KR101688061B1 - Transdermal drug delivery system comprising pilocarpine - Google Patents

Abstract

More particularly, the present invention relates to a percutaneously absorbable preparation comprising a drug-containing matrix layer formed on at least one surface of a support layer, the matrix layer comprising an active ingredient and a pressure-sensitive adhesive Wherein the active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof and the pressure-sensitive adhesive comprises an acrylate-based polymer having a hydroxyl group or no functional group. INDUSTRIAL APPLICABILITY The percutaneous absorption preparation of the present invention has an excellent skin permeability of pilocarpine and has an effect of being able to adhere to the skin surface for a long time without peeling off due to sweating caused by the side effects of pilocarpine.

Description

TRANSDERMAL DRUG DELIVERY SYSTEM COMPRISING PILOCARPINE [0002]

The present invention relates to a pillocarpine transdermal absorption preparation.

At ages 60 and older, saliva (saliva) and tear secretion are significantly reduced as compared with young adults due to aging, and this remarkable decrease in saliva secretion may lead to dry mouth or dry eye syndrome. These oral and ocular dryness symptoms are accompanied by persistent pain in everyday life, and development of a therapeutic agent for this is required.

There are three types of dry mouth syndrome. 1) Sjören syndrome or radiotherapy. 2) Side effects of drugs such as anticholinergics, coagulants and diuretics. 3 ) Is due to senility, hypertension, diabetes, and mouth breathing.

 Particularly, in view of the quality of life aiming at improving the quality of life of the aged society and patients, interest in treatment of dry mouth is increasing, and the development of the therapeutic agent is desperate.

For the treatment of ocular and dry mouth, pilocarpine, which promotes salivation, may be used as an agonist of parasympathetic nerves (Pharm. Research 9 (8) 1992, 1064-1069;

Pilocarpine is a parasympathetic alkaloid extracted from the leaves of a tropical American shrub, genus Pilocarpus, and is a (3S, 4R) -3-Ethyl-4 - ((1-methyl- 5-yl) methyl) dihydrofuran-2 (3H) -one, and a compound of the following formula (1): Widely used for applications such as dry mouth or glaucoma.

[Chemical Formula 1]

However, it has been reported that the oral administration of pilocarpine results in a transient effect and can not provide a continuous therapeutic effect.

In addition, pilocarpine should be more prone to long-term administration to patients with hypertension or Parkinson's disease or similar symptoms that are frequent in the elderly due to excitatory effects on the central nervous system and myocardium (Oral Therefore, it is preferable to use a preparation form such as an oral preparation or an injectable preparation which can be withdrawn at any time, rather than a preparation which can not be taken out once in a living body (see, for example, Surg. 61 (3) 1986. 243-248 .

Therefore, the topical application of the percutaneously absorbable preparation can be a solution, and is highly desirable.

Although a percutaneous delivery agent is considered to be preferable as a delivery method of the pillocarpin component, the percutaneous agent has the following problems.

First, in the percutaneous preparation, the skin becomes a strong barrier against drug permeation from the outside, so it is very difficult to transdermally absorb a sufficient amount of medicine for treatment.

In addition, pilocarpine promotes saliva secretion, but at the same time has a sweating action as a side effect (WIKIPEDIA "Pilocarpine", http://en.wikipedia.org/wiki/Pilocarpine, visited August 26, 2014; Non-patent reference 3). When percutaneous administration of pilocarpine for the purpose of treating dry mouth symptoms, sweating occurs as a side effect, and in the case of a conventional adhesive tape preparation, the skin adhesion force of the adhesive deteriorates due to such sweating, There may arise a problem of peeling.

Accordingly, there is a need for development of a transdermal preparation which can transmit skin-permeability of a pillocarin component more effectively and can maintain a strong adhesive force even under sweating.

A conventional technique for a percutaneous preparation containing pilocarpine as a main component can be understood with reference to U.S. Patent No. 5,869,086 (Patent Document 1).

U.S. Patent No. 5,869,086 discloses a transdermal therapeutic system comprising a support layer and a pressure sensitive adhesive storage layer, wherein the storage layer comprises a polymeric material, a plasticizer, and a phyllocarpine base or a pharmaceutically acceptable salt thereof. .

