Patch coated with capsaicin-containing silicone gel

Abstract

In the present invention, the amount of capsaicin delivered to the skin is 0.01 to 0.145 g / m2 relative to the area of ​​the skin. 2 , preferably 0.02 to 0.13 g / m 2 , more preferably 0.04 to 0.12 g / m 2 The present invention provides a patch in which a substrate is coated with a capsaicin-containing silicone gel, the range of which is 0.01 to 0.01 mm. Such a patch provides a balance between the adhesive strength of the silicone gel and the pleasant feel on the skin. The present invention also provides the use of capsaicin in a patch to provide a balance between the adhesive strength of the silicone gel and the pleasant feel on the skin, and a method for making a patch having a capsaicin-containing silicone gel.

Description

Technical Field

[0001] The present invention relates to a patch coated with a capsaicin-containing silicone gel and a method for producing the same.

Background Art

[0002] Many people suffer from neuropathic pain, which has a devastating impact on the quality of life. The causes of neuropathic pain are very diverse, such as reactivation of latent viruses, direct trauma to nerves, diabetes, HIV infection and treatment.

[0003] Capsaicin, its derivatives, and analogs (or so-called "capsaicinoids") have been known to be useful for pain relief for a very long time. Capsaicin, the pungent ingredient in chili peppers, activates the vanilloid receptor (TRPV1) expressed in cutaneous nociceptive sensory nerve fibers, acutely causing a sensation of burning pain, and then these nociceptors function for a long time.

[0004] For example, U.S. Patent No. 5,762,963 provides a method and composition for oral delivery of a temporarily increasing concentration of capsaicin or capsaicinoid. The composition provided therein contains one or more capsaicinoids dispersed in a solid carrier material such as a lollipop. Oral capsaicin formulations provide pain relief, but there are often inevitable thirst and nausea associated with oral administration of capsaicin or capsin. Furthermore, oral delivery of capsaicin or capsaicinoid or oral administration is limited and inconvenient.

[0005] Various other forms of capsaicin delivery have been developed. One of the most common capsaicin-bearing systems is a self-adhesive matrix based on silicone PSA or rubber or silicone gel. Chinese Patent Application Publication No. 105687125 discloses that capsaicin can be directly added to a polydimethylsiloxane-based mixture and can be applied directly to the skin.

[0006] Considering the patient's suitability and convenience, a therapeutic patch coated with a silicone gel containing capsaicin is suitable. WO 2005 / 102403 and WO 2008 / 057155 provide silicone gels for adhering transdermal drug delivery devices containing hydroxyl-functional siloxane resins to improve adhesion strength. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] However, when using capsaicin (usually solvent-based) in patches mainly based on PSA, silicone gel, or natural rubber adhesive systems, the adhesion strength is very high, so the patient's skin and the adhered object may be damaged during removal, causing pain to the patient. Also, they often exhibit cold flow characteristics at skin temperature, which is very uncomfortable for the patient's body. Therefore, there is a continuing need to improve PSA, silicone gel, or natural rubber, especially silicone gel, with respect to the above drawbacks in patch applications. MEANS FOR SOLVING THE PROBLEM

[0008] The inventors of the present application have surprisingly discovered that the dynamic process of transdermal administration of capsaicin from the patch to the skin (measured by the delivery amount of capsaicin) affects both the adhesion strength of the silicone gel and the comfortable feeling of the skin. Therefore, the above task can be solved by controlling the delivery amount of capsaicin to the skin. More specifically, when the delivery amount of capsaicin in the patch can be controlled within the range of 0.01 to 0.145 g / m 2 area, a balance between appropriate adhesion strength and comfortable feeling of the skin is achieved.

[0009] The term "delivery amount" as used throughout this application refers to the transdermal dosage of a medically active substance, such as capsaicin, that enters the skin from the patch. The delivery amount can be defined as the amount of the active substance added per unit area of the skin that the patch contacts. For example, the delivery amount of capsaicin can be calculated by the following formula: Capsaicin delivery amount (g / m 2 ) = Capsaicin amount (%) × Coating weight (g / m 2 ) / 100

[0010] Accordingly, the present invention relates to a patch coated on a substrate with a capsaicin-containing silicone gel, where the delivery amount of capsaicin to the skin is in the range of 0.01 - 0.145 g / m 2 . In a beneficial embodiment, the coating weight of the silicone gel that coats capsaicin on the skin is 100 g / m 2 - 500 g / m 2 , for example 120 - 400 g / m 2 or 150 - 220 g / m 2 .

[0011] In another aspect, the present invention relates to the use of capsaicin in a patch for balancing the adhesive strength of the silicone gel and the comfortable feeling of the skin.

[0012] In yet another aspect, the present invention relates to a method for producing a patch having a capsaicin-containing silicone gel.

Embodiments for Carrying Out the Invention

[0013] As outlined above, the present invention relates to a patch coated on a substrate with a capsaicin-containing silicone gel.

[0014] As used herein, the term "patch" refers to a medical device that can deliver a drug or active substance by a transdermal method, usually referring to materials commonly used in medicine, which are used to cover or repair wounds on the skin of humans or animals, and in particular, refers to topical or transdermal patches. Usually, it is made by coating, diffusing, or distributing a medically active substance, or a carrier or medium carrying these active substances, onto a substrate. The carrier or medium carrying the active substance has a consistency suitable for coating, diffusing, or distributing. Regarding the substrates useful for patches, they are well known to those skilled in the medical device field and can usually be continuous, discontinuous, or porous. The substrate can be the back 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, non-woven fabrics, knit fabrics, fiber networks, or kraft paper and cotton cloth, etc.; preferably, non-woven fabrics, polyurethane films, kraft paper, and cotton cloth.

