JP2016196426A - Fentanyl containing patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fentanyl containing patch having excellent percutaneous absorbency of fentanyl.SOLUTION: The present invention provides a fentanyl containing patch that comprises fentanyl and/or pharmaceutically acceptable salt thereof and absorption promoter, where the absorption promoter is one or two selected from lauromacrogol and laurylpyrrolidone with the number of addition moles of polyoxyethylene being less than 9.SELECTED DRAWING: None

Description

  The present invention relates to a patch containing fentanyl and / or a pharmaceutically acceptable salt thereof as an active ingredient and having good transdermal absorbability of the drug.

  Fentanyl and fentanyl citrate are synthetic narcotic analgesics that have been confirmed in animal studies to have an analgesic effect approximately 200 times that of morphine. Recently, for the purpose of treating cancer pain, a reservoir-type transdermal preparation containing fentanyl is commercially available. However, the reservoir-type preparation has a fairly slow drug absorption after administration, and does not reach an effective blood concentration until 12 to 24 hours after the first administration. The liquid has the problem of leakage due to its formulation and the disadvantage that it is very irritating at the administration site because it contains ethanol. Furthermore, the reservoir-type preparation is composed of a support, a drug storage layer, a controlled release layer, an adhesive layer, and a release liner, and has a drawback that the manufacturing process is complicated.

  Due to such problems, in recent years, a matrix-type fentanyl-containing patch has been developed. The matrix-type preparation is composed of a support, a drug-containing adhesive layer, and a release liner. The structure is simple compared to the reservoir-type preparation, the manufacturing process is simple, and it can be manufactured at low cost. Therefore, various matrix-type preparations have been studied. For example, as a matrix-type fentanyl-containing patch, a matrix preparation in which fentanyl citrate is added to an adhesive base added with N-methyl-2-pyrrolidone as a solubilizing agent (Patent Document 1), or a base such as fentanyl In order to improve the drug solubility and skin permeability of a sex drug or a salt thereof, a non-aqueous patch (Patent Document 2) containing an organic acid such as acetic acid or a salt thereof has been proposed. In addition, a fentanyl-containing preparation for external use (Patent Document 3) comprising a styrene-isoprene-styrene block copolymer, a tackifier resin, a softener, a fatty acid ester, and fentanyl, a styrene-isoprene-styrene block copolymer, and a tackifier resin , A fentanyl-containing preparation for external use (patent document 4) comprising a softening agent and fentanyl is also disclosed.

JP 2000-044476 A WO2000 / 061120 WO2009 / 096354 WO2011 / 010645

  However, since the preparation described in Patent Document 1 contains volatile N-methyl-2-pyrrolidone as a solubilizing agent, N-methyl-2-pyrrolidone is contained during production or storage. There is a problem that it volatilizes and the drug release ability and drug solubility decrease. In addition, the preparation described in Patent Document 2 has a problem in that the skin permeation rate of the drug rapidly decreases in about 3 to 12 hours after application, and a sustained drug release property cannot be obtained. In addition, the preparation described in the cited reference 3 or 4 is excellent as a preparation for long-term administration, for example, for 3 days, but the drug absorption rate at the initial stage of application is not sufficient, and it is not suitable as a preparation for once-daily administration. It is enough.

  In view of the present situation, the present invention is a patch containing fentanyl and / or a pharmaceutically acceptable salt thereof as an active ingredient, and has excellent fentanyl transdermal absorbability. It is an object of the present invention to provide a fentanyl-containing patch excellent in skin absorption rate and suitable for use as a once-daily preparation.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive studies. As a result, in an adhesive patch containing fentanyl and / or a pharmaceutically acceptable salt thereof and an absorption enhancer, the absorption enhancer is polyoxyl. It is found that the transdermal absorbability of fentanyl is drastically improved when the number of moles of ethylene added is one or two selected from lauromacrogol and laurylpyrrolidone with less than 9 and the present invention is completed. It came to.

  Therefore, the basic aspect of the present invention is that, in a patch containing fentanyl and / or a pharmaceutically acceptable salt thereof and an absorption enhancer, the absorption enhancer has an addition mole number of polyoxyethylene of less than 9. Provided is a fentanyl-containing patch that is one or two selected from lauromacrogol and laurylpyrrolidone.

