KR20060004399A - Transdermal delivery system of ketoprofen with self-heating element - Google Patents

Abstract

The present invention relates to a transdermal administration system of ketoprofen using a self heating element, and more particularly, a transdermal administration composition containing ketoprofen is attached to the bottom of the self heating element, and the present invention is suitable for the self heating element. The synergistic effect of the transdermal administration composition and the self-heating element is a synergistic effect of the ketoprofen skin penetration from the beginning, and can maximize the pharmacological action. There is an advantage that can be attached for a long time to sweat generated from the skin by fever.

Ketoprofen, transdermal administration, self heating element, polymethacrylate

Description

Transdermal delivery system of ketoprofen with self-heating element

Figure 1a is a cross-sectional view showing an embodiment of a self heating element that can be applied to the transdermal administration system of ketoprofen according to the present invention,

Figure 1b is a cross-sectional view showing another embodiment of the self heating element that can be applied to the transdermal administration system of ketoprofen according to the present invention,

FIG. 2 is a perspective view of the magnetic heating element according to FIG. 1B;

3 is a pharmacokinetic graph of the animal test of the transdermal administration system of ketoprofen according to the present invention,

Figure 4 is a pharmacokinetic graph of the human test of the transdermal administration system of ketoprofen according to the present invention.

※ Explanation of code about main part of drawing ※

1: self heating element 2: heating composition

3: moisture-permeable sheet 4: skin adhesive composition

5: release layer 12: cell

The present invention relates to a transdermal administration system for enhancing skin penetration of ketoprofen using a self heating element, and more particularly, when a transdermal administration composition suitable for a self heating element is attached to the skin by attaching it to the bottom of the self heating element, Due to the synergistic effect of the heating element's heating effect, ketoprofen skin penetration is very early and maximization of pharmacological action is possible. It relates to a transdermal administration system of ketoprofen using a self-heating element that can be attached to sweat for a long time.

Methods of promoting absorption of drugs through the skin include physical, biochemical and chemical methods. Physical methods mainly use heat, electricity and ultrasonic energy. As a biochemical method, a prodrug method is mainly used, and the drug is converted into a parent active drug during or after skin absorption, and the chemical structural formula is mainly used for a protein drug. Chemical methods are mainly used for complex formation, various kinds of substances, surfactants, solvents and fatty acids, and are the most widely used methods. The mechanism of percutaneous absorption promotion is to change the thermodynamic properties of the drug or to change the properties of the skin, in particular to change the fluidity of lipid components in the skin, to interact with sugars and proteins in skin cells and to promote the distribution of the drug to the stratum corneum. Because. As such, various methods are used to promote transdermal absorption of drugs, and methods of increasing drug absorption using dual absorption accelerators have been most common. However, side effects such as itching, erythema and skin rash often occur when the absorption accelerator is used excessively to improve the transdermal absorption of the drug or when the patient's disease is chronically and frequently administered. Primary irritation and sensitization of the skin act as a limiting factor in the application of drugs, and 20-30% of currently available products show side effects on the skin. On the other hand, the method of utilizing electricity and ultrasonic energy as a physical method is currently being actively researched, and some of them have been released as products, but the manufacturing process and related technologies are complicated and additional devices are still needed to be realized as products. Since the unit price increases, there is a disadvantage that can be applied only to expensive drugs.

The thermal energy used in the present invention has been used for a long time, and in recent years, an infrared lamp, an infrared heating pad, a hydrocolloid pack, a rubber heating container, an electric heating pad, and a chemical pack are common forms, and pain relief, blood circulation improvement, muscle relaxation, It is used as a means of physical therapy because it shows the effect of poultice. The mechanism of promoting transdermal administration using heat increases the diffusion coefficient of the drug by increasing the internal energy of the particles as the temperature rises in the system, and affects the concentration gradient of the drug in the system. Increasing the skin absorption of the drug by promoting the movement of the drug.

Self heating element according to the present invention is a kind of chemical pack in the form using the heat energy, the oxidizing metal powder is contained in the breathable sheet, the heat is generated when in contact with air, the temperature of about 40 to 80 ℃ depending on the application site and purpose Because it keeps for several hours, it is attached to skin or clothes to keep parts of the body warm for the purpose of warming, or it is used for the treatment of pain relief, blood circulation improvement, muscle relaxation, and poultice.

