] According to the present invention, the term "silyl" refers to a group of the formula -SiR3, wherein each symbol R independently represents an alkyl group containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The silyl group can be, for example, trimethylsilyl.

[0134] According to a specific implementation plan, in equation (D2), R 3 and R 4 C1-C can be the same or different and can be represented independently of each other. 12 Preferably, it is a C1-C6 alkyl or trimethylsilyl ester. The useful inhibitor D according to the invention is an α-α′-acetylene diester, which may be selected from the following compounds: dimethyl acetylenate dicarboxylate (DMAD), diethyl acetylenate dicarboxylate, tert-butyl acetylenate dicarboxylate, and bis(trimethylsilyl) acetylenate dicarboxylate.

[0135] The inhibitor D, of the ene-yne ​​conjugated compound type, can be selected from compounds of the following formula (D3):

[0136]

[0137] in:

[0138] -Group R 5 R 6 and R 7 Each can be independently represented by a hydrogen atom, alkyl group, cycloalkyl group, (cycloalkyl)alkyl group, or C6 to C6 alkyl group. 10 Aryl or C7 to C 18 Arylalkyl,

[0139] -or group R 5 R 6 and R 7 At least two groups in the ring, together with one or more carbon atoms to which they are bonded, form a 5, 6, 7 or 8-membered aliphatic ring that is optionally substituted once or multiple times.

[0140] According to a specific implementation plan, group R 5 R 6 and R 7 Each can be used to independently represent a hydrogen atom, C1-C. 12 Preferably C1-C6 alkyl or C6-C 10Aryl. The inhibitor D, useful as an alkene-yne ​​conjugated compound according to the present invention, can be selected from the following compounds: 3-methyl-3-penten-1-yne; 3-methyl-3-hexen-1-yne; 2,5-dimethyl-3-hexen-1-yne; 3-ethyl-3-buten-1-yne; and 3-phenyl-3-buten-1-yne. According to another specific embodiment, it is selected from the group R. 5 R 6 and R 7 The two groups together with the carbon atoms they are bonded to form an unsubstituted 5-, 6-, 7-, or 8-membered aliphatic ring, and the remaining third group represents a hydrogen atom or a C1-C ring. 12 Preferably, it is a C1-C6 alkyl group. The inhibitor D, useful as an alkene-yne ​​conjugated compound according to the present invention, can be 1-ethynyl-1-cyclohexene.

[0141] α-Alynone inhibitor D can be selected from compounds of formula (D4):

[0142]

[0143] Where: R 8 Indicates alkyl, cycloalkyl, (cycloalkyl)alkyl, C6 to C6 10 Aryl or C7 to C 18 Arylalkyl, wherein the alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl or arylalkyl may optionally be substituted once or multiple times with chlorine, bromine or iodine atoms.

[0144] According to a preferred embodiment, R 8 Representing C1-C 12 Preferably, it is a C1-C6 monovalent alkyl group, optionally substituted once or multiple times with chlorine or bromine atoms, or a cycloalkyl group, or a C6-C6 monovalent alkyl group. 10 Aryl. The inhibitor D useful according to the present invention as an α-acetylene can be selected from the following compounds: 1-octyno-3-one, 8-chloro-1-octyno-3-one; 8-bromo-1-octyno-3-one; 4,4-dimethyl-1-octyno-3-one; 7-chloro-1-heptyno-3-one; 1-hexyn-3-one; 1-pentyn-3-one; 4-methyl-1-pentyn-3-one; 4,4-dimethyl-1-pentyn-3-one; 1-cyclohexyl-1-propyn-3-one; benzo[a]acetylene and o-chlorobenzoylacetylene.

[0145] Acrylonitrile-type inhibitor D can be selected from compounds of the following formula (D5):

[0146]

[0147] Where: R 9 and R 10Each of the following can be independently represented: hydrogen atom, chlorine, bromine or iodine atom, alkyl group, cycloalkyl group, (cycloalkyl)alkyl group, C6 to C6. 10 Aryl or C7 to C 18 Arylalkyl, wherein the alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl or arylalkyl may optionally be substituted once or multiple times with chlorine, bromine or iodine atoms.

[0148] The useful inhibitor D for acrylonitrile according to the present invention can be selected from the group consisting of: acrylonitrile; methacrylonitrile; 2-chloroacrylonitrile; crotonitrile and cinnamonitrile.