That is, the present invention
[1] A base comprising one or two absorption enhancers selected from lauromacrogol and laurylpyrrolidone having an addition mole number of polyoxyethylene of less than 9, and fentanyl and / or a pharmaceutically acceptable salt thereof A fentanyl-containing patch comprising a composition comprising a salt;
[2] The fentanyl-containing patch according to the above [1], wherein the base further comprises a fat-soluble polymer, a tackifier resin, and / or an oil and fat;
[3] One type or two or more types in which the fat-soluble polymer is selected from polyisobutylene, polybutene, styrene-isoprene-styrene block copolymer, isoprene rubber, styrene-butadiene-styrene block copolymer, and acrylic polymer A fat-soluble polymer,
The tackifying resin is one or more tackifying resins selected from polyterpene resins, petroleum resins, rosin resins, rosin ester resins, and oil-soluble phenol resins,
The fat is one or more selected from liquid paraffin, squalane, olive oil, camellia oil, and peanut oil,
The patch containing fentanyl according to [2] above;
[4] The fentanyl-containing patch according to the above [2] or [3], wherein the fat-soluble polymer is one or two types of fat-soluble polymer selected from styrene-isoprene-styrene block copolymer and polybutene;
[5] The fentanyl-containing patch according to any one of the above [2] to [4], wherein the fat-soluble polymer is a combination of a styrene-isoprene-styrene block copolymer and polybutene;
[6] The fentanyl-containing patch according to any one of the above [2] to [5], wherein the tackifying resin is an alicyclic saturated hydrocarbon resin; and [7] the oil or fat is liquid paraffin It is related with the fentanyl containing patch as described in any one of [2]-[6].

A preferred embodiment of the present invention is:
[8] The fentanyl-containing patch according to any one of the above [1] to [7], wherein the number of moles of polyoxyethylene added to lauromacrogol is 2 to 4, preferably 2 or 4;
[9] The absorption enhancer is 0.5% to 10% by weight, preferably 1% to 5% by weight of lauromacrogol, or 1% by weight to the total weight of the composition. Fentanyl-containing patch according to any one of [1] to [8] above, which is -15 wt%, preferably 3 wt% to 10 wt% laurylpyrrolidone;
[10] The above [1], wherein the amount of fentanyl and / or a pharmaceutically acceptable salt thereof is 1% to 10% by weight, preferably 2% to 6% by weight, based on the total weight of the composition. -Fentanyl containing patch as described in any one of-[9];
[11] The above-mentioned [2], wherein the fat-soluble polymer contains styrene-isoprene-styrene block copolymer and polybutene in a blending ratio (weight ratio) of 1: 3 to 6: 1, more preferably 4: 1 to 3: 1. ] The patch containing fentanyl according to any one of [10];
[12] Any one of the above [2] to [11], wherein the amount of the fat-soluble polymer is 10% to 30% by weight, preferably 15% to 25% by weight, based on the total weight of the composition A patch containing fentanyl according to claim 1;
[13] Any one of the above-mentioned [2] to [12], wherein the compounding amount of the tackifying resin is 20% to 80% by weight, preferably 40% to 60% by weight, based on the total weight of the composition [14] The above-mentioned [2] to [2], wherein the amount of the fentanyl-containing patch; and [14] Oil and fat is 5% to 40% by weight, preferably 10% to 30% by weight, based on the total weight of the composition 13]. The fentanyl-containing patch according to any one of [13].

Another aspect of the present invention provides:
[15] The fentanyl-containing patch according to any one of the above [1] to [14], wherein the base further comprises a base; and [16] the above [1], wherein the base further comprises an antioxidant. It is related with the fentanyl containing patch as described in any one of-[15].

Yet another aspect of the present invention provides:
[17] A method for treating or preventing cancer pain or chronic pain, comprising a step of administering the fentanyl-containing patch according to any one of [1] to [16] above;
[18] A fentanyl-containing patch according to any one of [1] to [16] above for treating or preventing cancer pain or chronic pain;
[19] Use of the fentanyl-containing patch according to any one of [1] to [16] above in the manufacture of an analgesic for the treatment or prevention of cancer pain or chronic pain; and [20] The fentanyl-containing patch according to any one of the above [1] to [16] for use in the treatment or prevention of cancer pain or chronic pain.