Referring to the structure of a general self heating element, as shown in FIG. 1, the heat generating composition 2 is inserted into a sheet 3 having air pores through which air is allowed to pass through, and the sheet is sealed by a non-air-packing bag ( Not shown) and sealed in a vacuum state. If necessary, the adhesive composition 4 is attached to one side of the sheet 3 so as to attach the heat-generating self-heating body 1 to clothes or a body, and the composition layer to protect the adhesive force of the adhesive composition 4. The release layer 5 is formed on (4). Therefore, when the packaging bag is opened to take out the sheet in which the exothermic composition 2 is embedded, heat is generated while air transmitted through the pores formed in the sheet comes into contact with the exothermic composition 2.

On the other hand, the self-heating element is preferably attached directly to the affected area for treatment purposes, but when it is attached to the skin, the temperature of the attachment site rises due to heat generation, so that sweating occurs and the heat-generating composition hardens over time, making it difficult to attach to the skin for a long time. Self heating element products are limited to the clothing attached to the area, even if the heating element attached to the skin has a disadvantage that it does not stick for a long time while lifting from the skin.

In general, adhesives applied to the skin are designed to have an optimum adhesive force around 32 ° C. which is a typical skin temperature, and it is well known that the adhesive force of the adhesive decreases in inverse proportion to the temperature. In addition, attaching directly to the affected area for pain relief, blood circulation improvement, muscle relaxation, poultice, etc. among the self-heating elements is a concern for low temperature burn of the skin, and usually generates a heat of 40 to 45 ℃. Therefore, in general, when the adhesive used for the skin is attached to the bottom of the self-heating element and attached to the skin, the temperature of the self-heating element rises to 40-45 ° C., so that the adhesive force of the pressure-sensitive adhesive itself decreases. Sweating causes the self-heating element to stick to the skin and fall off easily. On the contrary, in the case of using a pressure-sensitive adhesive having a high adhesive strength in the vicinity of 40 ~ 45 ℃, when the exothermic ends after peeling off too strong adhesive strength near the skin temperature of 32 ℃, side effects accompanying detachment of the epidermal tissue, erythema and the like tends to occur.

Korean Patent Laid-Open Publication Nos. 1999-0044351, 1991-0010137, US Pat. No. 6,672,632, 59,4995, 5975074, 5879378, 5366492, and the like, provide various methods of manufacturing a self heating element. However, the above patents are technically focused only on the manufacture of the self heating element, and even though the adhesive is attached to one side of the self heating element and directly attached to the affected part, there is no consideration of the change in the adhesive force according to the temperature. There are no solutions to problems that arise.

Meanwhile, Korean Patent No. 382347 forms a plurality of cells, fills and seals a heat generating composition in the cell, and attaches a pressure-sensitive adhesive on the bottom thereof to produce a self-heating body that can be freely deformed, thereby improving the structure of the self-heating body to the skin. Attempts have been made to improve adhesion to the skin, and in Korean Patent Application No. 2004-11051, in addition to the addition of polymethacrylate having an amine functional group to the skin adhesive composition, the self-heating element is attached to the skin of a human body or an animal even when it is heated. The present invention discloses a pressure-sensitive adhesive composition suitable for a self-heating body that can be adhered to sweat for a long time without any decrease in adhesion strength and is generated due to heat generation.

Ketoprofen is a propionic acid-based anti-inflammatory drug that has a short half-life in blood and excellent efficacy at low doses compared to other non-steroidal anti-inflammatory drugs. In addition, because of its low molecular weight and excellent physical properties, it shows relatively high transdermal absorption. Many types of products have been developed as transdermal administration agents. Especially, many researches have been conducted as matrix-type transdermal administration patch, and some of them have been successfully commercialized. have.

However, due to the drug properties of anti-inflammatory analgesics, the initial skin absorption rate and high skin absorption rate should be satisfied for a long time so that it can be used quickly. There is no patch.