However, U.S. Patent No. 5,869,086 does not recognize the problem of peeling of the percutaneous preparation by sweating at all, but also has a problem of solving such problems (for example, Component ratio, content ratio, and the like), and have not completely solved the problems in the related art.

As described above, the technology as the background of the invention and the conventional technology have been described. Thus, all of the contents of the above-mentioned non-patent documents 1 to 2 and the patent document 1 are cited as the prior art in this specification, do.

US 5,869,086 A (Mar. 2, 1999)

 Weaver et al., &Quot; Pilocarpine disposition amd salivary flow responses following intravenous administration to dogs ", Pharm. Res. (1992) 9: 1064-1069.  Fox, P.C. et al., " Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction ", Oral Surg. (1986) 61 (3): 243-248.  WIKIPEDIA "Pilocarpine", http://en.wikipedia.org/wiki/Pilocarpine, visited August 26, 2014

An object of the present invention is to provide a percutaneous absorption preparation of pilocarpine which is excellent in the skin permeability of pilocarpine and can be attached to the skin surface for a long time without peeling off due to sweating caused by side effects of pilocarpine It is on.

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems of the prior art,

Wherein the drug-containing matrix layer is formed on at least one surface of the support layer,

Wherein the matrix layer comprises an active component and an adhesive,

Wherein the active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof,

Wherein the pressure-sensitive adhesive comprises an acrylate-based polymer having a hydroxyl functional group or no functional group.

The present invention also provides a percutaneous absorption preparation, wherein the pressure-sensitive adhesive comprises an acrylate-based polymer having a hydroxyl functional group.

Further, in the present invention, the above-mentioned matric layer preferably contains one kind selected from N-dodecyl-2-pyrrolidone, glycerol monooleate, sorbitan monostearate, sorbitan monooleate and propylene glycol monolaurate Or more of the skin permeation enhancer.

The present invention also provides a percutaneous absorption preparation characterized in that the skin permeation enhancer is N-dodecyl-2-pyrrolidone.

In the present invention, the matrix layer may also comprise a percutaneously absorbable preparation comprising pilocarpine, or a pharmaceutically acceptable salt thereof, in an amount of 5 to 20% by weight based on the total weight of the drug-containing matrix layer.

In addition, the application of the percutaneous absorption type preparation of the present invention is an ocular or dry mouth disease.

INDUSTRIAL APPLICABILITY The percutaneous absorption preparation of the present invention has an excellent skin permeability of pilocarpine and has an effect that it can be attached to the skin surface for a long time without peeling off due to sweating caused by side effects of pilocarpine.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross-sectional view showing the structure of one embodiment of the percutaneous absorption preparation of the present invention. Fig.
2 and 3 are graphs showing the skin permeability of the embodiments of the present invention.

Hereinafter, the present invention will be described in detail.

FIG. 1 is a cross-sectional view of one embodiment of the percutaneous absorption type preparation of the present invention. Referring to FIG. 1, one embodiment of the present invention includes a support layer A, a matrix layer B ), And a release layer (C).

First, the matrix layer (B) will be described.

The matrix layer contains a drug, wherein the " drug " includes not only an active ingredient for treating a primary indication but also an auxiliary ingredient (for example, vitamin, coenzyme, etc.) to be.

The matrix layer comprises an active component and a pressure-sensitive adhesive.

The active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof.

The pressure-sensitive adhesive is an acrylate-based polymer.

The term " arcylic-based polymer " is defined as any polyacrylate, polyacrylic polymer, acrylate polymer and acrylic polymer. The acrylic polymer may be any one of a homopolymer, a copolymer, a trimer and the like of various acrylic acids or esters. The acrylic polymer also includes copolymers of alkyl acrylate and / or methacrylate and / or copolymerizable secondary monomers.

As already known, since it exhibits a sweating action as a side effect, it is very likely that the preparation itself is peeled off due to sweating on the application site when applied to transdermal application. In such a situation, Water-soluble polymers such as styrene-butadiene-styrene (SBS), styrene-isoprene-styrene (SIS), styrene-ethylene, -propylene (SEP) The peeling of the preparation can be easily caused by the repulsive action of the agent.

Furthermore, since the pilocarpine is a water-soluble component that is relatively soluble in water, the non-hydrophilic polymer is not preferable from the viewpoint of compatibility with the active ingredient.