  According to the present invention, in a patch containing fentanyl and / or a pharmaceutically acceptable salt thereof and an absorption enhancer, the absorption enhancer is lauromacrogol and lauryl having an addition mole number of polyoxyethylene of less than 9. When it is one or two selected from pyrrolidone, it has a good absorption promoting effect in human skin, and as a transdermal absorption-type preparation to be applied to humans, fentanyl-containing patch An agent can be provided.

  That is, the fentanyl-containing patch provided by the present invention exhibits good fentanyl transdermal absorbability and is very effective as an analgesic for the treatment or prevention of cancer pain and chronic pain. .

Regarding the fentanyl-containing patch of Example 1 of the present invention, in comparison with each patch of Comparative Examples 1, 7, 8, 9, and 10, the cumulative drug permeation amount that is a parameter serving as an index of transdermal absorbability ( It is the figure which showed (microgram / cm < ² > / hr).

  Hereinafter, the fentanyl-containing patch of the present invention will be described in more detail. The patch of the present invention is a preparation containing at least a support and a composition, and includes both a so-called reservoir-type preparation and a matrix-type preparation.

  When comparing the above two types of dosage forms, in general, a matrix-type preparation in which a self-adhesive composition directly adheres to the skin has better adhesion and better drug permeability to the skin. Therefore, this dosage form is suitable for a transdermal preparation containing a systemic drug such as fentanyl. Hereinafter, the fentanyl-containing patch of the present invention will be described mainly using a matrix-type preparation as an example, but the present invention is not limited thereto. In a matrix type preparation, the composition forms an adhesive layer having self-adhesive strength.

  The present invention is a patch having a composition comprising fentanyl and / or a pharmaceutically acceptable salt thereof, lauromacrogol having an addition mole number of polyoxyethylene of less than 9 as an absorption enhancer, or laurylpyrrolidone, Or it is characterized by including both.

  When lauromacrogol is blended as an absorption promoter in the composition of the present invention, the number of moles of polyoxyethylene added is less than 9, that is, 2 to 8, preferably 2 to 4 in terms of transdermal absorbability. And more preferably 2 or 4. When a polyoxyethylene having an addition mole number of 9 or more is blended, a sufficient absorption promoting effect cannot be obtained. Various lauromacrogols having different numbers of added moles can be produced by a synthetic method, or can be obtained commercially.

  Moreover, the compounding quantity of the said lauromacrogol mix | blended with a composition is 0.5 weight%-10 weight% with respect to the composition total weight, and it is still more preferable that it is 1 weight%-5 weight%. If the blending amount is less than 0.5% by weight, the effect of promoting the absorption of the drug is not recognized. If the blending amount exceeds 10% by weight, the absorption promoter causes phase separation in the composition, resulting in adhesive strength. It is not preferable because the physical properties of the adhesive deteriorate, such as a decrease in the thickness.

  On the other hand, when lauryl pyrrolidone is blended in the composition as an absorption accelerator, the blending amount is preferably 1% by weight to 15% by weight with respect to the total weight of the composition, and is 3% by weight to 10% by weight. It is more preferable. If the blending amount is less than 1% by weight, the effect of promoting absorption is not observed. Conversely, if blending more than 15% by weight, phase separation occurs and the adhesive properties deteriorate, which is not preferable.

  Furthermore, lauromacrogol and laurylpyrrolidone can be combined and blended. In this case, the preferable blending amount is preferably 1.5% by weight to 15% by weight and more preferably 4% by weight to 10% by weight with respect to the total weight of the composition.

  The amount of fentanyl and / or a pharmaceutically acceptable salt thereof to be blended in the composition of the present invention is preferably 1% by weight to 10% by weight, more preferably 2% by weight to the total weight of the composition. 6% by weight. The pharmaceutically acceptable salt of fentanyl is not particularly limited, but fentanyl citrate is preferred.

  The composition of the present invention appropriately contains a fat-soluble polymer, a tackifier resin, and / or fats and oils as a base component.