Conventional techniques related to the matrix transdermal patch containing ketoprofen include US Pat. No. 5,059,563, Republic of Korea Patent No. 188180, and the like, wherein the matrix comprises two to five layers having different water contents. There is disclosed a technique for removing the water emanating from the skin to suppress skin irritation and deterioration of adhesion and a method of using hexylene glycol as a permeation enhancer, in Korea Patent No. 194968 is separated from the drug layer and adhesive layer Disclosed is a matrix patch agent comprising a composite laminate structure, a non-moisture-sensitive adhesive layer through which moisture can pass, a highly moisture-containing ketoprofen-containing drug layer, and a skin adhesive and drug control layer having a drug control structure. . However, the technique disclosed in the patent can be manufactured only through a complicated process due to the nature of the multi-layered multi-layered formulation, and there is a lot of room for improvement in the method of significantly increasing skin permeation.

In addition, among the techniques related to the matrix-type transdermal patch of ketoprofen, Korean Patent No. 228514 related to the disclosed technique to increase the skin permeability of ketoprofen, using a non-polar polymer material as an adhesive, skin permeability of ketoprofen Although a method of increasing the amount is disclosed, it is difficult to stably maintain a drug for a long time by using a nonpolar polymer material having a significantly lower solubility in ketoprofen as an adhesive than a commonly used acrylic adhesive. In addition, Korean Patent Laid-Open Publication No. 2000-000640 discloses a matrix type patch for improving skin permeability of ketoprofen using diethylene glycol ether and sorbitan ester as transdermal absorption accelerators. However, the above-described transdermal administration patch of ketoprofen has a disadvantage in that the skin absorption delay time (lag time) of the drug is long initially when it is attached in a simple matrix form, and it is difficult to show the skin absorption rate for a long time.

Accordingly, in the present invention, as a result of the research to solve the above problems, the bottom surface of the self-heating body by adding a polymethacrylate having an amine functional group to the transdermal administration composition containing ketoprofen or a salt thereof as a pharmacologically active substance When attached to the human skin or animal skin, ketoprofen's initial skin penetration rate is high due to synergy of heat generated from self-heating element and transdermal administration composition, and it shows skin absorption rate for a long time. The therapeutic effect is excellent, it was confirmed that there is an effect that can be attached for a long time by maintaining a constant adhesive strength without reducing the adhesive strength even in the sweat generated at the attachment site, the present invention was completed based on this

Accordingly, an object of the present invention is to provide a transdermal administration system of ketoprofen using a magnetic heating element that can improve the therapeutic effect of ketoprofen for pain relief by maintaining a constant adhesive force for a long time when directly attached to the human or animal skin. To provide.

The transdermal administration system of ketoprofen using a self heating element for achieving the present invention is a transdermal administration composition containing a ketoprofen, a tacky polymer, and a polymethacrylate having an amine functional group, or a moisture permeable film containing an oxidative metal powder or Filling and sealing the sheet is attached to the bottom of the self-heating element that generates heat when exposed to the air to adhere to the human or animal skin.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

1A and 1B are separate perspective views showing a self heating element that can be applied to the transdermal administration system of ketoprofen of the present invention, and FIG. 2 is a cross-sectional view showing a self heating element of the transdermal administration system of the present invention, FIGS. 3 and 4 Is the pharmacokinetic profile of the transdermal administration system of ketoprofen according to the present invention. Referring to this, the transdermal administration system (1) of the present invention comprises a self heating element filled / sealed the exothermic composition (2), and the skin adhesive composition (4) attached to the bottom of the self heating element contains ketoprofen Consisting of transdermal administration composition.

The transdermal administration composition containing ketoprofen includes a pharmacologically active component ketoprofen, an adhesive polymer, a polymethacrylate having an amine functional group, optionally a transdermal absorption accelerator, and an additive commonly used.

Ketoprofen as the pharmacologically active ingredient is preferably contained in an amount of 0.1 to 30% by weight of the transdermal composition, and if the amount thereof is too small, it is ineffective, and when added in excess, no therapeutic effect can be expected. Since it remains in the crystal state in the inside, side effects such as a decrease in penetration effect, a decrease in adhesive force, and skin irritation occur.

