KR102455157B1 - Ropinirole percutaneous drug delivery system - Google Patents

Abstract

Disclosed is a transdermal absorption agent for treating Parkinson's disease containing ropinirole.

Description

Ropinirole percutaneous drug delivery system

The present invention relates to a transdermal absorption agent for the treatment of Parkinson's disease containing ropinirole.

Parkinson's disease is one of the neurodegenerative diseases, and it is known that it occurs because dopamine is not produced. Therefore, it is known that supplying dopamine precursors to the body is very important for the treatment of Parkinson's disease and has the most powerful effect.

As a representative drug of a dopamine precursor having such a strong effect, there is levodopa. Levodopa greatly improves movement disorders common in Parkinson's disease, such as tremor, tremor, and stiffness. However, when levodopa is administered for more than 5 years, 50% of patients have a 'disappearance of efficacy' phenomenon in which the duration of the drug's effect is gradually shortened, resulting in the appearance of motor abnormalities.

Therefore, delaying the administration of the dopamine precursor as much as possible and minimizing the dose to delay the occurrence of the 'loss of efficacy' phenomenon should be considered as the top priority in the treatment of Parkinson's disease.

Ropinirole is a second-generation dopaminergic agonist, which enters the brain and directly stimulates dopamine receptors to improve the ataxia symptoms of Parkinson's disease. In addition, it can alleviate the loss of dopamine effect and has few motor complications, so it is mainly used for the treatment of early Parkinson's patients, and in severe cases, it can be administered together with levodopa.

Because Parkinson's disease suffers from cognitive impairment, it is often impossible to take treatment drugs on a regular basis, which makes Parkinson's disease worse.

If a drug for treating Parkinson's disease is administered in the form of a transdermally absorbable drug such as a patch, the convenience of taking the drug is improved by using it once a day, and the continuous administration of the drug is made easier, thereby increasing the therapeutic effect of Parkinson's disease, and the patient's awareness It can improve the quality of life of patients by reducing the possibility of functional impairment.

In addition, in order to prevent cognitive decline in Parkinson's disease patients, it is important to prevent the development of resistance to the drug itself, but it is also important to maintain a constant blood concentration of the therapeutic drug. Therefore, by maintaining a constant blood drug concentration, the patient can continuously maintain cognitive function.

In particular, the most frequent time for cognitive impairment is the blank time from waking up to taking the first drug, which is the time when the drug is taken in the evening and there is no new drug supplied to the body until the time of waking up in the morning. it happens because

In order to improve this problem, it is possible to maintain the blood concentration of the active ingredient by administering the drug through the transdermally absorbed formulation, and also to maintain the blood concentration regardless of the presence or absence of sleep, thereby reducing the possibility of cognitive dysfunction in the patient. Therefore, the development of such a transdermally absorbable formulation improves the patient's compliance with the dosage and reduces the cognitive function decline time, thereby increasing the life satisfaction of the patient himself/herself as well as the caregiver taking care of the patient.

As a prior art for transdermally absorbable formulations of ropinirole, Korean Patent Laid-Open No. 10-2014-0034814 discloses a configuration using a metal ion desalting agent to increase stability, but sodium hydroxide used as the desalting agent is a polymer. It may remain in the adhesive to dissolve the keratin of the skin and cause skin damage, and the low compatibility with rubber may cause a problem of homogeneity in the matrix.

Korean Patent Publication No. 10-2014-0034814

The present inventors confirmed that when preparing a transdermal absorbent containing ropinirole free base or a pharmaceutically acceptable salt thereof, problems of discoloration and crystal precipitation occur depending on the adhesive and excipient used. .

Accordingly, the present inventors have studied methods for improving the crystal precipitation and discoloration problems, and as a result, it was confirmed that the crystal precipitation problem and discoloration problem could be solved through the transdermal absorbent having a novel composition different from the prior art as described above.

Accordingly, the present invention is to provide a ropinirole-containing transdermal absorbent that does not cause crystal precipitation problems and discoloration problems.