[0149] Inhibitor D of the maleate or fumarate type can be selected from compounds of formulas (D6) and (D7):

[0150]

[0151] Where: R 11 and R 12 They can be the same or different, and can be independently represented as alkyl or alkenyl, cycloalkyl, (cycloalkyl)alkyl, C6 to C6. 10 Aryl or C7 to C 18 Arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, (cycloalkyl)alkyl, aryl and arylalkyl may be substituted with alkoxy groups.

[0152] According to the present invention, the term "alkenyl" refers to a saturated hydrocarbon chain containing 2-6 carbon atoms and having at least one double bond unsaturation. Preferably, the alkenyl group is selected from vinyl or allyl.

[0153] According to formula (D6) or (D7), the term "alkoxy" refers to an alkyl group as defined above that is bonded to an oxygen atom. Alkoxy groups may be selected from methoxy, ethoxy, propoxy, and butoxy groups.

[0154] According to a specific implementation plan, R 11 and R 12 They may be the same or different, and independently represent C1 to C6 alkoxy groups optionally substituted with C1 to C6 alkoxy groups. 12 Preferably, it is a C1 to C6 alkyl or alkenyl group.

[0155] The inhibitor D, which is useful as a maleate or fumarate ester inhibitor according to the present invention, can be selected from diethyl fumarate, diethyl fumarate, diallyl fumarate, diallyl maleate, and bis(methoxyisopropyl) maleate.

[0156] Inhibitor D, selected from α-alkynyl alcohols, α-α'-alkynyl diesters, en-alkynyl conjugated compounds, α-alkynyl ketones, acrylonitriles, maleates, and fumarates, is commercially available. Particularly noteworthy are ECH (1-ethynyl-1-cyclohexanol), commercially available from BASF; dimethyl maleate, commercially available from DMS; and dimethyl ethynyl dicarboxylate, commercially available from City Chemical LLC.

[0157] These inhibitors are added at a weight of 1 to 50,000 ppm, particularly 10 to 10,000 ppm, preferably 20 to 2,000 ppm, and even more preferably 20 to 500 ppm, relative to the total organosilicon composition.

[0158] If desired, additive K may be added to the precursor composition of the silica gel. Examples of additive K include solvents capable of dissolving the catalyst and stabilizers derived from the family of silylated derivatives of phosphoric acid, such as silylated esters of phosphoric acid.

[0159] In addition, the silicone gel composition may contain other active pharmaceutical ingredients or substances, such as camphor, menthol oil, methyl salicylate, eucalyptus oil, and clove oil, to promote pain relief or provide additional therapeutic effects in conjunction with capsaicin. If these are used, their amounts are preferably less than 1% by weight, for example, 0.5% by weight, preferably 0% by weight, based on the total weight of the silicone gel precursor composition.

[0160] As stated above, according to the inventors' findings, when applied to the skin, the delivery amount of capsaicin to the skin must be controlled between 0.01 and 0.145 g / m². 2 Preferably, the concentration is 0.02 to 0.13 g / m³. 2 More preferably 0.04 to 0.12 g / m 2 Within the skin area, an optimal balance can be achieved between the adhesive strength of the silicone gel and the comfort on the skin. The delivery amount can depend on the coating weight of the capsaicin-loaded silicone gel on the patch and the capsaicin content in the silicone gel. In one embodiment, advantageously, the coating weight of the capsaicin-coated silicone gel on the substrate is 100 g / m². 2 Up to 500g / m 2 For example, 120 to 400 g / m 2 Or 150 to 220 g / m 2 Therefore, the capsaicin content in the precursor composition of the gel can be 0.008 to 0.1% by weight, for example, 0.01 to 0.09% by weight or 0.02 to 0.08% by weight. By using the coating weight and content recommended above, not only can the required amount of capsaicin be delivered, but the negative impact on the overall mechanical properties and processability of the silicone gel can also be minimized.

[0161] Because adding capsaicin in the specific manner suggested above is sufficient to ensure excellent adhesion of the gel to the patch substrate, while maintaining a firm but not overly strong adhesion to humans or animals, the precursor composition of the organopolysiloxane B or silicone gel according to the invention may contain very small amounts, for example less than 0.1% by weight, preferably less than 0.01% by weight, or more preferably less than 0.001% by weight, of a hydroxyl-functionalized silicone resin or even a silicone resin without hydroxyl functionalization. Hydroxyl-functionalized silicone resins or hydroxyl-substituted silicone resins, or polysiloxanes containing at least one hydroxyl group bonded to silicon, are generally considered effective or beneficial in the art to increase the adhesion of the gel to medical substrates and skin.