[0015] In addition to the substrate and the carrier or medium carrying a medically active substance, such as silicone gel coated thereon, for example, for protection from contamination of the silicone gel during preparation, transportation, and storage, the patch may further include a release liner disposed on the surface of the carrier or medium, such as silicone gel, on the opposite side of the substrate. The release liner is peeled off before application to the skin.

[0016] As used herein, capsaicin is well known and refers not only to pure capsaicin powder but also to various forms of capsaicin, its derivatives, analogs (or capsinoids), and mixtures thereof. Capsaicin also has the following chemical structure, also known as 8-methyl-N-vanillyl-trans-6-nonenamide or (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-enamide:

Chemical formula

[0017] In addition to capsaicin, there are various capsaicin analogs and derivatives that are useful in the present invention and are included within the scope of "capsaicin" as used herein. Exemplary forms of capsaicin and its derivatives and analogs include, but are not limited to: N-vanillylalkanediamide, N-vanillyl-alkanedienyl, N-vanillyl-cis-monounsaturated alkenamide, capsaicin, dihydrocapsaicin, norhydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin, and capsaicin oleoresin naturally extracted from capsicum fruits having different capsaicin concentrations in the range of 0.5 wt% to 90 wt%, for example 5 wt% to 70 wt%, based on the total weight of the extracted product.

[0018] Accordingly, the term "capsaicin-containing silicone gel" refers to a silicone gel containing capsaicin, any form of capsaicin analogs and their derivatives, and / or mixtures thereof, which has the function of pain relief.

[0019] The term "silicone gel" refers to an elastic jelly-like solid material formed by a lightly crosslinked silicone polymer or a precursor silicone composition, indicating that there is no flow when in a stable state. In contrast, a silicone pressure-sensitive adhesive ("PSA") has low or no elasticity and is thus different from a silicone gel.

[0020] Silicone gels are generally formed by a crosslinking reaction from linear or branched silicones having reactive groups. Examples of crosslinking reactions include hydrosilylation reactions in which an organopolysiloxane having a silicone or Si-H reactive group reacts with an organopolysiloxane having a silicone or alkenyl or vinyl group (Si-alkenyl group), preferably in the presence of a hydrosilylation catalyst.

[0021] When used in humans or animals, the silicone gel needs to be sufficiently soft and flexible to ensure comfort for the user. Therefore, silicone gels are typically characterized by a certain degree of penetrability (or "penetration" or "cone penetrability"). This is measured using a penetrometer according to the standard NF ISO2137. Using a Petrotest penetrometer, model PNR12, the total weight of the rod and cone is fixed at 62.5 g. The cone penetrability of the silicone gel is determined by measuring the depth of penetration of the cone into the sample of the gel at 25°C. The said depth is obtained by releasing the cone assembly of the penetrometer and actuating the cone for 5 seconds.

[0022] However, as described above, the inventors have discovered that the addition of capsaicin particularly significantly affects the penetrability of the silicone gel. The penetration after the addition of capsaicin is closely related to the patch adhesion performance. At a penetrability of less than 100 mm / 10, the adhesion performance decreases, and when the penetrability exceeds 250 mm / 10, the cohesive performance leading to gel residues on the skin may deteriorate. Therefore, the penetrability of the gel by capsaicin needs to be controlled in the range of 100 - 250 mm / 10, preferably 140 - 210 mm / 10.

[0023] In a preferred embodiment according to the present invention, the silicone gel is formed by a hydrosilylation reaction from a precursor composition containing, in addition to capsaicin: 1) At least one organopolysiloxane B containing: (i) At least two siloxyl units of formula (B1) (Y) a (Z) b SiO (4-(a+b)) / 2 (B1) In the formula, · Y represents a monovalent radical containing 2 - 6 carbon atoms and having at least one alkenyl group, · Z represents a monovalent radical containing 1 - 20 carbon atoms and not containing an alkenyl group, · a and b represent integers, a is 1, 2, or 3, b is 0, 1, or 2, and (a + b) is 1, 2, or 3; (ii) and optionally, other siloxyl units of formula (B2): (Z) c SiO (4-c) / 2 (B2) In the formula, · Z has the same meaning as above, · c represents an integer of 0, 1, 2, or 3; 2) At least one organopolysiloxane CE containing the following, - Two siloxyl terminal units of formula (CE-1) (which may be the same or different) (H) p (R 1 ) q SiO 1 / 2 (CE-1) In the formula, · The symbol R 1 corresponds to an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 10 carbon atoms, · The symbol H represents a hydrogen atom, p = 0 or 1, q = 2 or 3, and (p + q) = 3; - At least one siloxyl group of formula (CE-2): (H) n (R 2 ) m SiO 2 / 2 (CE-2) In the formula, the radical R 2 is an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 10 carbon atoms, the symbol H represents a hydrogen atom, n = 0 or 1, m = 1 or 2, and (n + m) = 2, 1 ~C 8 alkyl group or C 6 ~C 10 aryl group, and the symbol H represents a hydrogen atom, n = 0 or 1, m = 1 or 2, and (n + m) = 2, However, the organopolysiloxane CE contains two hydrogen atoms bonded to different silicon atoms for each polymer. Preferably, the organopolysiloxane CE contains, for each polymer, two siloxyl units of formula (CE-1) with p = 1 and at least one siloxyl unit of formula (CE-2) with n = 0; 3) At least one organopolysiloxane XL comprising the following: - At least three siloxyl units of formula (XL-1): (H)(L) e SiO (3-e) / 2 (XL-1) In the formula, the symbol H represents a hydrogen atom, the symbol L represents an alkyl having 1 to 8 carbon atoms or an aryl of C 6 ~C 10 and the symbol e is equal to 0, 1, or 2; and - Optionally, other siloxyl units of formula (XL-2): (L) g SiO (4-g) / 2 (XL-2) In the formula, the symbol L represents an alkyl having 1 to 8 carbon atoms or an aryl of C 6 ~C 10 and the symbol g is equal to 0, 1, 2, or 3, provided that the organopolysiloxane XL contains 1.0 wt% to 15.0 wt% of Si-H functional groups per polymer, preferably 1.5 wt% to 15.0 wt% of Si-H functional groups per polymer, more preferably 1.5 wt% to 12.5 wt% of Si-H functional groups per polymer; 4) An effective amount of at least one hydrosilylation catalyst E; 5) At least one hydrosilylation reaction inhibitor D; Here, the molar ratio RHAlk = tH / tAlk is <1.0, preferably 0.4 to 0.9, more preferably 0.5 to 0.85, or >3, preferably 3 to 24, more preferably 3.5 to 20, where 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 directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition.