Therefore, an acrylate-based polymer exhibiting an appropriate hydrophilic property and an excellent adhesive strength can be preferably selected as the preferable adhesive component in the pillocarpine transdermal absorption preparation of the present invention. More details on this will be understood with reference to Examples and Experimental Examples to be described later.

Particularly, in the present invention, the acrylate-based polymer is preferably an acrylate-based polymer having a hydroxyl functional group or no functional group, and more preferably an acrylate-based polymer having a hydroxyl functional group.

Here, the " functional group " is broadly defined as all types of functional groups having in the acrylic polymer. Examples of the functional group include a carboxyl group, an epoxy group and a hydroxy group.

Examples of the acrylic adhesive polymer having a hydroxyl group include Durotec 87-2510, Durotec 87-2516, Durotec 87-2287, or Gela 787 and Gela 737 supplied by Monsanto Co., and the acrylic adhesive having no functional group Examples of the polymer include Durotech 87-900A, Durotech 87-9301, and Durotech 87-4098 by National Starchyas. Examples of the acrylic adhesive polymer having no functional group include Durotech 87-900A of National Starch, 87-9301, and Durotec 87-4098. Examples of the acrylic adhesive polymer having a carboxyl group include Durotec 87-2196 and Durotec 87-2852 by National Starchy.

However, the acrylic polymer having a carboxyl group has a problem that skin permeability is poor due to interaction with pilocarpine, unlike an acrylate polymer having a hydroxyl group or no functional group. More details on this will be understood with reference to Examples and Experimental Examples to be described later.

The acrylic polymeric adhesive preferably includes 50 to 90% by weight based on the total weight of the drug-containing matrix layer. If the amount of the acrylic polymer is less than 50% by weight, the adhesive strength may deteriorate. If the amount of the acrylic polymer is more than 90% by weight, the amount of the active ingredient may be lowered to lower the skin permeability, But it is not preferable because no further improved adhesion can be expected.

The above-mentioned pillocarpine or a pharmaceutically acceptable salt thereof is preferably contained in an amount of 5 to 20% by weight, more preferably 10 to 15% by weight, based on the total weight of the drug-containing matrix layer. If the amount is less than 5% by weight, not only the skin permeability of the drug is lowered but also the thickness of the matrix layer becomes thick and the adhesion may deteriorate. When the amount exceeds 20% by weight, the matrix layer is not retained due to the physical properties of pilocarpine There may be a problem.

Further, in the present invention, the above-mentioned metric layer may optionally further comprise a skin permeation enhancer. The skin permeation enhancer is a component for assisting the absorption of the active ingredient, pilocarpine, through transdermal preparation, and is a composition for skin permeation enhancers, which is obvious to a person skilled in the art (hereinafter referred to as "a person skilled in the art" Limited use. Examples of such a skin permeation enhancer include polyoxyethylene monooleate, polyglyceryldiisostearate, N-methyl-2-pyrrolidone, N-caprylyl-2 N-carprylyl-2-pyrrolidone, Ndodecyl-2-pyrrolidone, lauryl alcohol, glycerol lauryl alcohol, But are not limited to, oleyl alcohol, isopropyl myristate, sorbitan mono-oleate, propylene monolaurate, propylene monooleate, Oleic acid, oleoyl macrogolglyceride, oleic acid, lauroyl macrogolglyceride, linoleoyl macrogolglyceride, propylene glycol caprylate, propylene glycol But are not limited to, propylene glycol caprate, sorbitan monostearate monooleate, glycerol monolaurate, glycerol monooleate, propyleneglycol monolaurate, propylene glycol monocapryl But are not limited to, propyleneglycol monocaprylate, sorbitan monolaurate, sorbitan monooleate, lauryl lactate, caprylic triglyceride, capric triglyceride, Corn oil PEG-8 ester, corn oil PEG-6 ester, and triacetin.

However, the skin permeation enhancer may be at least one selected from N-dodecyl-2-pyrrolidone, glycerol monooleate, sorbitan monostearate, sorbitan monooleate, and propylene glycol monolaurate , And N-dodecyl-2-pyrrolidone is most preferable from the viewpoint of improving the permeability of the active ingredient. More details on this will be understood with reference to Examples and Experimental Examples to be described later.

