KR100576332B1 - Novel Glyceride Derivatives and Compositions for Pain Relief Comprising the Same - Google Patents

Abstract

The present invention relates to a novel glyceride derivative represented by the following formula (1), a composition for pain relief, and a transdermal administration patch for pain relief:

Formula 1

In the above formula, R ₁ , R ₂ and R ₃ are the same or different from each other, H, C ₁ -C ₂₀ Alkyl group, C ₂ -C ₂₀ Alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ Aryl, heteroaryl, arylalkyl, arylalkenyl, alkylaryl or C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radicals and at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical ; R ₄ is O, S, NH or CH ₂ ; R ₅ is C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl; and R ₆ is an acid group.

Glycerides, pain, stiffness, pain relief, patches

Description

Novel Glyceride Derivatives and Compositions for Pain Relief Comprising the Same             

1 is a graph showing a tendency to relieve pain over time after the cream agent containing the compound of the present invention is administered.

2A-2C are graphs showing the change in pain over time from initial pain after the cream containing the compound of the present invention is administered.

Figures 3a-3c is a graph showing the variation of the stiffness over time from the initial stiffness after the cream containing the compound of the present invention is administered.

4 is an NMR spectrum showing that the preparation of the compound of the present invention was successful.

Figure 5 is a graph showing the tendency to relieve pain over time after the patch agent containing the compound of the present invention is applied.

6A-6D are graphs showing the extent of pain change over time from initial pain after the patch comprising the compound of the present invention is applied.

7A-7D are graphs showing the variation in stiffness over time from initial stiffness after the patching agent comprising the compound of the present invention is applied.

The present invention relates to novel glyceride derivatives and compositions for pain relief and transdermal administration patches comprising the same.

Pain relief is a very important field in modern medicine.

Pain relief can be achieved in two ways. One way is to continue the pain but mask it from the patient. This is how many analgesics work. Although these painkillers prevent the patient from feeling pain, they do not block the underlying cause of analgesia and require analgesics to be administered continuously.

Another more effective way to relieve pain is to address the cause of the pain. That is, alleviating the physiological or neurotransmitter etiology of pain reduces the sense of pain.

On the other hand, pain relief agents such as analgesics are generally oral administration. However, currently developed pain relief agents for oral administration tend to cause various side effects such as liver damage, kidney damage, gastrointestinal damage, intoxication and weight gain. In addition, in the case of oral pain relievers, since they must be absorbed through the digestive system before entering the blood flow, time delay occurs in exerting the effect.

In order to solve the problem of delay in oral administration, parenteral administration methods such as vascular or intramuscular injection methods have been proposed, but these methods are not convenient and expensive, and are difficult to carry out outside the hospital. There is a very uncomfortable problem.

Accordingly, attempts have been made to administer pain relief agents in topical administration, in particular transdermal administration, and attempts have been made to develop drugs and / or pharmaceutical compositions suitable for transdermal administration.

As a patent for pain relief, US Pat. No. 6,444,238 discloses a composition for pain relief comprising aloe vera oil, eucalyptus essential oil, lemon essential oil, orange essential oil, peppermint essential oil and rosemary essential oil. US Pat. No. 6,572,880 discloses a transdermal composition for pain relief comprising lamotrigine, doxepin and muscle relaxants.

In addition, U.S. Patent No. 6,387,957 discloses a pain relief topical composition comprising ketamine and topical administration excipients, and pain relief oral cavity that exhibits rapid efficacy including the United States patent celecoxib as an active ingredient. Dosage compositions are disclosed. US Patent No. 4,576,951 discloses a pain relief composition comprising proglumide as an active ingredient.

The present inventors have overcome the problems of side effects caused by conventional pain relievers, and are suitable for topical administration, in particular transdermal administration, to develop a compound which can exhibit long-term and high-efficiency effects and develop various compounds. The ceride derivatives were synthesized, and as a result, the present invention was completed by discovering that certain glyceride derivatives had an effect consistent with the above-mentioned object.

Accordingly, it is an object of the present invention to provide novel glyceride derivatives.

Another object of the present invention to provide a pain relief composition (pharmaceutical composition and cosmetic composition) comprising a novel glyceride derivative as an active ingredient.

Another object of the present invention to provide a pain relief transdermal patch comprising a novel glyceride derivative as an active ingredient.

Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

According to one aspect of the present invention, the present invention provides a novel glyceride derivative represented by the following general formula (1):

In the above formula, R ₁ , R ₂ and R ₃ are the same or different from each other, H, C ₁ -C ₂₀ Alkyl group, C ₂ -C ₂₀ Alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ Aryl, heteroaryl, arylalkyl, arylalkenyl, alkylaryl or C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radicals and at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical ; R ₄ is O, S, NH or CH ₂ ; R ₅ is C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl; And R ₆ is an acid group.

According to another aspect of the present invention, there is provided a pain relief composition comprising the novel glyceride derivative as an active ingredient.

According to one embodiment of the composition of the present invention, the composition is a pharmaceutical composition or cosmetic composition.

The present inventors have greatly overcome the problems of the side effects caused by conventional pain relievers, and are suitable for topical administration, in particular percutaneous administration, and to develop a compound that can be long lasting while showing its efficacy at high speed, various articles Lyside derivatives were synthesized, and as a result, it was confirmed that the compound included in Chemical Formula 1 exhibits an effect consistent with the above-described purpose.