[0162] The preparation of therapeutic patches is itself very common and well known to those skilled in the art. In one exemplary embodiment, a precursor composition of a silicone gel containing a specific amount of capsaicin can be formed in a first step by uniformly mixing the individual components of the precursor composition of the gel, such as the preferred composition described above. Capsaicin can be added individually or together with other components of the precursor composition of the silicone gel at any time during the mixing process. The capsaicin used in this invention is added directly to the precursor composition of the silicone gel, meaning that the capsaicin is not dispersed or dissolved in any solvent or dispersant before being added to the precursor composition of the silicone gel. Alternatively, the capsaicin is not added to the precursor composition in the form of a dispersion or solution. Therefore, in the patch of this invention, capsaicin exists as a dispersed phase in the silicone gel matrix, and it is in direct contact with and surrounded by the silicone gel matrix. The patch can then be prepared by coating the obtained precursor composition onto a substrate, which may be a backing layer. The coating thickness of the gel precursor composition on the substrate can be in the range of 0.1 mm to 0.5 mm. The curing process can be carried out at an elevated temperature of about 100-250°C for 10 to 30 minutes.

[0163] On the other hand, the present invention relates to the use of capsaicin in patches for balancing the adhesive strength of silicone gel and comfort on the skin, wherein the amount of capsaicin delivered is from 0.01 to 0.145 g / m². 2 Preferably, the concentration is 0.02 to 0.13 g / m³. 2 More preferably 0.04 to 0.12 g / m 2 Skin area. Preferably, the silicone gel is as defined above.

[0164] On the other hand, the present invention relates to a method for preparing a patch having a capsaicin-containing silicone gel, comprising introducing capsaicin into a silicone gel adhered to a patch substrate, the amount being such that the capsaicin delivery is 0.01 to 0.145 g / m³. 2 Preferably, the concentration is 0.02 to 0.13 g / m³. 2 More preferably 0.04 to 0.12 g / m2 Skin area. Preferably, the silicone gel of the present invention as described above is used in the method.

[0165] The invention is further illustrated in more detail by the following non-limiting embodiments. Example

[0166] Measurement instructions

[0167] Penetration: Measured according to standard NF ISO 2137 by the penetration test method using a Petrotest PNR 12 penetrating tester, with the total weight of the rod and cone fixed at 62.5 g. The cone penetration of the silica gel was determined at 25°C by measuring the depth of penetration of the cone into the sample, obtained by releasing the cone assembly of the penetrating tester and allowing the cone to act for 5 seconds.

[0168] Coating weight: This is measured by weighing the pure gel on the substrate per square meter after coating.

[0169] Adhesion: According to ASTM D2979, silicone gel coated PET was tested using a PT-1000 probe adhesive tester.

[0170] Peel adhesion on paper: PET coated with silicone gel was measured by contacting it with a Bristol paper strip at a peel angle of 180°, according to FINAT no.1 test method.

[0171] Residue: Measured by the ratio of gel remaining on the skin after >5 hours of wear to the total area of ​​gel initially adhered to the skin. None: = 0%; Slight: 0 to 1%; Significant: >1%.

[0172] Pain relief performance: This can be reflected in the following details: the time to effect trigger, the degree of pain relief, and the duration of effect as assessed by humans, all of which are tested through actual user evaluation.

[0173] The trigger time refers to the time from when the capsaicin patch is applied to the skin until the analgesic effect begins with a slight warming or burning sensation. The ideal trigger time is 20-30 minutes.

[0174] The degree of heat effect indicates the level of pain relief and can vary depending on the individual user and the location on the body where the patch is applied. Based on numerous individual reviews, the degree can be categorized into several levels, from weak to strong: weak, moderate, best, strong, and (unacceptable) burning.

[0175] Duration refers to the time from when the capsaicin-loaded patch is applied to the skin until the pain relief effect is no longer felt.

[0176] raw material

[0177]

[0178]

[0179] Preparation of Examples 1 to 8

[0180] The components were uniformly mixed together in the amounts specified in Table 1 to prepare a precursor composition for the silicone gel. The mixture was then degassed for 10 minutes. The mixture was divided into two portions: 180 g of the mixture was sampled into a cup and cured at 120 °C for 60 minutes for penetration testing, and 20 g of the mixture was coated onto a 50 μm thick PET layer and cured at 120 °C for 20 minutes to form a silicone gel-coated PET for adhesion performance testing.