The skin permeation enhancer is preferably contained in the range of 0.1 to 40% by weight, more preferably in the range of 5 to 30% by weight, based on the total weight of the drug-containing matrix layer, in consideration of the balance between the adhesive strength and the cohesive force of the matrix layer. Can be added. If the skin permeation enhancer is contained in an amount of less than 0.1% by weight, the skin permeation enhancing effect may be insignificant. If the skin permeation enhancer is contained in an amount exceeding 40% by weight, the adhesive strength may be lowered and the matrix form may become difficult to maintain.

 The thickness of the matrix layer after drying is preferably 10 to 300 탆, more preferably 40 to 200 탆. If the thickness is less than 10 mu m, the amount of the drug contained in the matrix layer is too small to exhibit the effect. When the thickness exceeds 300 mu m, not only the amount of permeation through the skin increases but also, There may be a concern.

Further, in the present invention, the above-mentioned metric layer may optionally further include other additives such as an anti-perspirant, an absorbent material, a cohesive strength enhancer, an adhesion promoter, and an antioxidant.

The antiperspirant may be added to prevent weakening of the adhesive force of the percutaneously absorbable preparation due to side effects of the active ingredient, pilocarpine, and the antiperspirant commonly known to those skilled in the art may be used without limitation, For example, alum, aluminum hydroxide, zinc oxide, calcium oxide, aluminum oxide, calcium hydroxide, potassium alum, calcium citrate, aluminum alum, calcium chloride, calcium hydroxide, aluminum chlorohydrate and potassium alum , Aluminum chlorohydrate, and / or potassium alum may be preferably selected in terms of compatibility.

The antiperspirant is preferably in the range of 0.1 to 20 wt%, more preferably in the range of 0.5 to 10 wt%, based on the total weight of the drug-containing matrix layer. If it is less than 0.1, the anti-perspiration effect may be insignificant. If it is more than 20% by weight, the effect of suppressing sweating may be insignificant but the skin permeability of the active ingredient pilocarpine may be impaired or the property of the matrix layer may be adversely affected And is not preferable.

The absorbent material may be added for the purpose of absorbing perspiration due to side effects of the active ingredient, pilocarpine, to prevent weakening of the adhesive force of the percutaneous absorption preparation. Examples of the water absorbent material that can be used in the present invention include carboxymethylcellulose or its sodium salt, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose polymer, polyethylene oxide, There may be mentioned polyethylene glycol, polyacrylic acid, pectin, guar gum, low casted bean gum, karaya gum, xanthan gum, sodium alginate, calcium alginate, carrageenan, dextrin, gelatin and collagen. Of these, carboxymethyl Cellulose or its sodium salt is preferred.

The water absorbent material is preferably in the range of 1 to 20 wt%, more preferably 1 to 10 wt%, based on the total weight of the drug-containing matrix layer. If the weight average molecular weight is less than 1, the water absorbing effect may be insignificant. If the weight average molecular weight is more than 20 weight%, the properties of the matrix layer such as cohesive failure may be adversely affected.

The cohesion strengthening agent may be added to impart cohesion and retention by the cohesive force of the matrix layer, and silica dimethylsilylate may preferably be used.

The cohesive strength enhancer may be used in an amount of 0.1 to 10% by weight based on the total weight of the drug-containing adhesive layer. When the cohesive strength enhancer is contained in an amount of less than 0.1% by weight, There is a problem.

The adhesive force enhancer is added to improve the adhesive strength of the matrix layer, and includes rosin glycerin ester, hydrogenated rosin glycerin ester rosin pentaerythritol ester, hydrogenated rosin pentaerythritol ester, alpha methyl styrene, alicyclic ring having 5 to 9 carbon atoms An aromatic hydrocarbon resin, a hydrogenated dicyclopentadiene resin, a terpene resin, a coumarone indene resin, and a terpene resin may be used as the curing agent, , But it is not necessarily limited thereto, and rosin glycerin ester is preferably used.

The adhesion-promoting agent is preferably in the range of 1 to 10% by weight based on the total weight of the drug-containing matrix layer. If it is less than 1, the adhesion strengthening effect may be insignificant. If it exceeds 10% by weight, it may adversely affect the physical properties of the matrix layer, which is not preferable.