In the general formula (1) representing the compound of the present invention, R ₁ , R ₂ and R ₃ are the same as or different from each other, preferably the same as each other. Further, at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical, preferably a C ₁₆ -C ₂₀ unsaturated fatty acid radical. Substituents which may be in the R ₁ , R ₂ and R ₃ positions include H, C ₁ -C ₂₀ alkyl groups, C ₂ -C ₂₀ alkenyl groups, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, hetero Aryl, arylalkyl, arylalkenyl, alkylaryl or C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radicals.

When R ₁ , R ₂ or R ₃ is a C ₁ -C ₂₀ alkyl group, preferably a C ₁ -C ₄ alkyl group such as methyl, ethyl, n -propyl, isopropyl, isobutyl, n -butyl and t -butyl, most preferably ethyl. When R ₁ , R ₂ or R ₃ is a C ₂ -C ₂₀ alkenyl group, preferably C ₂ -C ₆ alkenyl, for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl , t -butenyl, n -pentenyl and n -hexenyl, most preferably ethenyl.

When R ₁ , R ₂ or R ₃ is C ₃ -C ₈ cycloalkyl, it includes cyclopropyl, cyclobutyl and cyclopentyl, most preferably cyclohexyl.

When R ₁ , R ₂ or R ₃ is C ₅ -C ₂₀ aryl, the term “aryl” means a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated, and preferably Is monoaryl or biaryl. It is preferable that monoaryl has 5-6 carbon atoms, and it is preferable that biaryl has 9-10 carbon atoms. Most preferred as said monoaryl is phenyl, most preferred as biaryl is naphthyl.

When R ₁ , R ₂ or R ₃ is C ₅ -C ₂₀ heteroaryl, the term “heteroaryl” is a heterocyclic aromatic group, which includes N, O or S as a heteroatom. Preferably, heteroaryl is heterobiaryl containing N as heteroatom. Most preferred heterobiaryl is indolyl. When R ₁ , R ₂ or R ₃ is indolyl, it is substituted by a halo group, more preferably a chloro group and most preferably two chloro groups.

When R ₁ , R ₂ or R ₃ is C ₅ -C ₂₀ arylalkyl, the term “arylalkyl (aralkyl)” means an aryl group bonded to the structure by one or more alkyl groups, preferably benzyl Qi. When R ₁ , R ₂ or R ₃ is C ₅ -C ₂₀ alkylaryl, the term “alkylaryl” means an alkyl group bonded to a structure consisting of one or more aryl groups. The term "arylalkenyl" means an aryl group bonded to a structure by one or more alkyl groups, preferably a phenylethenyl group.

According to a preferred embodiment of the invention, R ₁ , R ₂ and R ₃ are independently of each other H, a C ₁ -C ₂₀ alkyl group, or a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical, more preferably H Or a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical, even more preferably a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical, most preferably a C ₁₆ -C ₂₀ unsaturated fatty acid radical.

Thus, in summary, the preferred compounds of the present invention are those wherein at least one of R ₁ , R _2, and R ₃ is a C ₁₆ -C ₂₀ unsaturated fatty acid radical and the other substituent is H, more preferably R ₁ At least two of R ₂ and R ₃ are C ₁₆ -C ₂₀ unsaturated fatty acid radicals and the other substituents are H, and most preferably R ₁ , R ₂ and R ₃ are all C ₁₆ -C ₂₀ unsaturated fatty acid radicals. If it is.

It is preferable that there are 1-4 double bonds in the unsaturated fatty acid radical, and more preferably, the double bond exists in cis-configuration. Even more preferably, R ₁ , R ₂ and R ₃ are palmitoleate, oleate, linoleate, linoleate and arachidonate, even more preferably oleate, linoleate , And arachidonate, most preferably oleate.

In Formula 1, R ₄ is O, S, NH or C ₁ -C ₁₀ Alkyl group. When R ₄ is a C ₁ -C ₁₀ alkyl group, it is preferably C ₁ -C ₅ , more preferably C ₁ -C ₃ , most preferably a C ₁ alkyl group. In the position of R ₄ , preferably O, S or NH is positioned, more preferably O or NH, most preferably NH, rather than a C ₁ -C ₁₀ alkyl group.

In Formula 1 representing a compound of the present invention, R ₅ is a C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, heteroaryl, aryl Alkyl, arylalkenyl or alkylaryl. Preferably, R ₅ is an alkyl group of C ₁ -C ₂₀ or an alkenyl group of C ₂ -C ₂₀ , more preferably R ₅ is an alkyl group of C ₁ -C ₂₀ .

When R ₅ is an alkyl group of C ₁ -C ₂₀ , preferably R ₅ is C ₁ -C ₄ alkyl groups such as methyl, ethyl, n -propyl, isopropyl, isobutyl, n -butyl and t -butyl, most preferably ethyl. When R ₅ is an alkenyl group of C ₂ -C ₂₀ , preferably R ₅ is C ₂ -C ₆ alkenyl, for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, t − Butenyl, n -pentenyl and n -hexenyl, most preferably ethenyl.

When R ₅ is C ₃ -C ₈ cycloalkyl, R ₅ comprises cyclopropyl, cyclobutyl and cyclopentyl, most preferably cyclohexyl.

When R ₅ is C ₅ -C ₂₀ aryl, the term "aryl" means a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated, preferably monoaryl or biaryl to be. It is preferable that monoaryl has 5-6 carbon atoms, and it is preferable that biaryl has 9-10 carbon atoms. Most preferred as said monoaryl is phenyl, most preferred as biaryl is naphthyl.