[0024] In one particular embodiment of the precursor composition of the silicone gel: · The organopolysiloxane B has a dynamic viscosity of 100 mPa·s to 120000 mPa·s at 25°C, · The organopolysiloxane CE has a dynamic viscosity of 1 mPa·s to 500 mPa·s at 25°C, preferably 5 to 200 mPa·s, · The organopolysiloxane XL has a dynamic viscosity of 5 mPa·s to 2000 mPa·s at 25°C, preferably 5 to 500 mPa·s.

[0025] All viscosities considered in this specification correspond to the magnitude of the "Newtonian" dynamic viscosity at 25°C, i.e., the dynamic viscosity measured by using a Brookfield viscometer at a shear rate gradient that is sufficiently low so that the measured viscosity is independent of the velocity gradient, by a method known per se.

[0026] According to one advantageous embodiment, the properties and parts by weight of the organopolysiloxanes B, CE, and XL are selected such that the dynamic viscosity of the silicone gel precursor composition at 25°C is 200 mPa·s to 100000 mPa·s, preferably 200 mPa·s to 80000 mPa·s.

[0027] It is advantageous to comply with the following two conditions: · The organopolysiloxane CE has at least 5 silicon atoms, and the ratio: (moles of SiH groups) / (total number of silicon atoms) is between 0.05 and 0.40, preferably between 0.08 and 0.35; · The organopolysiloxane XL has at least 5 silicon atoms, and the ratio (moles of SiH groups) / (total number of silicon atoms) is between 0.05 and 0.80, preferably between 0.05 and 0.50.

[0028] According to the invention, regarding the definition of the organopolysiloxane B of formula (B1), it is advisable that the symbol a is equal to 1 or 2, and more preferably equal to 1. Further, in formula (B1) and formula (B2), the formula Z can preferably represent a single radical selected from the group consisting of: an alkyl group containing 1 to 8 carbon atoms (optionally substituted with at least one halogen atom), and C 6 ~C 10an aryl group. Z can preferably represent a monovalent group selected from the group consisting of methyl, ethyl, propyl, 3,3,3-trifluoropropyl, xylyl, tolyl, and phenyl. Further, in formula (B1), the symbol Y can preferably 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.

[0029] The organopolysiloxane B may have a linear, branched, cyclic, or network structure. In the case of a linear organopolysiloxane, it can be essentially composed of the following: · Formula (Y) 2 SiO 2 / 2 , (Y)(Z)SiO 2 / 2 and (Z) 2 SiO 2 / 2 a siloxyl unit "D" selected from the units of · Formula (Y) 3 SiO 1 / 2 , (Y) 2 (Z)SiO 1 / 2 , (Y)(Z) 2 SiO 1 / 2 and (Z) 3 SiO 2 / 2 a siloxyl unit "M" selected from the units of · In the formula, the symbols Y and Z are as defined above.

[0030] Examples of the unit "D" include dimethylsiloxy, methylphenylsiloxy, methylvinylsiloxy, methylbutenylsiloxy, methylhexenylsiloxy, methyldecenylsiloxy, and methyldecadienylsiloxy groups.

[0031] Examples of the unit "M" include trimethylsiloxy, dimethylphenylsiloxy, dimethylvinylsiloxy, and dimethylhexenylsiloxy groups.

[0032] Organopolysiloxane B can be a silicone oil having a dynamic viscosity of 50 mPa·s to 120,000 mPa·s, preferably 100 mPa·s to 120,000 mPa·s at 25°C, especially in the case of a straight chain.

[0033] When organopolysiloxane B is cyclic, it can be composed of siloxyl units "D" selected from units of the formula Y 2 SiO 2 / 2 , YZSiO 2 / 2 and Z 2 SiO 2 / 2 . Examples of such units "D" have been described above. This cyclic organopolysiloxane can have a dynamic viscosity of 1 mPa·s to 5000 mPa·s at 25°C.