The fat-soluble polymer to be blended in the composition of the present invention is not particularly limited, but is polyisobutylene (PIB), polybutene, styrene-isoprene-styrene block copolymer (SIS copolymer), isoprene rubber, styrene-butadiene. A styrene block copolymer (SBS copolymer) and an acrylic polymer (2-ethylhexyl acrylate, vinyl pyrrolidone, vinyl acetate, methacrylate, methoxyethyl acrylate, acrylic acid, and octyl acrylate) A copolymer using a kind of compound as a monomer) and the like, and these can be used alone or in combination of two or more. Among these, it is preferable to use one or more selected from SIS copolymers, polybutenes, and acrylic polymers. In particular, in the patch containing fentanyl of the present invention, considering the balance between the solubility of the drug in the base and the release of the active ingredient, only the SIS copolymer is used, or the SIS copolymer and polybutene are used in combination. It is preferable to do this. Particularly preferably, a SIS copolymer and polybutene are used in combination. The blending ratio (weight ratio) of the SIS copolymer and polybutene is preferably 1: 3 to 6: 1, more preferably 4: 1 to 3: 1.
The blending amount of the fat-soluble polymer in the composition is preferably 10% by weight to 30% by weight and more preferably 15% by weight to 25% by weight with respect to the total weight of the composition.

In the present invention, a tackifier resin can be blended with the composition in order to impart tackiness to the patch. Examples of tackifying resins include polyterpene resins, petroleum resins, rosin resins, rosin ester resins, and oil-soluble phenol resins, and these can be used alone or in combination. Among these, it is preferable to use a petroleum resin in consideration of the balance between the drug release property and the drug stability in the base. Petroleum resins include alicyclic saturated hydrocarbon resins, aliphatic saturated hydrocarbon resins, and aromatic saturated hydrocarbon resins, and it is preferable to blend alicyclic saturated hydrocarbon resins.
The compounding amount of the tackifying resin in the composition is preferably 20% by weight to 80% by weight and more preferably 40% by weight to 60% by weight with respect to the total weight of the composition. If the blending amount of the tackifying resin is less than 20% by weight, the tackiness is lowered, which is not preferable. Moreover, when there are more compounding quantities than 80 weight%, the composition of a patch will become hard and an adhesive force will also fall here.

  Moreover, fats and oils can also be mix | blended with a composition as a softening agent for the improvement of the workability of the patch of this invention, and adjustment of adhesiveness. As the fats and oils, for example, liquid paraffin, squalane, olive oil, camellia oil, peanut oil and the like can be used, and one or a mixture of two or more thereof can be used, and liquid paraffin is particularly preferable. The blending amount of fats and oils is preferably 5% by weight to 40% by weight and more preferably 10% by weight to 30% by weight with respect to the total weight of the composition.

  In addition, in the composition of the present invention, various base components used in usual external preparations can be used as long as they do not adversely affect the physical properties of the patch. The base component is not particularly limited, but for example, capric acid, caprylic acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl Alcohol, cetyl alcohol, methyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, diethyl sebacate, hexyl laurate, oleyl oleate, salicylic acid, methyl salicylate, ethylene glycol salicylate, crotamiton, etc. Plasticizers; water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid; ethyl cellulose, hydroxypropyl cellulose, and hydroxy Cellulose derivatives such as propylmethylcellulose; silicon compounds such as silicic anhydride and light anhydrous silicic acid; surfactants such as polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and sorbitan fatty acid ester; oxidation Examples thereof include zinc, aluminum oxide, titanium dioxide, silicas, magnesium oxide, iron oxide, inorganic fillers such as zinc stearate and magnesium stearate; and antioxidants such as dibutylhydroxytoluene.

In addition, when a pharmaceutically acceptable salt of fentanyl is blended with the base of the present invention, a base is preferably blended for the purpose of desalting the salt. The base is not limited, but amines are preferably used, and monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine are particularly preferable.
Furthermore, a preservative, a refreshing agent, a bactericidal agent, a flavoring agent, and / or a coloring agent can be added to the composition of this invention as needed.

The support of the patch of the present invention is not particularly limited, and a stretchable or non-stretchable one is used.
Specifically, a film or sheet formed of a synthetic resin such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, and polyurethane, or a laminate thereof, porous A film, a foam, a woven fabric, a non-woven fabric, or a paper material can be used.

In the patch of the present invention, the composition laminated on the support may be covered with a release liner. The release liner is not particularly limited as long as it can stably protect the surface of the composition, and polyethylene terephthalate, polypropylene, paper, and the like can be used, and polyethylene terephthalate is particularly preferable.
The release liner may be siliconized as necessary to optimize the release force.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples of the present invention. However, the present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention. Can be changed.
In addition, the compounding quantity of each component in the composition of an Example, a comparative example, and a prescription example is all displayed by the unit of "weight%".