When R ₅ is C ₅ -C ₂₀ heteroaryl, the term “heteroaryl” is a heterocyclic aromatic group, which includes N, O or S as a heteroatom. Preferably, heteroaryl is heterobiaryl containing N as heteroatom. Most preferred heterobiaryl is indolyl. When R ₅ is indolyl, it is substituted by a halo group, more preferably a chloro group and most preferably two chloro groups.

When R ₅ is C ₅ -C ₂₀ arylalkyl, the term “arylalkyl (aralkyl)” means an aryl group bonded to the structure by one or more alkyl groups, preferably a benzyl group. When R ₅ is C ₅ -C ₂₀ alkylaryl, the term “alkylaryl” means an alkyl group bonded to a structure consisting of one or more aryl groups. The term "arylalkenyl" means an aryl group bonded to a structure by one or more alkyl groups, preferably a phenylethenyl group.

In Chemical Formula 1, which represents a compound of the present invention, R ₆ is an acid group, and is a carboxyl group or an inorganic acid group. Preferably, the acid which may be located in R ₆ is acetate, adipate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, hemisulfate, butyrate, citrate , Camphorsulfonate, dodecyl sulfate, ethanesulfonate, fumarate, phosphate, hexanoate, 2-hydroxyethanesulfate, lactate, maleate, methanesulfonate, nicotinate, oxalate, tosylate, carbonate Or nitrate, more preferably R ₆ is acetate, benzoate, benzenesulfonate, bisulfate, sulfamate, sulfate, hemisulfate, butyrate, ethanesulfonate, fumarate, phosphate, 2-hydroxyethanesulfate, Lactate, maleate, methanesulfonate, oxalate, carbonate or nitrate; R ₆ is straight as the acetate, bisulfate, sulfate, butyrate, ethane sulfonate, fumarate, phosphate, 2-hydroxy-ethane sulfate, a sulfonate, or oxalate, more still more preferably, acetate, sulfate, Ethanesulfonate, phosphate, methanesulfonate or oxalate, most preferably sulfate or phosphate which is an inorganic acid.

More specific and preferred examples of the compounds of the present invention are mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane Phosphate, tri-linoleolyl tromethamine ethane sulfate, tri-arachidonyltromethamine ethane sulfate, tri-oleoyl tromethamine propane sulfate and the like. More preferably, the compound of the present invention having pain relief activity is mono-oleoyltromethamine ethane sulfate, di-oleoyltromethamine ethane sulfate or tri-oleoyltromethamine ethane sulfate, most preferably, Tri-oleoyl tromethamine ethane sulfate.

Compounds of the present invention have pain relief activity as a physiological feature.

Accordingly, according to another aspect of the present invention, the present invention provides a pharmaceutically effective amount of a novel glyceride derivative represented by the formula (1); And (b) a pharmaceutical composition for pain relief comprising a pharmaceutically acceptable carrier.

In addition, the composition comprising the compound of the present invention may be prepared as a cosmetic composition, in which case the present invention (a) an effective amount of the novel glyceride derivative represented by the formula (1); And (b) a cosmetic composition for pain relief comprising a cosmetically acceptable carrier.

Since the content of the preferred embodiment of the compound represented by Formula 1 in the pharmaceutical composition of the present invention is the same as that of the compound of the present invention described above, the description thereof is omitted in order to avoid excessive complexity of the present specification.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention is particularly suitable for parenteral administration, preferably for parenteral administration, more preferably for transdermal administration.

When formulated for transdermal administration of the pharmaceutical composition of the present invention, it may be formulated as a warning agent, pasta agent, linen agent and cream agent. For example, in the case of a warning agent, it can be formulated using lead monoxide, olive oil and lard, and in the case of pasta, it can be formulated using zincated semal, salicylic acid semal, starch and petrolatum, and linen In the case of zero, it can be formulated using camphor oil, olive oil, methyl salicylate, tragacanta, sodium carboxymethylcellulose, glycerin and zinc oxide. When the pharmaceutical composition of the present invention is a cream, it can be formulated using animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc and zinc oxide. .

Suitable dosages of the pharmaceutical compositions of the invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to reaction, Usually a skilled practitioner can easily determine and prescribe a dosage effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dose of the pharmaceutical composition of the present invention is 0.01-1000 mg / kg.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container.

The components included in the cosmetic composition of the present invention include components conventionally used in cosmetic compositions in addition to the above glyceride derivatives as active ingredients, and include, for example, conventional agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and perfumes. Phosphorus aids, and carriers.

Cosmetic compositions of the present invention may be prepared in any formulation conventionally prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, oils, powder foundations, emulsions It may be formulated as a foundation, wax foundation, spray, and the like, but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, massage cream, essence, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components. Can be.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.

The compounds of the present invention are not only very effective as pain-relieving agents, but also suitable for topical administration, in particular transdermal administration, with a very short time to exert their efficacy, with excellent sustainability of efficacy and side effects such as liver damage, Kidney damage, gastrointestinal damage, intoxication and weight gain).

According to another aspect of the present invention, the present invention provides a pain relief transdermal patch comprising the glyceride derivative of the present invention as an active ingredient.

As mentioned above, the glyceride derivatives of the present invention are particularly suitable for transdermal administration, and furthermore, application to patches in transdermal formulations is most preferred in terms of persistence of efficacy and patient compliance.

The patch of the present invention can be prepared in two forms, namely, a reservoir type having a matrix type and a drug storage layer in which an active ingredient is dispersed in an adhesive layer.

When the patch of the present invention has a reservoir type, the patch of the present invention (a) a backing layer; (b) a drug storage layer comprising a glyceride derivative of Formula 1 of the present invention and positioned below the backing layer; (c) an adhesive layer located below the drug storage layer; And (d) a peeling liner layer positioned below the adhesive layer.