[0181] The composition and test results of the silica gel are given in Table 1.

[0182]

Claims

1. A patch having a silicone gel containing capsaicin coated on a substrate, wherein the amount of capsaicin delivered to the skin is between 0.04 and 0.145 g / m². 2 Within the area of ​​the skin; in Based on the total weight of the silicone gel, the capsaicin content in the silicone gel is from 0.008% to 0.1% by weight; and the delivery amount is calculated according to the following equation: Capsaicin delivery rate (g / m 2 Capsaicin content (%) Coating weight (g / m) 2 ) / 100; and The penetration of the capsaicin-containing silica gel is in the range of 140-250 mm / 10.

2. The patch according to claim 1, characterized in that, The capsaicin is delivered to the skin at a rate of 0.04 to 0.13 g / m². 2 Within the skin's surface area.

3. The patch according to claim 1, characterized in that, The capsaicin is delivered to the skin at a rate of 0.04 to 0.12 g / m². 2 Within the skin's surface area.

4. The patch according to claim 1, characterized in that, Capsaicin exists as a dispersed phase in the silica gel matrix, and is in direct contact with and surrounded by the silica gel matrix.

5. The patch according to claim 1, characterized in that, The penetration of the capsaicin-containing silica gel is in the range of 140-210 mm / 10.

6. The patch according to any one of claims 1 to 5, characterized in that, The capsaicin-coated silicone gel has a skin application weight of 100 g / m². 2 Up to 500g / m 2 .

7. The patch according to any one of claims 1 to 5, characterized in that, The capsaicin-coated silicone gel has a skin application weight of 120 g / m². 2 Up to 400g / m 2 .

8. The patch according to any one of claims 1 to 5, characterized in that, The capsaicin-coated silicone gel has a skin application weight of 150 g / m². 2 Up to 220g / m 2 .

9. The patch according to any one of claims 1 to 5, characterized in that, Based on the total weight of the silica gel, the capsaicin content in the silica gel is from 0.01% to 0.09% by weight.

10. The patch according to any one of claims 1 to 5, characterized in that, Based on the total weight of the silica gel, the capsaicin content in the silica gel is from 0.02% to 0.08% by weight.

11. The patch according to any one of claims 1 to 5, characterized in that, The silica gel is formed from a precursor composition via a hydrosilylation reaction, wherein the precursor composition, in addition to the capsaicin, also contains: 1) At least one organopolysiloxane B, comprising: (i) at least two silanoxy units of formula (B1) (Y) a (WITH) b SiO (4-(a+b)) / 2 (B1) in -Y represents a monovalent group containing 2 to 6 carbon atoms and having at least one alkenyl group; -Z indicates a monovalent group containing 1 to 20 carbon atoms and not an alkenyl group; -a and b represent integers, where a is 1, 2 or 3, b is 0, 1 or 2, and (a+b) is 1, 2 or 3; (ii) and optionally include other silanoxy units of formula (B2). (Z) c SiO (4-c) / 2 (B2) in - Z has the same meaning as described in equation (B1), and - c represents an integer of 0, 1, 2 or 3; 2) At least one organopolysiloxane CE, which contains: - Two silyloxy-terminal units, having the same or different formula (CE-1) (H) p (R 1 ) q SiO 1 / 2 (CE-1) in - Symbol R 1 Corresponding to C1 to C8 alkyl or C6 to C 10 Aryl; - and the symbol H represents a hydrogen atom, where p = 0 or 1, q = 2 or 3 and (p + q) = 3; - At least one silyl group of formula (CE-2): (H) n (R 2 ) m SiO 2 / 2 (CE-2) Wherein group R 2 Corresponding to C1 to C8 alkyl groups or C6 to C 10 An aryl group, symbol H, represents a hydrogen atom and where n = 0 or 1, m = 1 or 2 and (n + m) = 2, and The condition is that each organopolysiloxane (CE) polymer contains two hydrogen atoms, and each hydrogen atom is bonded to a different silicon atom. 3) At least one organopolysiloxane XL, comprising: - At least three silyloxy units of formula (XL-1): (H) (L) e SiO (3-e) / 2 (XL-1) The symbol H represents a hydrogen atom, and the symbol L represents an alkyl group with 1 to 8 carbon atoms (including the terminal value) or a C6 to C6 group. 10 Aryl group, and the symbol e equals 0, 1, or 2; and - Optional other silanoxy units of formula (XL-2): (L) g SiO (4-g) / 2 (XL-2) The symbol L represents an alkyl group having 1 to 8 carbon atoms (including the terminal value) or a C6 to C6 group. 10 Aryl, and the symbol g equals 0, 1, 2 or 3, and The condition is that the organopolysiloxane XL contains 1.0% to 15.0% by weight of Si-H functional groups / polymer. 4) An effective amount of at least one hydrosilylation catalyst E, 5) At least one inhibitor of hydrosilylation reaction D, Where the molar ratio RHAlk = tH / tAlk < 1.0 or ≥ 3, where tH = the number of hydrogen atoms directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition, and tAlk = the number of alkenyl groups directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition.

