Fentanyl-containing patch for external use

Abstract

A patch for external use which has a laminate structure comprising a substrate and a pressure-sensitive adhesive layer which contains a styrene/isoprene/styrene block copolymer as the base and further contains a tackifier resin consisting of a rosin resin and at least one other tackifier resin, a softening agent consisting of polybutene and liquid paraffin, a fatty acid ester, and fentanyl, characterized in that the weight ratio of the rosin resin to fentanyl is 1 to 5, the weight ratio of the rosin resin to the whole tackifier resin is 0.1 to 0.6, and the tackifier resin accounts for 30 to 60 wt % of the whole pressure-sensitive adhesive layer. The patch is excellent in the permeation of fentanyl through the skin and in storage stability, and is weak in irritation to skin.

Claims

1. An external patch consisting essentially of an adhesive layer laminated on a support, wherein said adhesive layer consists essentially of: a styrene-isoprene-styrene block copolymer (SIS) base component; a tackifier component, wherein the tackifier component consists essentially of a hydrogenated rosin glycerol ester and an alicyclic saturated hydrocarbon resin; a softening component consisting of poly-butene and liquid paraffin; a fatty acid ester component, wherein the fatty acid ester component is isopropyl myristate; fentanyl; and optionally one or more ingredients selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymers, titanium dioxide, silica species, and dibutylhydroxytoluene, wherein: (1) the amount of said rosin resin is 1 to 5 times as much as the amount by weight of fentanyl, (2) the amount of said rosin resin is 0.1 to 0.6 times as much as the total amount by weight of the tackifier component, (3) the amount of said tackifier component is 30 to 60% by weight based upon the total amount of components in the adhesive layer, (4) the ratio by weight of liquid paraffin to poly-butene is 11:10 to 3:1, and (5) the amount of said styrene-isoprene-styrene block copolymer (SIS) base component is 10 to 30% by weight, the amount of said softening component is 5 to 40% by weight, the amount of said fatty acid ester component is 1 to 20% by weight, and the amount of said fentanyl is 0.1 to 10% by weight, based upon the total amount of components in the adhesive layer.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 The FIGURE shows results of plasma concentration assaying on rabbit carried out in Test Example 4.

BEST MODE FOR CARRYING OUT THE INVENTION

(2) The combination ratio of the SIS used as the main base constituent in the pressure-sensitive adhesive layer according to the present invention to the whole pressure-sensitive adhesive layer is preferably 5 to 50% by weight, more preferably 10 to 30% by weight.

(3) The tackifier resins to be incorporated in the pressure-sensitive adhesive layer according to the present invention, which when mixed with the SIS, provide with tackiness to the skin, include rosin resins as well as petroleum resins, polyterpene resins, phenol resins, terpene phenol resins, xylene resins, and the like. As the rosin resins, there may be mentioned rosin esters, hydrogenated rosins, glycerin rosin esters, hydrogenated rosin glycerol esters, rosin acids, polymerized rosins, and the like; hydrogenated rosin glycerol esters are particularly preferred, however.

(4) Preferably used as tackifier resins other than rosin resins are petroleum resins, including aliphatic saturated hydrocarbon resins, alicyclic saturated hydrocarbon resins, aromatic hydrocarbon resins, and the like; among them, alicyclic saturated hydrocarbon resins are more preferred.

(5) The tackifier resins are used in an amount of 30 to 60% by weight to the weight of the whole pressure-sensitive adhesive layer. At levels lower than 30% by weight, tack characteristics unfavorably become poor for a patch, while at levels higher than 60% by weight, the tackiness unfavorably becomes so strong that physical skin irritation occurs on the occasion of peeling off the preparation from the skin.

(6) When the balance between the solubility of fentanyl in the preparation and the percutaneous permeability thereof is taken into consideration, it is effective to add the rosin resin in an amount (at a weight ratio) of 1 to 5 times, preferably 2 to 4 times the amount of fentanyl. At rosin resin levels higher than 5 times the amount of fentanyl, the percutaneous permeability of the drug decreases and, at levels lower than 1 time, the solubility of the drug decreases and unfavorable influences are exerted on the physical characteristics of the preparation, for example crystallization of the main drug component.