[0034] Examples of useful organopolysiloxane B include the following: · Polydimethylsiloxane containing dimethylvinylsilyl end groups, · Poly(methylphenylsiloxane-co-dimethylsiloxane) containing dimethylvinylsilyl end groups, · Poly(vinylmethylsiloxane-co-dimethylsiloxane) containing dimethylvinylsilyl end groups, · Poly(dimethylsiloxane-co-vinylmethylsiloxane) containing trimethylsilyl end groups, · And cyclic polymethylvinylsiloxane.

[0035] As organopolysiloxane B, polydimethylsiloxane containing dimethylvinylsilyl end groups and having a dynamic viscosity between 50 mPa·s and 120,000 mPa·s, preferably between 100 mPa·s and 120,000 mPa·s at 25°C is particularly advantageous. A particularly advantageous organopolysiloxane B includes those of the formula M Vi D x M Vi , where: · M Vi = a siloxyl unit of the formula: (vinyl)(CH 3 ) 2 SiO 1 / 2 , · D = a formula: (CH3 ) 2 SiO 2 / 2 siloxyl units of · x is a numerical value from 1 to 1000, preferably from 5 to 1000.

[0036] In some embodiments, the silicone gel precursor composition optionally contains organopolysiloxane B', and organopolysiloxane B' is present in an amount of 1 to 40%, preferably 1.5 to 30%, more preferably 2.5 to 20%, for example 2.5 to 10%, based on the total weight of the precursor composition, and has only one vinyl or alkenyl group arranged at one end or one terminal siloxyl unit (for example, when the alkenyl group is present only in one terminal siloxyl unit such as "unit M").

[0037] In one possible embodiment, organopolysiloxane B' is of formula M as an organopolysiloxane having an alkenyl group only at one terminal siloxyl unit Vi D x M and here: · M Vi = formula: (vinyl)(Z) 2 SiO 1 / 2 , preferably (vinyl)(CH 3 ) 2 SiO 1 / 2 siloxyl units of · M = formula (Z) 3 SiO 1 / 2 , preferably (CH 3 ) 3 SiO 1 / 2 siloxyl units of · D = formula (Z) 2 SiO 2 / 2 , preferably (CH 3 ) 2 SiO 2 / 2 , · x is a number from 1 to 1000, preferably from 50 to 800, more preferably from 100 to 800.

[0038] Particularly advantageously, a vinyl or alkenyl group (M Vi Dx The organopolysiloxane B' containing (such as M) has a dynamic viscosity of 100 mPa·s to 10,000 mPa·s at 25°C, preferably 100 mPa·s to 8,000 mPa·s, more preferably 100 mPa·s to 5,000 mPa·s.

[0039] In a preferred embodiment, the organopolysiloxane in the precursor composition has the formula M Vi D x M Vi and the organopolysiloxane B' of the formula M Vi D x M. Here, the amount of the organopolysiloxane B' of the formula M Vi D x M is 1 to 40%, preferably 1.5 to 30%, more preferably 2.5 to 20%, for example 2.5 to 10% based on the total weight of the precursor composition of the silicone gel.

[0040] Examples of the organopolysiloxane CE having a "chain extender" function include polydimethylsiloxane containing dimethylhydrosilyl end groups and having a dynamic viscosity between 1 mPa·s and 500 mPa·s at 25°C, 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 poly(dimethylsiloxy)α,ω(dimethylhydroxysiloxy) of the formula M H D x' M H where: ·M H = the siloxyl unit of the formula (H)(CH 3 ) 2 SiO 1 / 2 ; ·D = the siloxyl unit of the formula (CH 3 ) 2 SiO 2 / 2 ; ·x' is an integer from 1 to 200, preferably from 1 to 150, and more preferably from 3 to 120.

[0041] Organopolysiloxane CE is called a "chain extender" because it is estimated to have the effect of increasing the mesh size of the network during crosslinking. When the SiH reactive functional group is at the chain end, the term "telechelic" may be preferred over the term "chain extender".

[0042] As the organopolysiloxane XL having a crosslinking function and used according to the present invention, there are those of the formula M H D x'' D w H M H ,M H D x'' D y H M and MD x'' D z H M, and examples thereof include those of the formula: ·M H = the siloxyl unit of the formula (H)(CH 3 ) 2 SiO 1 / 2 ·D H = the siloxy unit of the formula (H)(CH 3 )SiO 2 / 2 ·D = the siloxyl unit of the formula (CH 3 ) 2 SiO 2 / 2 ·M = the siloxyl unit of the formula (CH 3 ) 3 SiO 1 / 2 ·However, x'' is a numerical value from 0 to 500, preferably from 2 to 250, more preferably from 5 to 80, w is a number from 1 to 500, preferably from 1 to 250, or from 1 to 100, even more preferably from 1 to 70, y is a number from 2 to 500, preferably from 3 to 250, or from 2 to 100, even more preferably from 2 to 70, z is a number from 3 to 500, preferably from 3 to 250, or from 3 to 100, more preferably from 3 to 70, Each polymer contains 2.5 wt% to 15.0 wt% of Si-H functional groups, preferably 3.0 wt% to 15.0 wt% of Si-H functional groups per polymer, and more preferably 3.5 wt% to 12.5 wt% of Si-H functional groups per polymer.