If the patch of the present invention has a matrix form, the patch of the present invention (a) a backing layer; (b) an adhesive layer comprising a glyceride derivative of the present invention and an adhesive base and positioned below the backing layer; And (c) a peeling liner layer located below the adhesive layer.

In the patch of the present invention, the glyceride derivative of the formula (1) used as a pain relief active ingredient, preferably at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ unsaturated fatty acid radical and the other substituents H, more preferably at least two of R ₁ , R ₂ and R ₃ are C ₁₆ -C ₂₀ unsaturated fatty acid radicals and the other substituents are H, most preferably R ₁ , R ₂ and R _{3 is} all C ₁₆ -C ₂₀ unsaturated fatty acid radicals.

It is preferable that there are 1-4 double bonds in the unsaturated fatty acid radical, and more preferably, the double bond exists in cis-configuration. Even more preferably, R ₁ , R ₂ and R ₃ are palmitoleate, oleate, linoleate, linoleate and arachidonate, even more preferably oleate, linoleate , And arachidonate, most preferably oleate.

In Formula 1, R ₄ is O, S, NH or C ₁ -C ₁₀ Alkyl group. When R ₄ is a C ₁ -C ₁₀ alkyl group, it is preferably C ₁ -C ₅ , more preferably C ₁ -C ₃ , most preferably a C ₁ alkyl group. In the position of R ₄ , preferably O, S or NH is positioned, more preferably O or NH, most preferably NH, rather than a C ₁ -C ₁₀ alkyl group.

In Formula 1 representing a compound of the present invention, R ₅ is a C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, heteroaryl, aryl Alkyl, arylalkenyl or alkylaryl. Preferably, R ₅ is an alkyl group of C ₁ -C ₂₀ or an alkenyl group of C ₂ -C ₂₀ , more preferably R ₅ is an alkyl group of C ₁ -C ₂₀ . When R ₅ is an alkyl group of C ₁ -C ₂₀ , preferably R ₅ is C ₁ -C ₄ alkyl groups such as methyl, ethyl, n -propyl, isopropyl, isobutyl, n -butyl and t -butyl, most preferably ethyl.

In Chemical Formula 1, which represents a compound of the present invention, R ₆ is an acid group, a carboxyl group or an inorganic acid group, and most preferably sulfate or phosphate which is an inorganic acid.

More specific and preferred examples of the compounds of the present invention are mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane Phosphate, tri-linoleolyl tromethamine ethane sulfate, tri-arachidonyltromethamine ethane sulfate, tri-oleoyl tromethamine propane sulfate and the like.

In the patch of the present invention, the content of the glyceride derivative of Formula 1 used as an active ingredient is 0.5-20% by weight, preferably 1-10, based on the weight of the drug storage layer (reservoir type) or the adhesive layer (matrix type). % By weight, most preferably about 5% by weight (ie, equivalent to about 5 mg / cm 2 in patch).

In the patch of the present invention, the material of the backing layer is conventionally used in the art, for example, polyethylene, polypropylene, polyurethane, polyethylene terephthalate, polyester, polyvinyl chloride, polyvinylidene chloride, plasticization Vinyl acetate copolymers, plastic films, cellulose films, metal foils such as aluminum foil, nonwoven fabrics, cotton fabrics and woven fabrics, but are not limited thereto.

In the patch of the present invention, the material of the release liner layer is conventionally used in the art, for example, polyester, low density polyethylene (LPDE), high density polyethylene (HDPE), polypropylene, polystyrene, polyamide, nylon, Plastic films and cellulose films are included, but are not limited thereto.

In the patch of the present invention, the material of the adhesive layer, ie the adhesive base, is a pressure-sensitive adhesive commonly used in the art, for example, polyisobutene (PIB), rubber adhesives, acrylates and methacrylates. Adhesives, polyvinyl alkylether adhesives and silicone adhesives, preferably non-closable adhesives, acrylate / methacrylate adhesives and silicone adhesives.

According to a preferred embodiment of the present invention, the drug storage layer of the reservoir patch further comprises glucosamine as a pain relief active ingredient. According to a preferred embodiment of the present invention, the adhesive layer of the matrix patch further comprises glucosamine as a pain relief active ingredient.

Glucosamine is a natural substance used to regenerate cartilage and connective tissue in the human body. In healthy joints, high levels of glucosamine are present. Glucosamine acts to protect joints and lubricious synovial fluid from oxidative damage caused by free radicals. Glucosamine has been extensively studied as a representative arthritis agent for pain and inflammation caused by osteoarthritis (Spencer-Green, G., Postgrad. Med. , 93 (7): 129-140 (1993); and Setnikar, I. , Int. J. Tissue-React. 14 (5): 253-261 (1992).

Glucosamine used as an additional active ingredient in the present invention, in addition to glucosamine, glucosamine derivatives known for pain relief efficacy, such as glucosamine hydrochloride, glucosamine sulfate, glucosamine iodide, N-acetyl-glucosamine, glucosamine phosphate, glucosamine acetate, glucosamine acid And N-acetyl-glucosamine phosphate and sulfate. According to a preferred embodiment of the present invention, the content of glucosamine in the patch of the present invention is 0.5-20% by weight, preferably 1-10% by weight, based on the weight of the drug storage layer (reservoir type) or adhesive layer (matrix type) Preferably about 5% by weight (ie, equivalent to about 5 mg / cm 2 in patch).