(7) The composition ratio (ratio by weight) of the rosin resin to the whole tackifier resin is preferably 0.1 to 0.6, more preferably 0.2 to 0.4. At rosin resin addition levels higher than 0.6 times the amount of the whole tackifier resin component, the percutaneous permeability of the drug decreases and, at levels lower than 0.1 times, the solubility of the drug decreases and unfavorable influences are exerted on the physical characteristics of the preparation, for example crystallization of the main drug component.

(8) The fatty acid ester, when incorporated in the pressure-sensitive adhesive layer according to the present invention, serves as an absorption enhancer, and includes, but is not limited to, isopropyl myristate, diisopropyl adipate, diethyl sebacate, and the like; among them, isopropyl myristate is particularly preferred. The level of addition thereof in the pressure-sensitive adhesive layer is preferably 1 to 20% by weight, more preferably 2 to 10% by weight. When the fatty acid ester level is not higher than 1% by weight, the percutaneous drug permeation becomes insufficient while, at levels not lower than 20% by weight, the cohesive force of the pressure-sensitive adhesive layer decreases, unfavorably causing the problem of the base remaining on the skin.

(9) The softening agent consisting of liquid paraffin and polybutene is incorporated in the pressure-sensitive adhesive layer according to the present invention to soften the pressure-sensitive adhesive and thereby improve the adaptability to the skin and, further, adjust the tackiness and reduce the physical skin irritation and, further, in consideration of the solubility of fentanyl and the effects on the physical characteristics of the preparation; the level of addition thereof is preferably 5 to 40% by weight, more preferably 10 to 30% by weight. At levels lower than 5% by weight, the adaptability to the skin becomes poor and the preparation easily peels off and, at levels higher than 40% by weight, the cohesive force of the pressure-sensitive adhesive decreases and adhesive deposits are unfavorably allowed to remain at the site of application. As for the solubility of fentanyl in liquid paraffin and polybutene, the solubility is higher in polybutene and the solubility of the main drug in the preparation can also be adjusted by the level of addition thereof. The liquid paraffin:polybutene mixing ratio is preferably 0.5:1 to 3:1, more preferably 1:1 to 2:1. When the proportion of liquid paraffin is higher than 3:1, the solubility of fentanyl in the preparation decreases and such an unfavorable influence as crystallization of the main drug is produced and, further, the adhesiveness of the preparation to the skin decreases. When the ratio is lower than 0.5:1, the tackiness becomes excessively strong and the skin irritation becomes strong.

(10) As a base of the adhesive layer other than the SIS, one which is generally used in preparing patch pressure-sensitive adhesive layer is appropriately selected and added according to need for adjusting the adhesiveness and stability of the base. Specifically, water-absorbing macromolecules such as polyvinylpyrrolidone and polyvinylpyrrolidone/vinyl acetate copolymers, inorganic fillers such as titanium dioxide and silica species, dibutylhydroxytoluene (BHT) and the like may be added each at an appropriate level.

(11) Fentanyl is incorporated in the pressure-sensitive adhesive layer according to the present invention preferably in an amount of 0.1 to 10% by weight, more preferably 1 to 8% by weight, most preferably 3 to 8% by weight.

(12) The thickness of the pressure-sensitive adhesive layer according to the present invention is not particularly restricted; however, when the layer is too thin, the adhesive force decreases and, when it is too thick, the amount of the drug remaining unutilized in the preparation increases, the cost increases and the preparation becomes easily peelable upon rubbing against clothing; therefore, the thickness in question is desirably 20 to 100 m.

(13) Generally, it has been revealed that the flexibility and stretchability of a backing in the patch influence the adaptability to the skin and greatly contribute to improved percutaneous drug absorption. Therefore, the backing having high flexibility and stretchability is used in the patch according to the present invention as well and, as such backing, there may be mentioned a low-density polymer film, a nonwoven fabric, a woven fabric, and the like; from the viewpoints of general versatility and economy, among others, a polyethylene terephthalate film is desirable. Thickness of the film is desirably 0.1 to 100 m. When the thickness is in excess of 100 m, the patch can no longer adapt to or follow the unevenness and/or motion of the skin due to the stiffness of the polyethylene terephthalate film, with the result that the percutaneous absorption of the drug decreases.