[0043] Examples of the hydrosilylation catalyst E useful according to the present invention include compounds of metals belonging to the platinum group well known to those skilled in the art. The metals of the platinum group are metals known as platinoids in addition to platinum, ruthenium, rhodium, palladium, osmium, and iridium. Compounds of platinum and rhodium are preferably used. In particular, platinum complexes and organic products (described in U.S. Patent Nos. 3,159,601, 3,159,602, 3,220,972, and European Patent Application Publication Nos. 0057459, 0188978, 0190530), and the platinum and vinyl organosiloxane complexes described in U.S. Patent No. 3,419,593 can be used. Generally preferred catalysts are platinum. By way of example, in particular, platinum black, chloroplatinic acid, chloroplatinic acid modified with an alcohol, complexes of chloroplatinic acid with olefins, aldehydes, vinyl siloxanes or acetylene alcohols can be mentioned. Preferred are Karstedt solutions or complexes, chloroplatinic acid hexahydrate, or platinum catalysts containing carbene ligands as described in U.S. Patent No. 3,775,452.

[0044] Examples of the hydrosilylation reaction inhibitor D useful according to the present invention include those selected from α-acetylene alcohols, α-α'-acetylene diesters, enyne conjugated compounds, α-acetylene ketones, acrylonitrile, maleates, fumarates, and mixtures thereof. These compounds capable of performing the hydrosilylation inhibitor function are well known to those skilled in the art. These can be used alone or as a mixture.

[0045] The α-acetylene alcohol type inhibitor D can be selected from compounds of the following formula (D1): (R 1 )(R2 ) C(OH)-C≡CH (D1) In the formula, · R 1 The group is an alkyl group, a cycloalkyl group, a (cycloalkyl)alkyl group, C 6 ~C 10 aryl group of or C 7 ~C 18 arylalkyl group of, and · R 2 The group is a hydrogen atom, an alkyl group, a cycloalkyl group, a (cycloalkyl)alkyl group, C 6 ~C 10 aryl group of or C 7 ~C 18 arylalkyl group of, and · Or, R 1 and R 2 Together with the carbon atom to which they are attached, form a 5-, 6-, 7- or 8-membered aliphatic ring (optionally substituted one or more times).

[0046] According to formula (D1): · The term "alkyl" is intended to mean a saturated hydrocarbon-based chain containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The alkyl group can be selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, tert-butyl, isobutyl, n-butyl, n-pentyl, isoamyl and 1,1-dimethylpropyl groups. · According to the present invention, the term "cycloalkyl" is intended to mean a saturated monocyclic or polycyclic, preferably monocyclic or bicyclic, hydrocarbon-based group containing 3 to 20 carbon atoms, preferably 5 to 8 carbon atoms. When the cycloalkyl group is polycyclic, the plurality of cyclic nuclei may be bonded to each other via a covalent bond and / or a spiran atom, and / or may be condensed with each other. The cycloalkyl group can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantane and norbornane. · According to the present invention, the term “(cycloalkyl)alkyl” is intended to also mean a cycloalkyl group as defined above attached to an alkyl group as defined above. · According to the present invention, the term “aryl” is intended to mean a monocyclic or polycyclic aromatic hydrocarbon-based group containing 6 to 10 carbon atoms. The aryl group can be selected from the group consisting of phenyl, naphthyl and anthracenyl. · According to the present invention, the term “arylalkyl” is intended to also mean an aryl group as defined above attached to an alkyl group as defined above.

[0047] According to a preferred embodiment, in formula (D1), R 1 and R 2 together with the carbon atom to which they are attached form an unsubstituted 5-, 6-, 7- or 8-membered aliphatic ring. According to another preferred embodiment, R 1 and R 2 may be the same or different and, independently of one another, represent a monovalent alkyl group of C 1 to C 12 , preferably C 1 to C 6 .

[0048] Inhibitor D, which is a useful α-acetylene alcohol according to the present invention, can be selected from the group consisting of the following compounds: 1-ethynyl-1-cyclopentanol; 1-ethynyl-1-cyclohexanol (also called ECH); 1-ethynyl-1-cycloheptanol; 1-ethynyl-1-cyclooctanol; 3-methyl-1-butyn-3-ol (also called MBT); 3-methyl-1-pentyn-3-ol; 3-methyl-1-hexyn-3-ol; 3-methyl-1-heptyn-3-ol; 3-methyl-1-octyn-3-ol; 3-methyl-1-nonyn-3-ol; 3-methyl-1-decyn-3-ol; 3-methyl-1-dodecyn-3-ol; 3-methyl-1-pentadecyn-3-ol; 3-ethyl-1-pentyn-3-ol; 3-ethyl-1-hexyn-3-ol; 3-ethyl-1-heptyn-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-heptyn-3-ol; 3,6-diethyl-1-nonyn-3-ol; 3,7,11-trimethyl-1-dodecyn-3-ol (also called TMDDO); 1,1-diphenyl-2-propyn-1-ol; 3-butyn-2-ol; 1-pentyn-3-ol; 1-hexyn-3-ol; 1-heptyn-3-ol; 5-methyl-1-hexyn-3-ol; 4-ethyl-1-octyn-3-ol; and 9-ethynyl-9-fluorenol.

[0049] The α,α'-acetylene diester type inhibitor D can be selected from the compounds of the following formula (D2):

Chemical formula

[0050] According to the present invention, the term "silyl" is intended to mean a group of the formula -SiR 3 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, a trimethylsilyl group.