In the transdermal administration composition according to the present invention, the adhesive polymer may be water-based or organic solvent-based materials as a pressure sensitive adhesive (PSA) for medical use, and preferably, an acrylate polymer, a vinyl acetate-acrylate copolymer, or the like. Synthetic rubbers, natural rubbers, silicone-based adhesives and the like which are acrylic pressure sensitive adhesives, polyisobutylene, polystyrene, polybutadiene or copolymers thereof may be used alone or in combination of two or more thereof. The adhesive polymer is preferably contained 30 to 90% by weight of the content of the transdermal administration composition.

Polymethacrylates having an amine functional group in the transdermal composition according to the present invention are fully polymerized copolymers of methacrylic acid and acrylic acid esters or methacrylic acid esters (USPN, USPNF), and typically have amine functional groups. It is preferable to use a pharmaceutically usable one suitable according to the type of general adhesive polymer and the method for preparing the transdermal administration composition.

The content of the polymethacrylate is preferably 0.5 to 20% by weight of the total transdermal composition, and if the amount is too small, the adhesive strength is not kept constant in the temperature range of 30 to 45 ° C. When added, the adhesion to the skin is weakened, the absorption of the skin is reduced due to the lowering of the release rate of ketoprofen, and the viscosity of the transdermal administration composition is excessively increased, so that the preparation of the transdermal administration composition is impossible.

Percutaneous absorption enhancer according to the present invention is optionally added as needed, to increase the skin permeation of ketoprofen oleic acid, linoleic acid, lauryl acid, palmitic acid, stearic acid, capric acid, in advance Fatty acids such as succinic acid, fatty acid alcohols such as oleyl alcohol and lauryl alcohol, fatty acid esters such as isopropyl myristate, propylene glycol monolaurate, polyethylene glycol laurate, and propylene glycol oleate. The percutaneous absorption accelerator is 0.01 to 20% by weight of the transdermal administration composition, if the content thereof is less than 0.01% by weight has little effect of addition, when it exceeds 20% by weight of the skin side effects occur and reduce the adhesion to the skin.

The self heating element according to the present invention is generally provided in a form in which an inlet is sealed by filling an exothermic composition containing an oxidizing metal powder into an envelope having a structure made to allow air to pass through one or both sides thereof.

The envelope having a structure made to pass through the air is made of paper, nonwoven fabric, woven fabric, natural or synthetic rubber, PET, PP, PVC, PU, PS, PC, PETG, EVOH, PE and nylon in the form of a moisture-permeable film or sheet One or more may be selected from the group, and the unit weight of the moisture-permeable film or sheet is usually 20 to 200 g / m 2, preferably 30 to 150 g / m 2, and the water vapor transmission rate is preferably 100 to 2000 g / m 2 .24 hr. In order to prevent low-temperature burns of the skin when attached to the skin, it is most preferable to have a moisture permeability of 300 to 1000 g / m 2 .24 hr.

As a method of imparting breathability to the moisture-permeable film or sheet, a film is formed in addition to a method of stretching the film or sheet to form a ventilation hole, and extracting a specific component from the film or sheet to form a ventilation hole. After that, a method of mechanically forming the air vents by punching, puncturing with a fine needle, or the like can be given. The exothermic composition containing the oxidative metal powder is filled and sealed in the moisture-permeable film or sheet thus formed to produce a self heating element.

As a raw material constituting the exothermic composition containing the oxidizing metal powder, all compositions can be conventionally used, and the mixing ratio of the exothermic composition as a whole may not be collectively specified depending on the intended exothermic performance, but for example, the oxidizing metal powder It is 5-20 weight part of activated carbon, 1.5-10 weight part of inorganic electrolytes, and 25-60 weight part of water with respect to 100 weight part. Examples of the oxidizing metal powder include iron powder, zinc powder, aluminum powder, and the like, and iron powder is usually used, and reduced iron powder, crushed iron powder, electrolytic iron powder, and the like are preferable. The particle size of the exothermic composition powder is usually 60 mesh or less, preferably 50 mesh or less. In addition, as desired, water-retaining agents such as pearl rock powder, vermiculite, and high-quality aqueous resins, or hydrogen generating inhibitors and anti-caking agents may be mixed.

Hereinafter, the manufacturing method according to the present invention will be described with an example.