The antioxidant is used to prevent the molecular structure or the molecular weight of the polymer material used in the adhesive layer from being changed by reacting with light or oxygen to cause molecular cleavage or cross-linking, and specific examples thereof include butyryl Irganox® 565 (manufactured by Ciba-Geigy), Iganox 1010 (manufactured by Ciba-Geigy) and Iganox 1076 (manufactured by Ciba-Geigy) can be mentioned.

The antioxidant is preferably used in an amount of 0.01 to 2% by weight, more preferably 0.1 to 1% by weight, based on the total weight of the drug-containing matrix layer.

Next, the support layer (A) will be described.

The support layer supports at least one side of the drug-containing matrix layer, and should be capable of imparting self-supporting property to the preparation (improvement in handling operability) and preventing curing phenomenon after attachment, and in particular, The effective drug released from the drug should be completely blocked so that the effective drug amount can be prevented from being lowered.

Therefore, the membrane used as the support layer should be impermeable to the active component, and may be permeable or impermeable to air or moisture. As the material of the support layer for this purpose, polyurethane, polyester, polyolefin, polyvinyl chloride, Various plastic films, such as vinylidene and ethylene / vinyl acetate copolymer, pulp, metal foil, and a composite film obtained by laminating them can be used.

In addition, the support layer may be formed of not only a blank sheet but also a porous sheet obtained by perforating the blank sheet such as punching or needling, or a non-porous sheet as an independent foam or a support, A porous fibrous sheet using a foam sheet such as an independent foam, a continuous foam, or a semi-continuous foam, a woven fabric, a nonwoven fabric, a woven fabric, a hollow fiber yarn or the like can be used.

The thickness of the support layer can be changed as necessary by those skilled in the art. However, considering the adhesion to the skin and the feeling of adhesion, the thickness of the support layer is usually 1 to 300 탆, more preferably 5 to 200 탆 have.

Finally, the release layer (C) will be described.

The release layer of the present invention is also used in the art by those skilled in the art as "releasing paper", "release film", "release liner" and the like, and can be selectively formed unlike the support layer or matrix layer which is essentially formed.

The release layer serves to protect the matrix layer during storage of the preparation and is desorbed and removed at the time of use. When the release layer is removed from the matrix layer, the debris of the matrix layer does not remain in the release layer Be removed.

As the material for forming the release layer, a release paper, a metal foil, an aluminum foil and a plastic film which are subjected to a silicone resin treatment or a fluorine resin treatment can be used. More specifically, a silicone-coated polyethylene film or a fluorocarbon acrylic resin Lt; RTI ID = 0.0 > coated paper, < / RTI >

Hereinafter, the present invention will be described in more detail by way of examples. It should be understood, however, that the following examples are for the purpose of illustration only, and are not intended to limit the scope of the invention.

Example

A solution obtained by completely dissolving phylloquinone, a pressure-sensitive adhesive, a skin permeation enhancer and an anti-perspiration agent, an absorbent material, an adhesion-promoting agent and a cohesion-enhancing agent in a solvent in a blending ratio as shown in Tables 1 to 3 was coated on a silicone resin-coated polyester film (About 75 탆 in thickness), dried to form a drug-containing matrix layer having a thickness of about 110 탆, and then lapped with a polyester film (about 12 탆 thick) to prepare a transdermal patch preparation.

The units in Table 1 are the weights of the components in relation to the total weight of the matrix layer.

Experimental Example

Skin permeability test

The percutaneous absorption patch preparations prepared in Examples 1 to 23 were subjected to skin permeation under a sink condition using a Franz diffusion cell (effective area: 0.64 cm 2, volume of aqueous phase: 5.2 ml) Test.

Phosphate buffered saline (PBS), pH 7.4, was used for the aqueous phase.

First, the aqueous phase was filled in a Franz diffusion cell and maintained at 32 ± 0.5 ° C. Then, the sample was cut into a circular shape (area 0.64 cm 2), attached to the center of a human cadaver skin epidermis, The donor portion was covered with a clamp, and then a permeation experiment was carried out.

The skin was purchased from the human cadaver skin epidermis layer and stored at -70 ° C after purchase. The skin was treated at 60 ° C for 1 minute and then only the skin layer was used. The HPLC was used for the analysis. Under the analysis conditions, the mobile phase was a 25:75 (volume ratio) mixed solution of 70 mM ammonium formate (pH 3.8) containing acetonitrile and 0.3% EDTA and 0.005% sodium octyl sulfate , The injection amount was 20 μl, the flow rate was 0.8 ml / min, the detection wavelength was 250 nm, and the C18 reverse phase column was used as the column.