In order to solve the above problems, the ropinirole-containing transdermal absorbent of the present invention includes a drug-containing adhesive layer, a support layer, and a release layer, wherein the drug-containing adhesive layer includes ropinirole or a pharmaceutically acceptable salt thereof and an acrylic-based adhesive layer. Contains a polymer adhesive. The transdermal absorbent of the present invention contains C8-C18 fatty acids or derivatives thereof in the adhesive layer, so that the skin permeability of ropinirole is excellent, sufficient adhesiveness is ensured, discoloration over time is suppressed, and stability is improved, Crystals do not precipitate.

In the transdermal absorbent containing ropinirole of the present invention, the content of ropinirole and/or a pharmaceutically acceptable salt thereof is 5 to 25 wt%, preferably 15 wt%, based on the total mass of the adhesive layer when converted into a ropinirole free body. ~20% by weight.

The ropinirole-containing transdermal absorption agent of the present invention further includes a transdermal absorption enhancer. As such a transdermal absorption enhancer, C8-C18 fatty acids or derivatives thereof may be used. The C8~C18 fatty acid or its derivative may be selected from the group consisting of oleic acid, stearic acid, palmitic acid, lauric acid, sorbitan monooleate, propylene glycol monolaurylate, monooleic acid glycol, and the like. can The fatty acid is preferably contained in an amount of 0.5 to 2 equivalents based on 1 equivalent of ropinirole or a pharmaceutically acceptable salt thereof in view of the effect of inhibiting discoloration.

On the other hand, when a material with a large molecular weight such as fatty acids is used, the weight of the fatty acid used must be increased in order to maintain an appropriate equivalent ratio to ropinirole and a pharmaceutically acceptable salt thereof. Since the relative content ratio is reduced, the transdermal absorbent may not maintain its shape, thereby reducing stability, and may limit the input of other excipient components.

In this case, when a pH adjuster is used, the above-described problems can be solved. That is, when a pH adjuster such as ascorbic acid, citric acid, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, acetic acid, sodium acetate, triethyl citrate, glycerin, or oleyl alcohol is used, the effect of inhibiting discoloration and crystallization is reduced. It is possible to reduce the use weight of fatty acids while achieving it, so that the content of the adhesive agent can be relatively increased, and thus, it is possible to exhibit a discoloration inhibitory effect while stably maintaining its shape even when the adhesive layer is in contact with the skin.

The present invention may further include a solubilizing agent such as a surfactant in the adhesive layer. As such a solubilizing agent, propylene glycol, propylene glycol monocaprelate, propylene glycol monolaurate, propylene glycol ricinoleide, propylene glycol monoole Eight, propylene glycol dicaprelate, propylene glycol dioctanoate, etc. may be used, and may contain 0.3 to 1.5 parts by weight based on 1 part by weight of the free body equivalent of ropinirole or a pharmaceutically acceptable salt thereof.

The ropinirole-containing transdermal absorbent of the present invention has a fast initial drug release rate, continuous release is possible, discoloration is suppressed, high stability, no crystal precipitation, simple storage and use, and easy manufacture. In addition, since the relative content of the pressure-sensitive adhesive is not reduced, the shape can be stably maintained even when the pressure-sensitive adhesive layer is in contact with the skin. In addition, the transdermally absorbent agent of the present invention can significantly improve the patient's medication compliance compared to the oral formulation, thereby improving the patient's cognitive impairment, and thus can be usefully used as a therapeutic agent for Parkinson's disease.

1 shows the effect of preventing discoloration of the present invention.
Figure 2 shows the crystal formation inhibitory effect of the present invention.
3 is a graph showing the skin permeation rate of ropinirole of the present invention.
4A and 4B are photographs taken with a microscope (magnification X850) to confirm the presence or absence of crystal formation of the present invention.
5 is a graph showing the change in the transdermal absorption rate according to the ratio of the transdermal absorption enhancer of the present invention.
6 is a graph showing the change in the transdermal absorption rate according to the use of the transdermal absorption enhancer of the present invention.
7 schematically shows a cross-section of the transdermal absorbent of the present invention.

The present invention relates to a transdermal absorption agent comprising ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient.

More specifically, the present invention relates to a transdermal absorption agent comprising ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient, (a) ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient; and a drug-containing adhesive layer containing an acrylic polymer adhesive; (b) a support layer; and (c) a release layer.

In the present invention, the drug-containing adhesive layer may further include excipients such as transdermal absorption enhancers, antioxidants, pH adjusters, and solubilizers in addition to ropinirole or pharmaceutically acceptable salts and adhesive agents.