12. The patch according to claim 11, characterized in that, Each organopolysiloxane CE polymer contains two silanoxy units of formula (CE-1) with p=1 and at least one silanoxy unit of formula (CE-2) with n=0.

13. The patch according to claim 11, characterized in that, Organopolysiloxane XL contains 1.5% to 15.0% by weight of Si-H functional groups / polymers.

14. The patch according to claim 11, characterized in that, Organopolysiloxane XL contains 1.5% to 12.5% ​​by weight of Si-H functional groups / polymers.

15. The patch according to claim 11, characterized in that, The molar ratio RHAlk = tH / tAlk is 0.4 to 0.

9.

16. The patch according to claim 11, characterized in that, The molar ratio RHAlk = tH / tAlk is 0.5 to 0.

85.

17. The patch according to claim 11, characterized in that, The molar ratio RHAlk = tH / tAlk is 3 to 24.

18. The patch according to claim 11, characterized in that, The molar ratio RHAlk = tH / tAlk is 3.5 to 20.

19. The patch according to claim 11, characterized in that, The precursor composition contains an additional organopolysiloxane B', which contains only one vinyl or alkenyl group located at one or one terminal silanoxy unit, in an amount of 1-40% based on the total weight of the precursor composition.

20. The patch according to claim 11, characterized in that, The precursor composition contains an additional organopolysiloxane B', which contains only one vinyl or alkenyl group located at one or one terminal silanoxy unit, in an amount of 1.5-30% based on the total weight of the precursor composition.

21. The patch according to claim 11, characterized in that, The precursor composition contains an additional organopolysiloxane B', which contains only one vinyl or alkenyl group located at one or one terminal silanoxy unit, in an amount of 2.5-20% based on the total weight of the precursor composition.

22. The patch according to claim 11, characterized in that, The precursor composition contains an additional organopolysiloxane B', which contains only one vinyl or alkenyl group located at one or one terminal siloxy unit, in an amount of 2.5-10% based on the total weight of the precursor composition.

23. The patch according to any one of claims 1 to 5, characterized in that, The silicone gel contains less than 0.1% by weight of hydroxyl-functionalized siloxane resin.

24. The patch according to any one of claims 1 to 5, characterized in that, The silicone gel contains less than 0.01% by weight of hydroxyl-functionalized siloxane resin.

25. The patch according to any one of claims 1 to 5, characterized in that, The silicone gel contains less than 0.001% by weight of hydroxyl-functionalized siloxane resin.

26. The patch according to any one of claims 1 to 5, characterized in that, Silicone gels do not contain hydroxyl-functionalized siloxane resins.

27. Use of capsaicin in the preparation of patches according to any one of claims 1 to 26, for balancing the adhesive strength of the silicone gel and comfort on the skin, wherein the amount of capsaicin delivered is from 0.04 to 0.145 g / m 2 Within the skin's surface area.

28. The use according to claim 27, wherein the capsaicin delivery amount is from 0.04 to 0.13 g / m³. 2 Within the skin's surface area.

29. The use according to claim 27, wherein the capsaicin delivery amount is from 0.04 to 0.12 g / m³. 2 Within the skin's surface area.

30. A method for preparing a patch having any one of claims 1 to 26, comprising introducing capsaicin into a silicone gel adhered to a patch substrate, the amount such that the capsaicin delivery is between 0.04 and 0.145 g / m³. 2 Within the skin's surface area.

31. The method of claim 30, wherein capsaicin is introduced into the silicone gel adhered to the patch substrate in an amount such that the capsaicin delivery is between 0.04 and 0.13 g / m². 2 Within the skin's surface area.

32. The method of claim 30, wherein capsaicin is introduced into the silicone gel adhered to the patch substrate in an amount such that the capsaicin delivery is between 0.04 and 0.12 g / m². 2 Within the skin's surface area.

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