Ketoprofen, transdermal absorption accelerator, polymethacrylate, and the like are uniformly mixed with the adhesive polymer solution, and then applied on release paper and dried as necessary to prepare a transdermal composition 4 containing ketoprofen. Next, the exothermic composition 2 containing the oxidizing metal powder, activated carbon, inorganic electrolyte, water-retaining agent, water and the like is filled into a bag of the moisture-permeable film or sheet 3 and sealed to prepare a self-heating body 1. Finally, the transdermal administration composition (4) containing ketoprofen prepared in advance is transferred to the bottom of the self-heating body and cut into a suitable size to prepare a transdermal administration system that can be attached to the skin.

In the transdermal administration system of ketoprofen using the self heating element thus prepared, when a single transdermal administration system containing 30 mg of ketoprofen is attached to human skin, blood ketoprofen concentration reaches 50 ng / ml. In less than 3 hours, the initial skin penetration of ketoprofen is very fast due to the synergy of heat generated from the self heating element and the transdermal composition, and the synergistic effect of the heat effect can maximize the pharmacological action. However, the adhesive force does not decrease even during heat generation during adhesion, and the percutaneous administration system provides the effect of attaching for a long time even in the sweat generated at the attachment site.

Hereinafter, the present invention will be described in more detail with reference to Preparation Examples, Examples, and Comparative Examples, but the scope of the present invention is not limited to the following Examples.

Preparation Example 1

50% by weight of iron, 10% by weight of activated carbon, 8% by weight of diatomaceous earth, 5% by weight of wood powder, and 2% by weight of sodium chloride were mixed well and 25% by weight of water was added to the exothermic composition. After filling the moisture permeability of 450 ± 50 g / ㎡ 24h) was sealed in all directions to produce a self-heating body that generates heat by air contact.

Preparation Example 2

An exothermic composition prepared by mixing 50% by weight of iron, 10% by weight of activated carbon, 8% by weight of diatomaceous earth, 5% by weight of wood powder, and 2% by weight of sodium chloride and mixed with 25% by weight of water was added to the Example of Korean Patent No. 382347. After filling into a breathable sheet (Byrin Korea, moisture permeability 450 ± 50g / ㎡24h) crimped in the same structure as 2 and sealed in all directions to prepare a self-heating body that generates heat by contact with air.

Example 1

The polymethacrylate (Eudragit E100) powder was mixed in an acrylic adhesive polymer solution (Gelva 1753, Monsanto, Ltd.) to 5.0 dry weight%, and then dissolved in ethyl acetate to dry weight of ketoprofen 25 dry weight in advance. After the solution was added and mixed evenly, it was applied at 350 μm on a release sheet and dried at 90 ° C. for 5 minutes to make a transdermal administration composition, and then transferred to the bottom of the self heating element prepared in Preparation Example 1, cut into a suitable size, and vacuum packed. Was stored.

Example 2

Polymethacrylate (Eudragit E100) powder was mixed with an acrylic adhesive polymer solution (Gelva 1753, Monsanto) to a dry weight of 10.0%, and then 10% by weight of ketoprofen to the ethyl acetate in advance. After the melted solution was added and mixed evenly, it was applied at 350 μm on a peeling place, dried at 90 ° C. for 5 minutes to make a skin adhesive composition, then transferred to the bottom of the self heating element prepared in Preparation Example 1, and cut into an appropriate size to vacuum. Packed and stored.

Example 3

Polymethacrylate (Eudragit E100) powder was mixed in an acrylic adhesive polymer solution (Gelva 1753, Monsanto) to 10.0% dry weight, and then dissolved in ethyl acetate to 20% dry weight of ketoprofen in advance. The solution was added to 7% by weight of oleic acid, mixed evenly, and then coated at 350 μm on a peeled paper, dried at 90 ° C. for 5 minutes to form a transdermal administration composition, and then transferred to a bottom surface of the self heating element prepared in Preparation Example 1 Cut to size and vacuum-packed.

Example 4

Polymethacrylate (Eudragit, Eudragit E100) powder was mixed in an acrylic adhesive polymer solution (Gelva 737, Monsanto) to 10.0% dry weight, and then dissolved in ethyl acetate to 20% dry weight of ketoprofen in advance. The solution and isopropyl myristate were added to 7% by weight, mixed evenly, and then applied at 350 μm on a release sheet, dried at 90 ° C. for 5 minutes to form a transdermal administration composition, and then placed on the bottom surface of the self heating element prepared in Preparation Example 1. Transferred, cut to suitable size, vacuum-packed and stored.