In the present invention, it is preferable to use a free base of ropinirole rather than a salt of ropinirole as an active ingredient in terms of improving the transdermal absorption rate. Therefore, the ropinirole glass body is used as a raw material to be used. When the salt of ropinirole is used as a raw material, the process of removing the salt is added and complicated, and there is a risk of skin irritation and damage due to the residue of the neutralization reaction.

In the present invention, ropinirole or a salt thereof is 5 to 25% by weight, preferably 15 to 20% by weight, more preferably 16 to 19% by weight based on the total weight of the drug-containing adhesive layer based on the ropinirole free body. It may be included in weight %. If the drug content with respect to the total weight of the drug-containing adhesive layer is less than 5% by weight, the concentration gradient of the main component is weak and the transdermal absorption rate of the drug is weakened, and if the drug content exceeds 25% by weight, the relative weight ratio of the adhesive after drying is It is lowered and there is a difficulty in that the structure of the pressure-sensitive adhesive is collapsed.

As the pressure-sensitive adhesive used in the present invention, any pressure-sensitive adhesive may be used, but an acrylic pressure-sensitive adhesive is preferably used. In the present invention, the acrylic pressure-sensitive adhesive is a pressure-sensitive adhesive composed of an acryl-based monomer or an acrylic polymer made from the synthesis of an acrylic monomer or a vinyl acetate-based monomer and an acrylic monomer, (i) having no functional group, (ii) having a hydroxyl (-OH) group as a functional group , (iii) having a carboxyl (-COOH) group as a functional group, and (iv) having both a hydroxyl group (-OH) and a carboxyl group (-COOH) as a functional group. have. Preferably, an acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) as a functional group may be used, or a functional group having both a carboxyl group (-COOH) and a hydroxyl group (-OH) may be used. When an adhesive having a carboxyl group (-COOH) or an adhesive having both a carboxyl group and a hydroxyl group is stirred with ropinirole, the color retention time is relatively long. However, when mixed alone with an adhesive having no functional group or a hydroxyl group (-OH), the color rapidly changed to red.

In the present invention, as the transdermal absorption enhancer, fatty acid derivatives such as C8~C18 fatty acids or fatty alcohols, fatty acid ethers, or fatty acid esters, pyrrolidone derivatives, polyhydric alcohol esters, and the like may be used. Preferably, one or more fatty acids such as oleic acid, palmitic acid, stearic acid, lauric acid, etc. having a discoloration inhibitory effect may be selected and used. The fatty acid is preferably contained in an amount of 0.5 to 2 equivalents based on 1 equivalent of ropinirole or a pharmaceutically acceptable salt thereof. When the transdermal absorption enhancer is included in excess of 2 equivalents, the physical strength of the transdermal absorption enhancer may be reduced, and in some cases, skin troubles of the user may be caused.

The present invention may include an antioxidant in order to inhibit the degradation and denaturation of ropinirole or a pharmaceutically acceptable salt. Antioxidants include butyl hydroxy toluene, butyl hydroxy anisole, propyl gallate, ascorbic acid, tocopherol, copherol acetate ( Tocopherolacetate), ascorbyl palmitate (Ascorbyl palmitate), cetylpyridinium chloride (cetylpyridinium chloride), etc. can be used at least one selected from the group consisting of, preferably butylhydroxytoluene, tocopherol, tocopherol acetate is used do. The antioxidant may be used in an amount of 0.1 to 5% by weight, preferably 0.1 to 1% by weight, based on the total weight of the drug-containing adhesive layer. When 5 wt% or more of the antioxidant is used, the antioxidant effect is no longer improved.

In the present invention, the support layer is thin, flexible, and does not cause an allergic reaction to the skin in order to prevent loss of the main ingredient from the formulation while it is attached to the skin or during distribution and storage of the product. Materials such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon (Nylon), and cotton may be used as the support layer, and the form of the support layer may use a single fabric, a nonwoven fabric or a film, or a combination of two or more fabrics and a film, a combination of a nonwoven fabric and a film, or a combination of a film and a film. Preferably, a polyethylene terephthalate (PET) material is used to prevent the drug from being transferred to the support layer, and a film or a combination of a nonwoven fabric and a film is used to prevent contact with oxygen or water vapor in the air. In addition, for light blocking, an aluminum thin film may be laminated in the middle or aluminum may be deposited on the film surface.