[0051] According to a specific embodiment, in formula (D2), R 3 and R 4 may be the same or different and, independently of each other, represent an alkyl group or a trimethylsilyl group of C 1 to C 12 , preferably C 1 to C 6 The inhibitor D, which is an α-α'-acetylenediester useful according to the present invention, can be selected from the group consisting of the following compounds: dimethyl acetylenedicarboxylate (DMAD), diethyl acetylenedicarboxylate, tert-butyl acetylenedicarboxylate, and bis(trimethylsilyl) acetylenedicarboxylate.

[0052] The inhibitor D of the en-yne conjugated compound type can be selected from the compounds of the following formula (D3):

Chemical formula

[0053] According to a particular embodiment, the group R 5 , R 6 and R 7 independently of one another represent a hydrogen atom, a C 1 -C 12 , preferably a C 1 -C 6 alkyl group, or a C 6 -C 10 aryl group. The inhibitor D, which is an en-yne conjugated compound useful according to the present invention, can be selected from the group consisting of 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 particular embodiment, two groups selected from the group consisting of the group R 5 , R 6 , and R 7 form, together with the carbon atom to which they are attached, an unsubstituted 5-, 6-, 7- or 8-membered aliphatic ring, and the remaining third group represents a hydrogen atom or a C 1 -C 12 , preferably a C 1 -C 6 alkyl group. The inhibitor D, which is an en-yne conjugated compound useful according to the present invention, can be 1-ethynyl-1-cyclohexene.

[0054] The α-acetylene ketone type inhibitor D can be selected from the compounds of the following formula (D4):

Chemical formula

[0055] According to a preferred embodiment, R 8 is C 1 ~C 12 , preferably C 1 ~C 6 monovalent alkyl group (optionally substituted one or more times with chlorine or bromine atoms), or cycloalkyl group, or C 6 ~C 10 aryl group. The inhibitor D, which is a useful α-acetylene ketone according to the present invention, can be selected from the group consisting of the following compounds: 1-octyn-3-one, 8-chloro-1-octyn-3-one; 8-bromo-1-octyn-3-one; 4,4-dimethyl-1-octyn-3-one; 7-chloro-1-heptyn-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; benzoacetylene and o-chlorobenzoylacetylene.

[0056] The acrylonitrile type inhibitor D can be selected from the compounds of the following formula (D5):

Chemical formula

[0057] Inhibitor D, which is acrylonitrile useful according to the present invention, can be selected from the group consisting of the following compounds: acrylonitrile; methacrylonitrile; 2-chloroacrylonitrile; crotonitrile and cinnamitrile.

[0058] The maleate or fumarate type inhibitor D can be selected from the compounds of the following formulas (D6) and (D7):

Chemical formula

Chemical formula

[0059] According to the present invention, the term "alkenyl" is intended to mean a saturated hydrocarbon-based chain containing 2 to 6 carbon atoms and at least one double bond. Preferably, the alkenyl group is selected from the group consisting of vinyl and allyl.

[0060] The term "alkoxy" is intended to mean, according to formula (D6) or (D7), the alkyl group as defined above bonded to an oxygen atom. The alkoxy group can be selected from the group consisting of methoxy, ethoxy, propoxy and butoxy.

[0061] According to a specific embodiment, R 11 and R 12 may be the same or different and, independently of each other, are optionally C 1 to C 6substituted with an alkoxy group, C 1 ~C 12 , preferably C 1 ~C 6 represents an alkyl group or an alkenyl group.

[0062] Inhibitor D, which is a maleate or fumarate useful according to the present invention, can be selected from the group consisting of diethyl fumarate, diethyl maleate, diallyl fumarate, diallyl maleate, and bis(methoxyisopropyl) maleate.

[0063] Inhibitor D selected from α-acetylene alcohol, α-α'-acetylene diester, enyne conjugated compound, α-acetylenyl ketone, acrylonitrile, maleate and fumarate is commercially available. In particular, ECH (1-ethynyl-1-cyclohexanol) commercially available from BASF, dimethyl maleate commercially available from DMS, and dimethyl acetylenedicarboxylate commercially available from City Chemical LLC can be mentioned.

[0064] These inhibitors are added in a weight of 1 to 50000 ppm, particularly 10 to 10000 ppm, preferably 20 to 2000 ppm, and even more preferably 20 ppm to 500 ppm based on the weight of the total silicone composition.

[0065] Additive K may be added to the precursor composition of the silicone gel as needed. Examples of additive K include, for example, a solvent capable of dissolving a catalyst, and a stabilizer derived from the group of silylated derivatives of phosphoric acid such as silylated esters of phosphoric acid.

[0066] Furthermore, the composition of the silicone gel may contain other effective pharmaceutical ingredients or substances such as camphor, menthol oil, methyl salicylate, eucalyptus oil, clove oil, etc. to promote analgesia together with capsaicin or to bring about an additional therapeutic effect. When using them, the amount is preferably less than 1% by weight, for example 0.5% by weight, preferably in the range of 0% by weight, based on the total weight of the silicone gel precursor composition.