<Examination of absorption promotion effect by Lauromacrogol 1 (comparison with various surfactants)>
Example 1
〔Production method〕
Toluene is added to fentanyl and dissolved, and styrene-isoprene-styrene block copolymer (SIS copolymer), alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries), liquid paraffin are dissolved in the solution. , Polybutene, dibutylhydroxytoluene, and lauromacrogol (BL-2, number of added moles: 2, manufactured by Nikko Chemicals Co., Ltd.), and each component of the composition shown in Table 1 and a toluene solution (coating solution) Prepared.
Next, the obtained coating solution is coated on a polyethylene terephthalate release paper so that the thickness after drying is about 50 to 60 μm, and the solvent is removed by drying to form a pressure-sensitive adhesive layer. A support made of polyethylene terephthalate was bonded to the adhesive layer to obtain the intended patch.

  As comparative examples, in the patch of Example 1, a patch containing no lauromacrogol (Comparative Example 1) and polyoxyethylene hydrogenated castor oil (Comparative Example 2), monooleic acid instead of lauromacrogol, respectively. Lauromacro was prepared by preparing a patch containing sorbitan (Comparative Example 3) and polyethylene glycol monolaurate (Comparative Example 4) and comparing with various surfactants conventionally used as a general absorption accelerator. The percutaneous absorbability of the goal was evaluated. The patches of each comparative example were prepared as follows.

〔Production method〕
(A) Comparative Example 1
Toluene is added to fentanyl and dissolved, and SIS copolymer, alicyclic saturated hydrocarbon resin, liquid paraffin, polybutene, and dibutylhydroxytoluene are added, and a coating solution comprising each component having the composition shown in Table 1 and toluene Was prepared.
The obtained coating solution was applied in the same manner as in Example 1 to prepare a patch.

(B) Comparative example 2
According to the composition shown in Table 1, polyoxyethylene hydrogenated castor oil was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(C) Comparative Example 3
According to the composition shown in Table 1, sorbitan monooleate was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(D) Comparative Example 4
According to the composition shown in Table 1, polyethylene glycol monolaurate was added to the composition of Comparative Example 1, the blending amount of liquid paraffin was changed, and a patch was produced by the same production method as Comparative Example 1.

  The following in vitro skin permeability test was conducted on the obtained patches of Example 1 and the patches of Comparative Examples 1 to 4.

[Test Example 1] In vitro skin permeability test <Method>
The white male thigh-extracted skin was treated with dermatol, and the thickness was adjusted to 500 to 1000 μm. The skin was attached to a Franz-type flow-through cell in which 37 ° C. warm water was circulated around the outer periphery so as to be a receptor tank.
Next, a patch (formulation area: 1.5 cm ² ) is applied to the stratum corneum side of the skin, and a pH 7.4 phosphate buffer solution is used as the receptor solution every 3 hours at 3 mL / hr. The receptor solution was sampled up to 24 hours, its weight was measured, and the drug concentration was measured using HPLC.
The accumulated drug permeation amount after 24 hours was calculated from the obtained measured values and summarized in Table 2.

  From the results shown in Table 2, the patch of Example 1 in which lauromacrogol was blended as an absorption accelerator was compared with the patch of Comparative Example 1 in which no surfactant was blended and Comparative Example 2 in which various surfactants were blended. The fentanyl transdermal absorbability was significantly higher than the -4 patches.

<Examination of absorption promotion effect by difference in added mole number of polyoxyethylene chain>
In the patch of Example 1, instead of lauromacrogol (BL-2, addition mole number: 2), lauromacrogol (BL-4.2) (addition mole number: different mol number of polyoxyethylene chain) was different. 4, patch preparations containing Example 2) and BL-9EX (addition moles: 9, comparative example 5) were respectively prepared, and the transdermal absorption promotion effect of fentanyl by the difference in the addition moles of the polyoxyethylene chain Was evaluated.

〔Production method〕
(Example 2)
According to the composition shown in Table 3, a patch was prepared in the same manner as in Example 1, except that Lauromacrogol (BL-4.2) was used instead of Lauromacrogol (BL-2) in Example 1. did.

(Comparative Example 5)
According to the composition shown in Table 3, a patch was prepared in the same manner as in Example 1, except that Lauromacrogol (BL-9EX) was used instead of Lauromacrogol (BL-2) in Example 1.