According to a preferred embodiment of the invention, in the glyceride derivative of formula 1, at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ unsaturated fatty acid radical, and R ₆ is sulfate or phosphate, Derivatives of formula 1 result in lipid compounds with liposome-forming ability and this form exhibits good transdermal permeability. In addition, when glucosamine is used as an additional active ingredient, glucosamine is contained in liposomes formed by the glyceride derivative of Formula 1 and passes through the skin, thereby increasing the percutaneous permeability of glucosamine. That is, the glyceride derivative of Formula 1 has a function as a permeation promoter for glucosamine, in which case the glyceride derivative of Formula 1 is (i) a pain relief active ingredient; And (ii) two uses as permeation accelerators.

According to a more preferred embodiment of the present invention, the patch of the present invention (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl trometha Glyceride derivatives as pain relief active ingredients selected from the group consisting of min ethane sulfate, tri-arachidonyltromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate and glucosamine as pain relief active ingredient A drug storage layer positioned below the backing layer; (c) an adhesive layer located below the drug storage layer; And (d) a peeling liner layer positioned below the adhesive layer.

On the other hand, when the patch of the present invention has a matrix type, the patch of the present invention (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl trometha Glyceride derivatives as pain relief active ingredients, glucosamine as pain relief active ingredients, selected from the group consisting of min ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate An adhesive layer disposed below the backing layer; And (c) a peeling liner layer located below the adhesive layer.

The drug storage layer or adhesive layer (in the case of the matrix type) may include, in addition to the above-mentioned components, additional components such as permeation accelerators, thickeners, solubilizers or dissolution aids, emulsifiers, liposome-forming phospholipids and stimulants.

Examples of permeation accelerators available are azone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethanol, isopropanol, glycerol, propylene glycol, cetyl alcohol, methyl caprylate, cetyl palmitate, cholesterol, decylate, Oleate, acetone, ethyl acetate, methyl ethyl ketone, n-decylmethyl sulfoxide (NDMS), N, N-diethyl- m -toluamide (DEET), dibutyl phthalate, limonene and 1-menthol It is not limited to this.

Examples of thickeners that may be used include, but are not limited to, cellulose acetate, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, acrylic acid, carboxymethylcellulose sodium and stearyl alcohol. Examples of solubilizers or dissolution aids available include, but are not limited to, ethylene glycol, diethylene glycol, triethylene glycol, dimethyl sulfoxide, isosorbitol, dimethyllaurylamide and squalene and lanolin. Examples of emulsifiers that can be used include, but are not limited to, lecithin, ceparin and polyalkylene glycols. Examples of irritant reducing agents available include, but are not limited to, glycerin monooleic acid, glycerin monolaurate and sorbitan monolaurate.

Available liposome-forming phospholipids include natural phospholipids (eg egg yolk lecithin or soy lecithin, sphingomyelin) and synthetic phospholipids (eg dipalmitoylphosphatidylcholine or hydrogenated lecithin), preferably lecithin. More preferably, the lecithin is naturally occurring unsaturated lecithin or saturated lecithin extracted from soybean or egg yolk. Typically, lecithin derived from nature has 23-95% phosphatidyl choline and 20% or less phosphadidylethanolamine.

On the other hand, oleate is most preferred as a permeation accelerator in the patch of the present invention. In the patch of the present invention, oleate not only serves as a permeation accelerator but also serves as a pain relief active ingredient.

According to the most preferred embodiment of the present invention, the patch of the present invention (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl tro As a pain relief active ingredient selected from the group consisting of metamin ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate, a glyceride derivative as a permeation accelerator, a pain relief active ingredient A glucosamine and a pain-relieving active ingredient and an oleate as a permeation accelerator and positioned below the backing layer; (c) an adhesive layer located below the drug storage layer; And (d) a peeling liner layer positioned below the adhesive layer.

On the other hand, when the patch of the present invention has a matrix type, the patch of the present invention (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl trometha Gluceamine as a pain relief active ingredient, a glyceride derivative as a pain stimulating agent, a pain relief active ingredient selected from the group consisting of min ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate An adhesive layer disposed below the backing layer, comprising an oleate and an adhesive base as a permeation stimulant and a permeation accelerator; And (c) a peeling liner layer located below the adhesive layer.

The patch of the present invention is excellent in pain relief efficacy, very short time to exhibit the efficacy, excellent persistence of efficacy, excellent percutaneous permeability of the pain relief active ingredient, side effects (eg liver damage, kidney damage) , Gastrointestinal damage, intoxication and weight gain).

Pain relieved by the patch of the present invention includes pain accompanying various conditions and diseases, and is particularly advantageous for alleviating the pain associated with arthritis (eg, rheumatoid arthritis and osteoarthritis). Thus, the patch of the present invention has an effect that is superior to any pain relief patch developed in the past, in particular any patch that is used to alleviate arthritis-related pain.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it is to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. Will be self-evident.

Example 1 Preparation of Mono-Oleoyltromethamine Ethane Sulfate

0.4 g of 2- [tris (hydroxymethyl) -methylamino] -1-ethanesulfonic acid (Sigma-Aldrich) dissolved in dimethyl formamide was added to the flask, followed by 0.9 g of oleoyl chloride (Sigma-Aldrich). Was slowly added dropwise with stirring, followed by reaction at room temperature for 3 days. The solvent dimethyl formamide was then removed under reduced pressure and the residue was washed several times with excess acetone. The resultant was then dried under vacuum to yield 0.70 g (yield: 54%) of the final product mono-oleoyltromethamine ethane sulfate: white weak oily powder.