In the present invention, the release layer is not particularly limited as long as it protects the drug-containing product while the product is packaged or during distribution and storage, and provides convenience so that it can be easily removed when using the product, polyester, polyvinyl chloride, poly As a film or paper made from vinylidene chloride, polyethylene terephthalate, polyethylene, ethylene vinyl acetate, etc., fine paper or a film laminated with glassine paper and polyolefin may be used. The release film is a silicone resin or fluorine resin applied to the surface that comes into contact with the adhesive layer. The film used for the release layer can also be laminated with an aluminum thin film in the middle to block light, or aluminum can be deposited on the surface of the film.

[Example]

Hereinafter, the present invention will be described in detail in Examples. However, the following examples only illustrate the present invention, the content of the present invention is not limited to the following examples

Example One:

Ingredients Control 1 test group 1 ropinirole vitreous 9.2% 9.2% oleic acid 2.0% 10.0% Acrylic adhesive (-COOH) 88.8% 80.8% Sum 100.0% 100.0% (* In the composition of Test Group 1, 1 equivalent of oleic acid was used with respect to 1 equivalent of ropinirole free body)

A transdermal absorbent having a drug-containing adhesive layer having the composition of the above table is prepared by the following method:

Add oleic acid to the acrylic adhesive and stir thoroughly. After confirming the homogeneity of the solution, the ropinirole free body is added thereto to completely dissolve it. The solution prepared in this way is applied to a release paper (release layer) using an applicator, dried in an oven at 80° C. for 3 minutes, then the supporting layer film is laminated and compressed using a compression roller. produced. As a result of observing the degree of discoloration by leaving the transdermal absorbent prepared in this way at room temperature for 2 months, it was observed that the color of the patch was red in Control 1, which did not contain a sufficient amount of oleic acid, but no discoloration was observed in Test Group 1. It was confirmed that the initial color was maintained (see FIG. 1).

The change in the color of the patch was due to ropinirole, and it was confirmed that the color gradually changed from light yellow or light brown to red as the stability of ropinirole decreased.

Example 2:

Ingredients control group 2 Control 3 test group 2 test group 3 ropinirole vitreous 4.4% 9.2% 13.6% 17.6% oleic acid 4.8% 10.0% 14.8% 19.2% Acrylic adhesive (-COOH) 90.8% 80.8% 71.6% 63.2% Sum 100.0% 100.0% 100.0% 100.0%

A transdermal absorbent having a drug-containing adhesive layer having the composition of the above table is prepared by the following method:

Controls 2 and 3 and test groups 2 and 3 were prepared in the same manner as in Example 1.

In general, crystals may be formed as the weight ratio of the main component increases in the transdermal absorbent, which also affects the release rate of the drug.

In both cases where the weight ratio of the main component used in the transdermal absorbent of the present invention was about 5 wt% and 17.6 wt%, it was confirmed that the crystal formation inhibition was maintained and commercial use was possible. In addition, when the ratio of fatty acids was 0.5 to 2 equivalents with respect to 1 equivalent of ropinirole, it was confirmed that discoloration was suppressed even after 2 months as in Example 1 (see FIG. 2 ).

However, when the weight ratio of the main component is increased as in Test Groups 2 and 3, the absorption rate can be improved (see FIG. 3 ).

Example 3:

Ingredients test group 4 test group 5 ropinirole vitreous 17.6% 17.6% oleic acid 19.2% 8.0% sodium acetate 0.4% acetic acid 0.4% antioxidant 1.6% 0.1% Acrylic adhesive (-COOH) 61.6% 73.5% Sum 100.0% 100.0%

Test group 4 was prepared in the following way: oleic acid and antioxidant were added to the acrylic adhesive and thoroughly stirred. After confirming the homogeneity of the solution, the ropinirole free body is added thereto to completely dissolve it. The solution prepared in this way is applied to a release paper (release layer) using an applicator, dried in an oven at 80° C. for 3 minutes, then the supporting layer film is laminated and compressed using a compression roller. produced. By exposing the thus-prepared transdermal absorbent to room temperature, the presence or absence of crystal formation was confirmed.