[Test Example 2] In Vitro Skin Permeability Test For the patches of Example 2 and Comparative Example 5 obtained above and the patches of Example 1 and Comparative Example 1 as control preparations, the method of Test Example 1 In vitro skin permeability test was performed. However, the specimen used was a white male dorsal skin.
Table 4 shows the obtained results.

  From the results shown in Table 4, the patch of each example in which lauromacrogol having an addition mole number of polyoxyethylene chain of 2 or 4 was blended with that of comparative example 5 in which lauromacrogol having an addition mole number of 9 was blended. Compared with the patch, it showed significantly higher transdermal absorbability of fentanyl.

<Examination of absorption promotion effect of lauryl pyrrolidone>
In the patch of Example 1, a patch (Example 3) containing fentanyl citrate and diisopropanolamine instead of fentanyl, and lauryl pyrrolidone instead of lauromacrogol (BL-2, added mole number: 2) A patch (Example 4) was prepared and evaluated for percutaneous absorption.

〔Production method〕
Example 3
According to the composition shown in Table 5, fentanyl citrate and diisopropanolamine were added instead of fentanyl in Example 1, and the blending amount of liquid paraffin was changed to prepare a patch in the same manner as in Example 1.

Example 4
According to the composition shown in Table 5, lauryl pyrrolidone was added instead of lauromacrogol (BL-2) in Example 1, the amount of liquid paraffin was changed, and a patch was prepared in the same manner as in Example 1.

[Test Example 3]: In Vitro Skin Permeability Test According to the method of Test Example 1, each of the patches of Examples 3 and 4 obtained above and Examples 1 and Comparative Examples 1 as control preparations was tested in vitro. A skin permeability test was performed. However, the specimen used was a white male dorsal skin.
The results obtained are shown in Table 6.

  From the results shown in Table 6, the patch of Example 4 containing lauryl pyrrolidone as an absorption enhancer showed significantly higher fentanyl transdermal absorbability than the patch of Comparative Example 1 containing no absorption enhancer. The transdermal absorbability of fentanyl was almost the same as that of a patch containing lauromacrogol.

<Examination of absorption promotion effect by Lauromacrogol 2 (comparison with various fatty acid esters)>
As comparative examples, in the patch of Example 1, instead of lauromacrogol, isopropyl myristate (Comparative Example 6), diethyl sebacate (Comparative Example 7), hexyl laurate (Comparative Example 8), and oleyl oleate (Comparative Example 8) Patches each containing Comparative Example 9) were prepared, and the transdermal absorbability of lauromacrogol was evaluated by comparison with various fatty acid esters conventionally used as general absorption accelerators.

〔Production method〕
(A) Comparative Example 6
According to the composition shown in Table 7, isopropyl myristate was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(B) Comparative Example 7
According to the composition shown in Table 7, diethyl sebacate was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(C) Comparative Example 8
According to the composition shown in Table 7, hexyl laurate was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(D) Comparative Example 9
According to the composition shown in Table 7, oleyl oleate was added to the composition of Comparative Example 1, the blending amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

[Test Example 4] In Vitro Skin Permeability Test According to the method of Test Example 1, in vitro skin was applied to each of the patches of Comparative Examples 6 to 9 obtained above and Example 1 and Comparative Example 1 as control preparations. A permeability test was performed. However, the specimen used was a white male dorsal skin.
Table 8 shows the obtained results.

  From the results shown in Table 8, the patch of Example 1 formulated with lauromacrogol as an absorption enhancer was significantly higher in fentanyl transdermal than the patches of Comparative Examples 6-9 blended with various fatty acid esters. Absorbability was shown.

<Examination of absorption promotion effect by Lauromacrogol 3 (Comparison with organic acids and alcohols)>
As a comparative example, the patch of Example 1 contains oleic acid (Comparative Example 10) and lauryl alcohol (Comparative Example 11), which are conventionally used as general absorption promoters, respectively, instead of lauromacrogol. A patch was prepared and the percutaneous absorbability was evaluated.

〔Production method〕
(A) Comparative Example 10
According to the composition shown in Table 9, oleic acid was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

(B) Comparative Example 11
According to the composition shown in Table 9, lauryl alcohol was added to the composition of Comparative Example 1 to change the blending amount of liquid paraffin, and a patch was prepared by the same production method as Comparative Example 1.