The measurement results for 24 hours are shown in Figs. 1, 2 and 4.

As shown in Table 4, Examples 1-4 showed similar patterns of skin permeability, but in Examples 3 and 4 with hydroxy functionalities, better skin permeability was shown. In contrast, Example 5 showed very low skin permeability due to the interaction of carboxyl group with pilocarpine, and Example 10, which is an aqueous gel preparation, also showed very low skin permeability.

In addition, as can be seen from the comparison between Examples 4 and 11 to 16, it was confirmed that N-dodecyl-2-pyrrolidone was the most excellent in terms of the penetrance of the pilocarpine among various components relating to the skin permeation enhancer , Examples 4 and 17 to 19, it was confirmed that the higher the concentration of the active ingredient of pilocarpine, the higher the skin permeability.

On the other hand, as can be seen from the comparison between Examples 4 and 21, the skin permeability was better when the hydrophilic polymer substance was used than when the anti-perspiration agent was used.

Adhesion test

Tests on the human body adhesiveness were conducted as follows in Examples 1 to 23.

I used stainless steel plate or plastic plate as a test substrate, but it was too easy to compare with stainless steel plate. I could not compare it with the plastic plate, so I could not compare them.

Each of the percutaneous absorption patch preparations of Examples 1 to 23 was cut so as to have a width of 3 cm and a length of 5 cm, and then lightly pressed with a thumb for 20 seconds and then peeled off by sweating for one hour. When peeling, the time of peeling was recorded.

In addition, the values of the adhesive force of the percutaneous absorption patch preparations of Examples 1 to 23 were measured using an auto peeling tester.

The measurement results are shown in Table 5 below.

Whether or not peeling Adhesion (kgf) Example 1 Yes (1 hour) 0.30 Example 2 No 0.30 Example 3 No 0.32 Example 4 No 0.33 Example 5 No 0.26 Example 6 Yes (immediate) No measurement (no stickiness) Example 7 Yes (1 minute) 0.02 Example 8 Yes (immediate) No measurement (no stickiness) Example 9 Yes (immediate) No measurement (no stickiness) Example 17 No 0.34 Example 18 No 0.33 Example 19 No 0.31 Example 20 Not measurable Not measurable
(Matrix layer formation X) Example 21 No 0.32 Example 22 No 0.35 Example 23 No 0.33

In Examples 3 and 4 having a hydroxy group in the pressure-sensitive adhesive component, the adhesive strength was better than that in the case of no functional group.

On the other hand, as can be seen in Examples 6 to 9, since pilocarpine is a water-soluble component, when a rubber-based adhesive is used as a pressure-sensitive adhesive component, phase separation with the active principle occurs and good adhesion can not be expected. 20 could not form the drug-containing matrix layer due to the high solubility of the phyllo-carnitine in the liquid phase and could not be easily crushed and measured for adhesion and peeling.

A: Support layer B: Matrix layer
C: Release layer

Claims (6)

Wherein the drug-containing matrix layer is formed on at least one surface of the support layer,
Wherein the matrix layer comprises an active component and an adhesive,
Wherein the active ingredient is at least 5 wt% and less than 20 wt% pilocarpine or a pharmaceutically acceptable salt thereof, relative to the total weight of the drug-containing matrix layer,
Wherein the pressure-sensitive adhesive comprises an acrylate-based polymer having a hydroxyl group or no functional group. The percutaneous absorption preparation according to claim 1, wherein the pressure-sensitive adhesive comprises an acrylate-based polymer having a hydroxyl functional group. [Claim 3] The method according to claim 1, wherein the matrix layer comprises at least one selected from N-dodecyl-2-pyrrolidone, glycerol monooleate, sorbitan monostearate, sorbitan monooleate, and propylene glycol monolaurate A transdermal absorption enhancer characterized by further comprising a skin permeation enhancer. 4. The percutaneous absorption preparation according to claim 3, wherein the skin permeation enhancer is N-dodecyl-2-pyrrolidone. delete 4. The percutaneously absorbable preparation according to any one of claims 1 to 4, wherein the application of the percutaneously absorbable preparation is ocular or dry mouth.

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