Example 5

Polymethacrylate (Eudragit, Eudragit EPO) powder was mixed with an acrylic adhesive polymer solution (Gelva 1753, Monsanto) to 13.0 dry weight%, and then 20% dry weight of ketoprofen in ethyl acetate. After mixing evenly so that the melted solution and oleyl alcohol to 7% by weight, apply 350㎛ to the peeling place and dried at 90 ℃ for 5 minutes to make a transdermal administration composition, and then transfer to the bottom of the self heating element prepared in Preparation Example 2 Cut to appropriate size and vacuum-packed.

Example 6

The polymethacrylate (Eudragit, Eudragit EPO) powder was mixed in an acrylic adhesive polymer solution (Gelva 1753, Monsanto) to 5.0 dry weight%, and then dissolved in ethyl acetate to 20 dry weight ketoprofen in advance. The solution and propylene glycol dilaurate were added to 3% by weight, mixed evenly, and then applied at 350 μm on a peeling place, dried at 90 ° C. for 5 minutes to form a transdermal administration composition, and then the bottom surface of the self heating element prepared in Preparation Example 2 Transferred to an appropriate size, cut into vacuum packaging and stored.

Example 7

The polymethacrylate (Eudragit EPO) powder was mixed with a polyisobutylene pressure-sensitive adhesive solution (Duro-Tak 87-2852, National Starch, Inc.) to 5.0 dry weight%, followed by ketoprofen in ethyl acetate in advance. 15% by weight of the solution dissolved to dry weight and 7% by weight of propylene glycol dilaurate was added and mixed evenly, and then applied to 350㎛ on a peeling place to dry for 5 minutes at 90 ℃ to prepare a transdermal administration composition, Preparation Example 2 Transfer to the bottom of the self-heating element prepared in the cut to the appropriate size and stored in vacuum packaging.

Comparative Example 1

A solution of 20% by weight of ketopropene and 3% by weight of propylene glycol dilaurate was previously added to the ethyl acetate, and the mixture was added to an acrylic adhesive polymer solution (Gelva 1753, Monsanto) and evenly mixed. To dry at 90 ° C. for 5 minutes to prepare a transdermal composition. This was transferred to the bottom of the self heating element prepared in Preparation Example 1, cut into appropriate sizes, and stored in a vacuum package.

After attaching the self heating elements prepared in Comparative Examples 1 and 2 to 6 to the skin of the abdomen, the time required to lift 25% and 50% of the attachment area was measured. As in Examples 2 to 6, a system in which a skin adhesive composition containing polymethacrylate and a self heating element are combined has an effect of being able to adhere to the skin for a longer time.

Test subject 25% area float time 50% area floats Example 2 6.8 hours 7.5 hours Example 3 6.3 hours 7.1 hours Example 4 6.5 hours 7.5 hours Example 5 10.5 hours 11.3 hours Example 6 11.8 hours 13.1 hours Comparative Example 1 3.9 hours 5.5 hours

Comparative Example 2

Blood concentrations were measured by applying the transdermal administration system prepared from Example 6 and Comparative Example 1 to rabbits (type: NZW, male, 2.6 kg ± 0.14 kg) to contain 30 mg of ketoprofen. As a test method, the hair on the back of the rabbit was removed one day before the experiment, and each transdermal administration system was attached to the back to collect blood for 8 hours. Five rabbits were tested in one group. The collected blood was centrifuged and plasma was taken. The analysis was performed by high performance liquid chromatography (HPLC) and the results are shown in Table 2 and FIG. 3. Table 2 and FIG. 3 shows that the absorption rate through the skin at the initial time is significantly higher than that of Comparative Example 1, which is a transdermal administration system in which the self heating element is combined, is a transdermal administration system without the self heating element, and ketoprofen is up to 8 hours. It can be seen that the absorption amount of AUC _{0-> 8 hr} and the peak blood concentration Cmax are maintained more than two times.