[Test Example 5] In Vitro Skin Permeability Test According to the method of Test Example 1, the in vitro skin of Comparative Patches 10 and 11 obtained above and the patches of Example 1 and Comparative Example 1 as control preparations were used. A permeability test was performed. However, the specimen used was a white male dorsal skin.
Table 10 shows the obtained results.

  From the results shown in Table 10, the patch of Example 1 formulated with lauromacrogol as an absorption promoter was significantly higher in fentanyl compared to the patches of Comparative Examples 10 and 11 blended with organic acids and alcohols, respectively. It showed transdermal absorbability.

<Examination of absorption effect by Lauro Macrogol 4 (comparison with Crotamiton)>
As a comparative example, in the patch of Example 1, a patch (Comparative Example 12) containing crotamiton, which has been conventionally used as a general absorption accelerator, was prepared instead of lauromacrogol, and percutaneous absorption was performed. Sexuality was evaluated.

〔Production method〕
(A) Comparative Example 12
According to the composition shown in Table 11, crotamiton was added to the composition of Comparative Example 1, the amount of liquid paraffin was changed, and a patch was prepared by the same production method as Comparative Example 1.

[Test Example 6] In Vitro Skin Permeability Test According to the method of Test Example 1, the in vitro skin permeability of each of the patches of Comparative Example 12 obtained above and Example 1 and Comparative Example 1 as a control preparation was determined. A test was conducted. The specimen was skin removed from a white male thigh.
The results obtained are shown in Table 12.

  From the results shown in Table 12, the patch of Example 1 formulated with lauromacrogol as an absorption accelerator showed significantly higher transdermal absorbability of fentanyl compared to the patch of Comparative Example 12 formulated with crotamiton. .

  As described above, as shown in each test example, it was found that the cumulative drug permeation amount was significantly higher in the human skin than in the respective patches of the comparative examples. That is, it can be seen that lauromacrogol and laurylpyrrolidone have an exceptionally superior absorption promoting effect on fentanyl as compared with other absorption promoters conventionally used as general absorption accelerators. It was. In particular, in the case of Lauromacrogol, this absorption promotion effect was confirmed only when the number of added moles of the polyoxyethylene chain was less than 9.

(Prescription Examples 1-7)
Table 13 shows a prescription example as a prescription showing the same effect as the example.
In the patch of Example 1, fentanyl was changed to fentanyl citrate, the amount of liquid paraffin was appropriately changed, and various amines (monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, or triisopropanolamine) ) Was added.

  As described above, the present invention can provide a fentanyl-containing patch exhibiting excellent fentanyl transdermal absorbability. Therefore, the present invention is very useful for the treatment or prevention of diseases such as pain such as cancer pain and chronic pain.

Claims (7)

  A base containing one or two absorption enhancers selected from lauromacrogol and laurylpyrrolidone having an addition mole number of polyoxyethylene of less than 9 and fentanyl and / or a pharmaceutically acceptable salt thereof A patch containing fentanyl, comprising the composition.   The fentanyl-containing patch according to claim 1, wherein the base further comprises a fat-soluble polymer, a tackifier resin, and / or an oil. One or more fat-soluble polymers selected from the group consisting of polyisobutylene, polybutene, styrene-isoprene-styrene block copolymer, isoprene rubber, styrene-butadiene-styrene block copolymer, and acrylic polymer Polymer,
The tackifying resin is one or more tackifying resins selected from polyterpene resins, petroleum resins, rosin resins, rosin ester resins, and oil-soluble phenol resins,
The fat is one or more selected from liquid paraffin, squalane, olive oil, camellia oil, and peanut oil,
The patch containing fentanyl according to claim 2.   The fentanyl-containing patch according to claim 2 or 3, wherein the fat-soluble polymer is one or two fat-soluble polymers selected from styrene-isoprene-styrene block copolymers and polybutene.   The fentanyl-containing patch according to any one of claims 2 to 4, wherein the fat-soluble polymer is a combination of a styrene-isoprene-styrene block copolymer and polybutene.   The fentanyl-containing patch according to any one of claims 2 to 5, wherein the tackifying resin is an alicyclic saturated hydrocarbon resin.   The fentanyl-containing patch according to any one of claims 2 to 6, wherein the fat is liquid paraffin.

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