[0067] As described above, according to the findings of the present inventor, when applied to the skin, the delivery amount of capsaicin onto the skin should be controlled within the range of 0.01 to 0.145 g / m 2 , preferably 0.02 to 0.13 g / m 2 , more preferably 0.04 to 0.12 g / m 2 to achieve an optimal balance between the adhesion strength of the silicone gel and the comfortable feeling of use on the skin. The delivery amount can depend on the coating weight of the silicone gel carrying capsaicin on the patch and the content of capsaicin in the silicone gel. In one embodiment, advantageously, the coating weight of the capsaicin-coated silicone gel on the substrate is 100 g / m 2 to 500 g / m 2 , for example 120 to 400 g / m 2 or 150 to 220 g / m 2 . Therefore, the content of capsaicin in the gel precursor composition can be in the range of 0.008 to 0.1% by weight, for example 0.01 to 0.09% by weight or 0.02 to 0.08% by weight. Using the coating weight and content proposed above not only ensures the required delivery amount of capsaicin but also minimizes the adverse effects on the overall mechanical properties and processability of the silicone gel.

[0068] Adding capsaicin in the specific manner suggested above can be sufficient to ensure excellent adhesion of the gel to the substrate of the patch while at the same time being sufficient to keep the gel from adhering too strongly to humans or animals. Therefore, the organopolysiloxane B or the precursor composition of the silicone gel according to the present invention can contain a very small amount of, for example, less than 0.1% by weight, preferably less than 0.01% by weight, more preferably less than 0.001% by weight of a hydroxy-functional silicone resin, or may not contain a hydroxy-functional silicone resin. Hydroxyl-functional silicone resins or hydroxyl-substituted silicone resins, or polysiloxanes containing at least one silicon-bonded hydroxyl group are generally considered in the art to be effective or beneficial in increasing the adhesion of gels to medical substrates and the skin.

[0069] The preparation of the therapeutic patch itself is very common and well known to those skilled in the art. In an exemplary embodiment, a precursor composition of a silicone gel containing a specific amount of capsaicin can be formed in a first step of uniformly mixing the individual components of the gel precursor composition, such as the preferred composition described above. Capsaicin can be added at any time during the mixing process, either alone or together with other components of the silicone gel precursor composition. The capsaicin used in the present invention is either added directly or dissolved in any solvent or dispersant before being added to the silicone gel precursor composition. Alternatively, capsaicin is not added to the precursor composition in the form of a dispersion or solution. Thus, in the patch of the present invention, capsaicin is present as a dispersed phase in the silicone gel matrix, in direct contact with and surrounded by the silicone gel matrix. The patch can then be prepared by coating the resulting precursor composition onto a substrate that can serve as the back layer. The coating thickness of the gel precursor composition on the substrate can range from 0.1 mm to 0.5 mm. The curing process can be carried out at a high temperature of about 100 - 250 °C for 10 - 30 minutes.

[0070] In another aspect, the present invention relates to the use of capsaicin in a patch for balancing the adhesive strength of a silicone gel and the comfortable feeling of the skin, and the delivery amount of capsaicin is 0.01 to 0.145 g / m with respect to the skin area 2 , preferably 0.02 to 0.13 g / m 2 , more preferably 0.04 to 0.12 g / m 2 . Preferably, the silicone gel is as defined above.

[0071] In yet another aspect, the present invention relates to a method for producing a patch having a capsaicin-containing silicone gel, wherein the delivery amount of capsaicin is 0.01 to 0.145 g / m with respect to the skin area 2 , preferably 0.02 to 0.13 g / m 2 , more preferably 0.04 to 0.12 g / m 2 , and includes introducing capsaicin into the silicone gel adhered to the substrate of the patch in an amount within the range. In this method, it is preferable to use the silicone gel of the present invention as described above.

[0072] The following non-limiting examples further illustrate the present invention in more detail.

Examples

[0073] Description of Measurement Penetration : Using a Petrotest penetrometer model PNR12, the total weight of the rod and cone is fixed at 62.5 g, and measured by penetrometer measurement according to the standard NF ISO2137. The cone penetrability of the silicone gel is determined by measuring the depth of penetration of the cone into the sample of the silicone gel at 25°C. The depth is obtained by releasing the cone assembly of the penetrometer and allowing the cone to act for 5 seconds.

[0074] Coating Weight : Measured by weighing the weight of the pure gel per square meter on the coated substrate.

[0075] Tack : The PET coated with silicone gel was tested with a probe tack tester PT-1000 in accordance with ASTM D2979.

[0076] Peel Adhesion on Paper : The PET coated with silicone gel was measured in accordance with the FINAT no.1 test method by contacting it with a strip of Bristol paper at a peel angle of 180°.

[0077] Residue: Measured by the area ratio of the gel remaining on the skin after wearing for 5 hours or more to the total amount of gel initially adhered to the skin. None: = 0%; Mild: 0 - 1%. Severe: > 1%.

[0078] Analgesic Performance : Evaluated by humans, reflected in the following details: trigger of the effective time, degree of analgesic effect, duration. All are tested by actual user evaluations.

[0079] The trigger of the effective time represents the time from when the capsaicin patch is applied to the skin until a slight heat sensation or burning sensation is felt and the analgesic effect begins. The ideal trigger time is within 20 - 30 minutes.

[0080] The degree of the warming effect indicates the degree of pain relief and may vary depending on the user and the body part where the patch is applied. The degree can be classified into several levels from weak to strong, such as weak, moderate, optimal, strong, (intolerable) burning sensation, etc., through a number of personal evaluations.

[0081] The duration is the time from when the capsaicin patch is applied to the skin until the analgesic effect is no longer felt.