Example 2: Preparation of Di-Oleoyltromethamine Ethane Sulfate

In the same manner as in Example 1, using 0.8 g of oleoyl chloride (Sigma-Aldrich), 0.88 g (yield: 52%) of di-oleoyloilmethamine ethane sulfate was obtained: white Weak oily powder.

Example 3: Preparation of Tri-Oleoyltromethamine Ethane Sulfate

In the same manner as in Example 1, but using 2.1 g of oleoyl chloride (Sigma-Aldrich), 1.2 g (yield: 48%) of tri-oleoyl tromethamine ethane sulfate was obtained. Oily powder.

4 is an NMR spectrum of the compound prepared in Example. NMR spectra were recorded using a Bruker AVANCE 500 spectrometer (Bruker): ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.18 (s, 1H), 5.336 (t, J = 6.15 Hz, 6H), 4.386 (s, 6H), 3.686 (s, 2H), 3.317 (s, 2H), 2.430 (t, J = 7.34 Hz, 6H), 2.008 (d, J = 5.87 Hz, 12H), 1.606 (t, J = 7.34 Hz, 6H), 1.284 (d, J = 14.68 Hz, 72H), 0.881 (t, J = 7.34 Hz, 9H).

Formulation Example 1-3: Preparation of Cream Formulation

A cream comprising the compounds prepared in Examples 1-3 was prepared using the components and content ratios of Table 1 below. In Formulation Examples of Table 1 below, Formulation Examples including the compound of Examples 1-3 were used as Formulation Examples 1-3.

ingredient Content (% by weight) Compounds of Examples 1-3 1.0 Lipophilic Monostearic Acid Glycerin 1.5 Stearyl alcohol 1.5 Stearic acid 1.0 Polysorbate 60 1.5 Sorbitan stearate 0.6 Isostearyl Isosterate 5.0 Squalane 5.0 Mineral oil 35.0 Dimethicone 0.5 Hydroxyethyl cellulose 0.12 glycerin 6.0 Triethanolamine 0.7 Preservative, fragrance, coloring a very small amount Distilled water Remaining amount Sum 100

Formulation Example 4 Preparation of Patch-1

68 weight percent acrylate adhesive (Duro-Tak 87-2287, National Starch and Chemical Co.), 10 weight percent tri-oleoyl tromethamine ethane sulfate of Example 3, 10 weight percent glucosamine (Sigma-Aldrich), oli 6% by weight of Duksan and 6% by weight of Polysorbate 80 (Merck) were homogeneously mixed. The mixture was then cast into 3M polyester backing and dried to prepare a patch having a thickness of 100 μm.

Formulation Example 5: Preparation of Patch-2

A patch was prepared in the same manner as in Formulation Example 4, but using 6% by weight of lauromacrogol, which is a polyoxyethylene-based emulsifier, instead of polysorbate 80.

Formulation Example 6: Preparation of Patches-3

A patch was prepared in the same manner as in Formulation Example 4, but using 6% by weight of propylene glycol instead of oleate.

Formulation Example 7 Preparation of Patch-4

In the same manner as in Formulation Example 4, 64% by weight of acrylate adhesive, 10% by weight of tri-oleoyl tromethamine ethane sulfate of Example 3, 10% by weight of glucosamine, 6% by weight of oleate, polysorbate 80 6 Weight percent and 4 weight percent hydrogenated lecithin were mixed homogeneously. The mixture was then applied to a silicone-treated polypropylene foil and dried to prepare a patch 100 μm thick.

Comparative Formulation Example 1 Preparation of Patches-5

70 weight percent acrylate adhesive, 10 weight percent glucosamine, 7 weight percent proylene glycol, 3 weight percent oleate and 10 weight percent polysorbate 80 were mixed homogeneously. The mixture was then applied to a silicone-treated polypropylene foil and dried to prepare a patch 100 μm thick.

Comparative Formulation Example 2: Preparation of Patches-5

70% by weight acrylate adhesive, 10% by weight glucosamine, 8% by weight proylene glycol and 12% by weight polysorbate 80 were mixed homogeneously. The mixture was then applied to a silicone-treated polypropylene foil and dried to prepare a patch 100 μm thick.

Experimental Example 1 Investigation of Pain Relief Efficacy

For 30 patients with a history of rheumatoid arthritis or osteoarthritis in the hands and / or knees and feeling pain and stiffness in the joints, This study was conducted to investigate the efficacy of pain relief and tonicity. What was used as a placebo in this Experimental Example is the lack of the compound of Examples 1-3 in Formulation Examples 1-3.

Pain relief efficacy was assessed by pain and stiffness using a visual analogue scale (VAS). VAS is a common measure of pain and stiffness, assessed in units of 0-10, with 0 being no symptom and 10 being the most symptomatic. The VAS value was measured three times and the average value was taken. In addition, a change in grip force was evaluated using a hydraulic hand dynamometer. All measurements were made at 5, 30, 60 and 120 minute intervals.

1 is a graph showing a tendency to relieve pain over time. As can be seen in Figure 1, the formulation of the present invention showed a significant pain reduction and a decrease in stiffness at all times. In some patients the pain was completely reduced and the stiffness was almost eliminated. On average, during the first 60 minutes, the formulation of the present invention showed a 45% pain reduction and the placebo group showed a 15% reduction. The formulation administration group of the present invention showed a continuous pain reduction effect after 60 minutes, the placebo administration group returned to its original state. Meanwhile, in the formulation of the present invention, 72% of the subjects showed immediate pain reduction and stiffness reduction within 5 minutes, but only 15% showed a decrease in the placebo administration group. Similarly, grip strength was increased in 50% of subjects within 5 minutes for the formulation of the present invention, but little effect was found in the placebo administration group.