Test group 5 was prepared in the following way: sodium acetate and acetic acid, each of which are pH adjusters, were first added to an appropriate amount of ethanol, and then thoroughly dissolved by stirring. Here, an acrylic adhesive, oleic acid, and antioxidant were added and mixed to mix evenly. After confirming the homogeneity of the solution, the ropinirole free body is added thereto to dissolve it, and the thus-prepared solution is applied to a release paper using an applicator, and then the ethanol is completely dried through a drying process to prepare a transdermal absorbent. The thus-prepared transdermal absorbent was exposed to room temperature to check whether crystals were formed.

In Test Groups 4 and 5, it was confirmed that crystals were not formed in the drying process, and crystals were not formed even when left at room temperature for 2 months (see FIGS. 4a and 4b).

In particular, when a small amount of the pH adjusting agent is added as in Test Group 5, the amount of fatty acid can be reduced, and thus a stable form of transdermal absorbent can be prepared by increasing the relative weight ratio of the pressure-sensitive adhesive. The inhibitory effect is still maintained.

Example 4:

Ingredients Control 4 test group 6 test group 7 test group 8 test group 9 ropinirole vitreous 17.6% 17.6% 17.6% 17.6% 17.6% oleic acid 0% 38.4% 19.2% 9.6% 9.6% BHT (Antioxidant) 0.88% 0.88% 0.88% 0.88% 0.88% Propylene glycol monolaurate
(solubilizer) 5% Acrylic adhesive (-COOH) 81.52% 43.12% 62.32% 71.92% 66.92% Sum 100% 100% 100% 100% 100%

Example 4 was prepared in a manner similar to Example 3.

Since the fatty acids used in the present invention are not a simple transdermal absorption enhancer, but also have a function of preventing discoloration, fatty acids must be included.

However, when the content of the active ingredient is increased for a sufficient percutaneous absorption rate, the content of fatty acids must also be increased accordingly (the content ratio of fatty acid is about 0.5 to 2.0 equivalents to 1 equivalent of the vitreous of the active ingredient). However, as the weight ratio of fatty acids increases, the relative weight ratio of the pressure-sensitive adhesive (acrylic pressure-sensitive adhesive) decreases, resulting in unstable shape.

At this time, when a solubilizing agent is included in addition to fatty acids as in Test Group 9, the transdermal permeability of the drug is not lowered even if the content of fatty acids is lowered, and discoloration inhibition can be maintained. On the other hand, it can be seen that in the control group 4, the drug is hardly released and therefore cannot be used in practice (see FIG. 5).

Specifically, referring to FIG. 5 , looking at the transdermal permeability of test groups 6 to 8, it can be seen that the higher the amount of oleic acid used, the higher the transdermal permeability. However, when a solubilizing agent was used as in Test Group 9, it can be seen that at least the amount of oleic acid used has high transdermal permeability. In addition, as the amount of oleic acid is reduced, the relative content ratio of the pressure-sensitive adhesive increases, thereby improving the morphological stability of the formulation. That is, Test Group 9 has a transdermal permeability value similar to that of Test Group 6, although the content ratio of the transdermal absorption enhancer is much lower than that of Test Group 6. On the other hand, since the content of the adhesive in Test Group 9 was much higher than that of Test Group 6, Test Group 9 was excellent in shape stability.

Example 5:

Ingredients test group 7 test group 10 test group 11 ropinirole vitreous 17.60% 17.60% 17.60% oleic acid 19.20% 9.60% 5.04% Propylene glycol monolaurate
(solubilizer) 2.56% 5.04% sodium acetate 0.41% acetic acid 0.37% Antioxidants (BHT) 0.88% 0.08% 0.1% Acrylic adhesive (-COOH) 62.32% 70.16% 71.44% Sum 100% 100% 100%

Test groups 10 and 11 of Example 5 were prepared in a similar manner to Examples 3 or 4.

In test group 10, oleic acid was used in an amount of 9.6%, and in test group 7, oleic acid was used in an amount of 19.2%. That is, the amount of oleic acid used in test group 10 was only half of the amount of oleic acid used in test group 7. Nevertheless, looking at the results of the percutaneous absorption test of Test Group 7 and Test Group 10, the total release amount at 24h is similar. Therefore, as in Test Group 10, when a transdermal absorption enhancer and a dissolution aid are used together, compared to the case of using the transdermal absorption enhancer alone, it is confirmed that the same drug release effect can be achieved while using a small amount of the transdermal absorption enhancer. did.