Pharmacokinetic Indicators AUC _{0-> 8 hr} (μg * hr / ml / kg) Cmax (μg / ml / kg) Example 6 21.11 ± 2.53 4.2 ± 0.68 Comparative Example 1 10.26 ± 3.75 2.07 ± 0.55

Comparative Example 3

Blood concentration and pain reduction time were measured by applying a transdermal administration system prepared from Example 6 and Comparative Example 1 to a person having arthritis pain or muscle pain to contain 30 mg of ketoprofen. As an experimental method, each percutaneous administration system was attached to the upper arm of the human and blood was collected for 12 hours, and the pain felt time was recorded as the pain reduction time. Cross-testing was carried out with 12 humans as a group, and the collected blood was centrifuged and plasma was taken. The analysis was performed by high performance liquid chromatography (HPLC) and the results are shown in Table 3 and FIG. 4. Looking at Table 3 and Figure 4 it can be seen that the absorption rate through the skin at the initial time is significantly higher, the absorption amount of ketoprofen AUC _{0-> 12 hr} and the peak blood concentration Cmax is maintained almost twice or more until 12 hours. In addition, arthritis pain or myalgia was decreased when the ketoprofen concentration in the blood was about 50 ng / ml from the pain reduction time measured in this experiment. When Example 6 was applied, it was very short compared to Comparative Example 1. The effect of improving pain at time was found.

Pharmacokinetic Indicators AUC _{0-> 12 hr} (ng * hr / ml / kg) Cmax (ng / ml / kg) Example 6 823 ± 149 94 ± 13 Comparative Example 1 348 ± 110 53 ± 12

As described above, the transdermal administration system of ketoprofen using the self heating element according to the present invention is combined with the transdermal administration composition comprising polymethacrylate having an amine functional group suitable for the heating element, thereby being raised by the thermal effect of the self heating element. It delivers ketoprofen skin permeation very quickly from the beginning, and it is possible to secure the maximization of pharmacological action by synergy by the heat effect. It is expected to overcome the limitations and disadvantages of cataplasmase or self heating elements containing conventional ketoprofen alone by providing an effect that the transdermal administration system can adhere to sweat for a long time.

Claims (7)

A transdermal administration composition comprising ketoprofen, an adhesive polymer, and a polymethacrylate having an amine functional group is filled with an oxidizing metal powder in a moisture-permeable film or sheet and sealed to attach to the bottom of a self-heating element that generates heat when exposed to air. Transdermal administration system of ketoprofen using a self heating element, characterized in that attached to the human or animal skin. The self heating element according to claim 1, wherein when a single transdermal administration system containing 30 mg of ketoprofen is attached to human skin, the time for reaching a blood ketoprofen concentration of 50 ng / ml is 3 hours or less. Transdermal administration system of ketoprofen using. The method of claim 1, wherein the transdermal composition is a keto using a self heating element, characterized in that it comprises 0.1 to 30% by weight of ketoprofen, 30 to 90% by weight of the adhesive polymer, and 0.5 to 20% by weight of polymethacrylate. Transdermal administration system of propene. The transdermal administration system of ketoprofen according to claim 1 or 3, wherein the transdermal composition further comprises a transdermal absorption accelerator, and the content thereof is 0.01 to 20% by weight. The ketoprofen according to claim 1, wherein the adhesive polymer is selected from the group consisting of acrylate polymers, acrylic pressure sensitive adhesives, synthetic rubbers, natural rubbers, and silicone pressure sensitive adhesives. Transdermal administration system. The transdermal absorption enhancer according to claim 4, wherein the percutaneous absorption enhancer is oleic acid, linoleic acid, lauryl acid, palmitic acid, stearic acid, capric acid, and fatty acids of myristic acid, fatty acid alcohols of oleyl alcohol, lauryl alcohol, and isopropyl. Keto using a self heating element, characterized in that selected from the group consisting of myristate, propylene glycol monolaurate, propylene glycol dilaurate, polyethylene glycol laurate, and fatty acid esters of propylene glycol oleate Transdermal administration system of propene. The transdermal administration system of ketoprofen according to claim 1, wherein the moisture permeable film or sheet has a moisture permeability of 300 to 1,000 g / m 2 24hr.

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