2A-2C are graphs showing the extent of pain change over time from initial pain. The background value is the VAS pain value before administration of Formulation Example 1-3 or placebo. As can be seen in the figure, it can be seen that Formulation Examples 1-3 continuously reduce initial pain. On the other hand, in the placebo administration group, the change value is remarkably low.

3A-3C are graphs showing the variation in stiffness over time from initial stiffness. Similar to the data in FIG. 2, it can be seen that Formulation Examples 1-3 of the present invention consistently reduce initial stiffness, with the change being significantly lower in the placebo-administered group.

As can be seen from the above experimental results, the compounds of the present invention rapidly reduce pain and stiffness. Pain relief began within 5 minutes and lasted throughout the trial. In addition, the compounds of the present invention are also very efficient in increasing grip force. Therefore, it can be seen that the compounds of the present invention are not only very effective as pain-relieving agents, but also suitable for topical administration, in particular, transdermal administration, and have excellent sustainability of efficacy while having a very short time.

Experimental Example 2: Skin Permeation Test of Patch

Skin permeation tests of tri-oleoyl tromethamine ethane sulfate and glucosamine, which are active ingredients of the patch, were carried out. A drug permeation test was performed on hairless mouse skin in a Franz diffusion cell (Hanson Research), using a 0.05 M phosphate buffer (pH 7.4) as a receptor solution. The temperature was kept at 37 ° C. The collected sample was analyzed by HPLC (CAPCELL PAK C18, mobile phase: acetonitrile / 0.02 M phosphate buffer, flow rate: 1.0 mL / min). The results of the analysis are summarized in Table 2.

Drug Type Drug penetration amount of the formulation example (24 hr) (µg / cm 2) Formulation Example 4 Formulation Example 5 Formulation Example 6 Formulation Example 7 Comparative Formulation Example 1 Comparative Formulation Example 2 Tri-Oleoyltromethamine Ethane Sulfate 437 423 397 464 - - Glucosamine 419 409 383 448 320 281

As described in Table 1, Formulation Example 4 showed excellent skin permeability, and Formulation Example 5 showed similar skin permeability as Formulation Example 4. In the case of Formulation Example 6, propylene glycol was used instead of oleate as the permeation accelerator in Formulation Example 4, and it can be seen that oleate exhibits a better permeation promoting effect, and oleate has more pain relief efficacy. Exerts dual use in the patch of the present invention. Formulation Example 7 was the case of additionally including the lecithin, a liposome-forming phospholipid, the skin permeability was the largest.

On the other hand, Comparative Formulation Example 1 is a formulation without tri-oleoyl tromethamine ethane sulfate, and the skin permeation of glucosamine is greatly reduced, which is attributed to the tri-oleoyl tromethamine ethane sulfate significantly for skin permeation of glucosamine. Shows. Comparative Formulation Example 2 is a formulation free of tri-oleoyltromethamine ethane sulfate and oleate, showing the smallest skin penetration of glucosamine, and the result shows that tri-oleoyltromethamine ethane sulfate and oleate It is shown that it contributes greatly to the skin penetration of glucosamine.

Experimental Example 3: Skin irritation test

The skin safety experiment of the patch of this invention was performed. Twenty subjects (average age 30 years) were included in the study. Psoriasis, eczema, and other skin lesion holders and those who were pregnant, lactating or contraceptives, and antihistamines were excluded from this study. The patch of Formulation Example 4-7 was attached to the knee for 24 hours, and then the test site was marked with a marking pen, and the test site was observed after 24 hours and 48 hours, respectively. Determinations were made 24 and 48 hours after patch removal, and skin irritation was determined according to the following criteria: microstimulation (Doubtful or slight reaction and erythema, 0-0.9 points), hard stimulation (Erythema + Induration, 1.0). -2.9 points), medium stimulation (Erythema + Induration + Vesicle, 3.0-4.9 points), strong stimulation (Erythema + Induration + Bullae, 5.0 or higher) and non-stimulation (negative, 0).

As a result of the determination after 24 hours and 48 hours of the patch of the present invention, the skin irritation degree of zero point was shown, and it was confirmed that the skin safety was very excellent.

Experimental Example 4: Pain Relief Test of Patch

Thirty patients with a history of rheumatoid arthritis or osteoarthritis in the knee and feeling pain and stiffness in the joints were treated with the patches of Formulations 4-7 and Comparative Formulations 1 and 2 above. After application over time, the pain and stiffness alleviation efficacy was investigated. Pain and stiffness alleviation efficacy evaluation method was performed in the same manner as in Experimental Example 1 (see Fig. 5, Fig. 6a-6d and Fig. 7a-7d).

5 is a graph showing the tendency of pain relief over time. As can be seen in Figure 5, Formulation Example 7 having the best skin permeability exhibited the best pain relief effect, and Formulation Examples 4 and 5 showed the excellent efficacy. In the case of Formulation Example 6, the pain relief effect was somewhat reduced because the pain relief effect of oleate itself was lost along with the decrease in skin permeability. On the other hand, in Comparative Formulation Example 1, the pain relief effect was greatly reduced because the skin permeability of glucosamine was decreased and the pain relief effect by tri-oleoyl tromethamine ethane sulfate was lost. Comparative Formulation Example 2 showed the lowest pain relief effect, as this result was due to a decrease in the skin permeability of glucosamine and the pain relief effect by tri-oleoyl tromethamine ethane sulfate and oleate disappeared.

6A-6D are graphs showing the extent of pain change over time from initial pain. The background value is the VAS pain value prior to application of the formulation. As can be seen in the figure, the patch of the present invention showed a significant pain relief effect up to 30 minutes after application.