[0082]

Table 1

[0083] Preparation of Examples 1 - 8 The precursor composition of the silicone gel was prepared by uniformly mixing each component in the amounts shown in Table 1. Subsequently, the mixture was degassed for 10 minutes. This blend was divided into two parts: 180 g of the blend was sampled into a cup and cured at 120 °C for 60 minutes to conduct a penetration test; 20 g of the blend was coated onto a PET layer with a thickness of 50 μm and cured at 120 °C for 20 minutes to form a silicone gel-coated PET for the adhesion performance test.

[0084] The composition and test results of the silicone gel are shown in Table 2.

[0085]

Table 2

Claims

1. A patch coated on a substrate with a capsaicin-containing silicone gel, wherein the delivery amount of capsaicin to the skin is in the range of 0.01 to 0.145 g / m 2 with respect to the area of the skin, and the penetration of the capsaicin-containing silicone gel is in the range of 140 to 210 mm / 10, The penetration of the capsaicin-containing silicone gel is measured with a penetrometer in accordance with the standard NF ISO 2137, where a Petrotest penetrometer, model PNR12, is used and the total weight of the rod and cone is fixed at 62.5 g, patch.

2. A patch coated on a substrate with a capsaicin-containing silicone gel, wherein capsaicin is present in the silicone gel matrix as a dispersed phase, in direct contact with and surrounded by the silicone gel matrix, and the amount of capsaicin delivered to the skin is in the range of 0.01 to 0.145 g / m 2 with respect to the area of the skin, and the penetration of the capsaicin-containing silicone gel is in the range of 140 to 210 mm / 10, The penetration of the capsaicin-containing silicone gel is measured with a penetrometer in accordance with the standard NF ISO 2137, where a Petrotest penetrometer, model PNR12, is used and the total weight of the rod and cone is fixed at 62.5 g, patch.

3. The coating weight of the silicone gel coating the capsaicin on the skin is 100 g / m 2 to 500 g / m 2 The patch according to claim 1, wherein the patch is as described above.

4. The patch according to claim 1, wherein the content of capsaicin in the silicone gel is in the range of 0.008 to 0.1% by weight based on the total weight of the silicone gel.

5. The content of capsaicin in the silicone gel ranges from 0.02 to 0.08% by weight based on the total weight of the silicone gel, and the delivery amount of capsaicin to the skin ranges from 0.04 to 0.12 g / m 2 of the patch according to claim 1.

6. The patch according to claim 1, wherein the silicone gel contains less than 0.1% by weight of a hydroxy-functional silicone resin or does not contain a hydroxyl-functional silicone resin.

7. A method for producing a patch having a capsaicin-containing silicone gel as defined in claim 1, wherein the delivery amount of capsaicin is in the range of 0.01 to 0.145 g / m 2 to the area of the skin, and introducing capsaicin into the silicone gel adhered to the substrate of the patch.

8. A method for manufacturing a patch having a capsaicin-containing silicone gel according to claim 1, comprising forming a silicone gel by a hydrosilylation reaction from a precursor composition containing, in addition to capsaicin, the following components: 1) at least one organopolysiloxane B containing: (i) at least two siloxyl units of formula (B1) (Y) a (Z) b SiO (4-(a+b)) / 2 (B1) wherein, - Y represents a monovalent radical containing 2 to 6 carbon atoms having at least one alkenyl group, - Z represents a monovalent radical containing 1 to 20 carbon atoms and not containing an alkenyl group, - a and b represent integers, a is 1, 2, or 3, b is 0, 1, or 2, and (a + b) is 1, 2, or 3; 2) at least one organopolysiloxane CE containing: - two siloxyl terminal units of formula (CE-1) (which may be the same or different) (H) p (R 1 ) q SiO 1 / 2 (CE-1) wherein, - Symbol R 1 corresponds to an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 10 carbon atoms, and - the symbol H represents a hydrogen atom, p = 0 or 1, q = 2 or 3, and (p + q) = 3; - At least one siloxyl group of formula (CE-2): (H) n (R 2 ) m SiO 2 / 2 (CE-2) In the formula, radical R 2 is a C 1 -C 8 alkyl group or a C 6 -C 10 aryl group, the symbol H represents a hydrogen atom, n = 0 or 1, m = 1 or 2, and (n + m) = 2 However, the organopolysiloxane CE contains two hydrogen atoms bonded to different silicon atoms for each polymer; 3) At least one organopolysiloxane XL comprising the following: - At least three siloxyl units of formula (XL-1): (H)(L) e SiO (3-e) / 2 (XL-1) In the formula, the symbol H represents a hydrogen atom, and the symbol L represents an alkyl having 1 to 8 carbon atoms or an aryl of C 6 ~C 10 and the symbol e is equal to 0, 1, or 2. However, the organopolysiloxane XL contains 1.0% to 15.0% by weight of Si—H functional groups for each polymer; 4) An effective amount of at least one hydrosilylation catalyst E; 5) At least one hydrosilylation reaction inhibitor D; Here, the molar ratio RHA lk = tH / tA lk is <1.0 or >3, where tH = the number of moles of hydrogen atoms directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition, and tA lk = the number of moles of alkenyl directly bonded to the silicon atoms of the organopolysiloxane contained in the precursor composition. **Claim 9** The method according to claim 8, wherein the precursor composition further comprises an organopolysiloxane B', and the organopolysiloxane B' contains only one vinyl or alkenyl group arranged at one end or one terminal siloxyl unit in an amount of 1 to 40% based on the total weight of the precursor composition.

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