In addition, in Test Group 10, as the content of the transdermal absorption enhancer decreased, the relative content of the adhesive increased, but the drug release did not decrease despite the increase in the content of the adhesive, and as the content of the adhesive increased, There is an advantage in that the form of the formulation is stably maintained.

As in the results of the percutaneous absorption test of Test Group 11, it can be seen that the release rate of the drug does not decrease even when the content ratio of oleic acid is reduced by adding a pH adjusting agent and a solubilizing agent and the content ratio of the adhesive agent is increased.

Therefore, in the present invention, the content ratio of the adhesive agent is increased and the content ratio of the absorption enhancer used is decreased while increasing the drug release rate, thereby maintaining the morphological stability of the dosage form and preparing a patch having an excellent drug release rate. is possible

7 schematically shows a cross-section of the transdermal absorbent of the present invention, where A is a support layer, B is a drug-containing adhesive layer, and C is a release layer.

[Method for measuring transdermal absorption used in the above experiment]

Put isotonic phosphate buffer (Phosphate buffered saline solution, PBS solution pH=7.4) as a receptor in the Franz-type diffusion cell and maintain 32℃ similar to the skin temperature, and a magnetic stirrer at a stirring speed of 600rpm The dissolved gas in the solution was removed by constant stirring. Thereafter, the patch cut to fit the upper donor cell of the Franz-type diffusion mechanism was attached to the transdermal membrane (Strat-M, Merck KGaA, Darmstadt, Germany) and mounted on the Franz-type diffusion mechanism. After that, a solution of the receptor part was collected every predetermined time and a new buffer solution was supplemented according to the collected amount. The collected samples were analyzed by liquid chromatography (HPLC), and the analysis conditions are as follows.

[Analysis Conditions]

Detection wavelength: 250nm

Flow rate: 1ml/min

Column size: 4.6 x 250 5um C-8

Column temperature: 30℃

Mobile phase: 2.53 mM disodium hydrogen phosphate (pH 7.0 adjusted with phosphoric acid): methanol = 25: 75

Injection volume: 20 μl

Claims (12)

(a) ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient; acrylic polymer adhesive; transdermal absorption enhancers; and a drug-containing adhesive layer containing a pH adjusting agent;
(b) a support layer;
(c) a transdermal absorbent comprising a release layer,
The pH adjusting agent is a combination of acetic acid and sodium acetate. delete delete The method according to claim 1, wherein the acrylic polymer adhesive is (i) having a carboxyl group (-COOH) as a functional group, and (ii) a carboxyl group (-COOH) and a hydroxyl group (-OH) as a functional group. Transdermal absorbent, characterized in that at least one selected from the group. The transdermal absorption agent according to claim 1, wherein the transdermal absorption enhancer is a C8-C18 fatty acid, a derivative thereof, or a surfactant. The method of claim 1, wherein the transdermal absorption enhancer is at least one selected from the group consisting of oleic acid, palmitic acid, stearic acid, lauric acid, sorbitan monooleate, propylene glycol monolaurylate, and monoolein glycol. Characterized by a transdermal absorbent. The transdermal absorption agent according to claim 1, wherein the transdermal absorption enhancer contains 0.5 to 2 equivalents based on 1 equivalent of ropinirole vitreous. delete According to claim 1, wherein the drug-containing adhesive layer further comprises an antioxidant,
The antioxidant is at least one selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid, tocopherol, tocopherol acetate, ascorbyl palmitate, and cetylpyridium chloride. transdermal absorbent. The transdermal absorbent according to claim 1, wherein the drug-containing adhesive layer further comprises a solubilizing agent. 11. The method of claim 10, wherein the solubilizing agent is propylene glycol, propylene glycol monocaprelate, propylene glycol monolaurate, propylene glycol ricinoleide, propylene glycol monooleate, propylene glycol dicaprelate, propylene glycol diocta The drug-containing adhesive layer capable of using noate or the like further comprises a pH adjusting agent. The transdermal absorbent according to claim 10, wherein the solubilizing agent is a surfactant.

Images