7A-7D are graphs showing the variation in stiffness over time from initial stiffness. It can be seen that the patch of the present invention exhibits a significant stiffness alleviation effect up to 30 minutes after application.

As described in detail above, the present invention provides a novel glyceride derivative. The present invention also provides a pain relief composition (pharmaceutical composition and cosmetic composition) comprising a novel glyceride derivative as an active ingredient. The present invention provides a pain relief transdermal patch comprising a novel glyceride derivative as an active ingredient. The compounds of the present invention are not only very effective as pain-relieving agents, but also suitable for topical administration, in particular transdermal administration, with a very short time for the efficacy to be exerted, and excellent in duration of efficacy and few side effects. The patch of the present invention exhibits superior efficacy over conventionally developed pain relief patches, in particular any patch used to relieve arthritis-related pain.

Claims (20)

Novel glyceride derivatives represented by the following formula (1): Formula 1

In the above formula, R ₁ , R ₂ and R ₃ are the same or different from each other, H, C ₁ -C ₂₀ Alkyl group, C ₂ -C ₂₀ Alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ Aryl, heteroaryl, arylalkyl, arylalkenyl, alkylaryl or C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radicals and at least one of R ₁ , R ₂ and R ₃ is a C ₁₆ -C ₂₀ saturated or unsaturated fatty acid radical ; R ₄ is O, S, NH or CH ₂ ; R ₅ is C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₃ -C ₈ cycloalkyl, C ₅ -C ₂₀ aryl, heteroaryl, arylalkyl, arylalkenyl or alkylaryl; And R ₆ is an acid group. Pain relief composition comprising the novel glyceride derivative of claim 1 as an active ingredient. The method of claim 2, wherein the composition is a pharmaceutical composition. The composition of claim 2, wherein the composition is a cosmetic composition. 5. The composition of claim 2, wherein at least one of R ₁ , R ₂ and R ₃ of Formula 1 is a C ₁₆ -C ₂₀ unsaturated fatty acid radical and the other substituent is H. 6. 5. The composition of claim 2, wherein R ₆ in Formula 1 is sulfate or phosphate. 5. The glyceride derivative according to any one of claims 2 to 4, wherein the glyceride derivative is mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate , Tri-oleoyl tromethamine ethane phosphate, tri-linoleolyl tromethamine ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate Composition. 8. The glyceride derivative according to claim 7, wherein the glyceride derivative is selected from the group consisting of mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate and tri-oleoyl tromethamine ethane sulfate. Composition. Pain relief transdermal patch comprising the novel glyceride derivative of claim 1 as an active ingredient. 10. The method of claim 9, wherein said patch is reservoir type and comprises: (a) a backing layer; (b) a drug storage layer comprising the glyceride derivative of claim 1 and positioned below the backing layer; (c) an adhesive layer located below the drug storage layer; And (d) a peeling liner layer positioned below the adhesive layer. 10. The method of claim 9, wherein the patch is matrix and comprises: (a) a backing layer; (b) an adhesive layer comprising the glyceride derivative of claim 1 and an adhesive base and positioned below the backing layer; And (c) a peeling liner layer positioned below the adhesive layer. 11. The method of claim 10, wherein the drug storage layer for pain relief transdermal patch, characterized in that it further comprises glucosamine as a pain relief active ingredient. 12. The method of claim 11, wherein the adhesive layer is a pain relief transdermal patch for pain relief, characterized in that it further comprises glucosamine as a pain relief active ingredient. 10. The method of claim 9, wherein at least one of R ₁ , R ₂ and R ₃ of Formula 1 is a C ₁₆ -C ₂₀ unsaturated fatty acid radical and the other substituent is H, a transdermal patch for pain relief. 10. The method of claim 9, wherein R ₆ of Formula 1 is a pain relief transdermal patch, characterized in that the sulfate or phosphate. The pain relief transdermal patch according to claim 10, wherein the drug storage layer further comprises oleate as a pain relief active ingredient and a permeation accelerator. 12. The pain relief transdermal patch according to claim 11, wherein the adhesive layer further comprises oleate as a pain relief active ingredient and a permeation accelerator. The method of claim 10, wherein the patch comprises: (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl trometha Glyceride derivative as a pain-relieving active ingredient selected from the group consisting of min ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate, glucosamine as a pain-relieving active ingredient And a drug storage layer disposed at the bottom of the backing layer, including oleate as a pain-relieving active ingredient and a permeation accelerator; (c) an adhesive layer located below the drug storage layer; And (d) a peeling liner layer positioned below the adhesive layer. The method of claim 11, wherein the patch comprises: (a) a backing layer; (b) mono-oleoyl tromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane sulfate, tri-oleoyl tromethamine ethane phosphate, tri- linoleolyl trometha Gluceamine as a pain relief active ingredient, a glyceride derivative as a pain stimulating agent, a pain relief active ingredient selected from the group consisting of min ethane sulfate, tri-arachidonyl tromethamine ethane sulfate and tri-oleoyl tromethamine propane sulfate An adhesive layer disposed below the backing layer, comprising an oleate and an adhesive base as a permeation stimulant and a permeation accelerator; And (c) a peeling liner layer positioned below the adhesive layer. 20. The method according to claim 18 or 19, wherein the glyceride derivative is from the group consisting of mono-oleoyltromethamine ethane sulfate, di-oleoyl tromethamine ethane sulfate and tri-oleoyl tromethamine ethane sulfate Pain relief transdermal patch, characterized in that selected.

Images