(14) The patch according to the present invention has a release liner on the pressure-sensitive adhesive layer. As the release liner, used is polyethylene terephthalate, polypropylene or paper, for instance. If necessary, the release liner is silicone-treated for optimizing the release force.

(15) The patch according to the present invention can be prepared, for example, in the following manner.

(16) The base, including the tackifier, is dissolved in an organic solvent, for example toluene, and then agitated and mixed with other components dissolved in an appropriate organic solvent. The obtained solution is applied onto a silicone-treated release liner, followed by 10 minutes of drying at 90 C. to form a pressure-sensitive adhesive layer with a thickness of 20 to 100 m. The obtained pressure-sensitive layer is laminated with a polyethylene terephthalate substrate, followed by cutting to an appropriate size and shape, whereby the percutaneous absorption preparation according to the present invention can be obtained.

EXAMPLES

(17) The following examples illustrate the present invention more specifically. They, however, by no means limit the scope of the present invention. In the examples, part(s) means part(s) by weight, unless otherwise specified.

Examples 1 to 7

(18) According to the formulations given in Table 1, respective patches for external use were produced. The rosin resin/fentanyl ratio (ratio by weight) and the rosin resin/total tackifier resin ratio (ratio by weight) are also shown in the table.

(19) TABLE-US-00001 TABLE 1 Composition Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Styrene-isoprene- 16 16 16 16 16 16 16 styrene block copolymer Hydrogenated rosin 15 5 9 24 10 15 15 glycerol ester Alicyclic saturated 35 45 41 26 40 35 35 hydrocarbon resin Polybutene 10 10 10 10 10 14 6 Liquid paraffin 11 15 11 11 15 7 15 BHT 2 2 2 2 2 2 2 Isopropyl myristate 5 5 5 5 5 5 5 Fentanyl 6 2 6 6 2 6 6 Rosin resin/Fentanyl 2.5 2.5 1.5 4.0 5.0 2.5 2.5 (ratio by weight) Rosin resin/Whole 0.30 0.10 0.18 0.48 0.20 0.30 0.30 tackifier resin (ratio by weight)

Reference Examples 1-5

(20) According to the formulations given in Table 2, respective patches for external use were produced. The rosin resin/fentanyl ratio (ratio by weight) and the rosin resin/total tackifier resin ratio (ratio by weight) are also shown in the table.

(21) TABLE-US-00002 TABLE 2 Ref. Ref. Ref. Ref. Ref. Composition Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Styrene-isoprene-styrene 16 20 16 16 16 block copolymer Hydrogenated rosin 5 4 12 15 15 glycerol ester Alicyclic saturated 20 3 11 35 35 hydrocarbon resin Polybutene 10 10 10 1 20 Liquid paraffin 40 54 38 20 1 BHT 2 2 2 2 2 Isopropyl myristate 5 5 5 5 5 Fentanyl 2 2 6 6 6 Rosin resin/Fentanyl 2.5 2.0 2.0 2.5 2.5 (ratio by weight) Rosin resin/Whole 0.20 0.57 0.52 0.30 0.30 tackifier resin (ratio by weight)

Comparative Examples 1-9

(22) According to the formulations given in Table 3-1 and Table 3-2, patches for external use of Comparative Examples 1 to 6 were prepared according to the production process mentioned above. In Comparative Example 7, a patch was produced referring to Example 1 in WO 2004/024155. In Comparative Example 8, a patch was produced referring to Test Example No. 6 in Japanese Patent Publication 2006-76994. In Comparative Example 9, any patch could not be produced due to lack of cohesive force.

(23) TABLE-US-00003 TABLE 3-1 Comp. Comp. Comp. Comp. Comp. Composition Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Styrene-isoprene-styrene 16 20 16 16 16 block copolymer Hydrogenated rosin 3 8 6 35 3 glycerol ester Alicyclic saturated 47 3 44 15 47 hydrocarbon resin Polybutene 10 10 10 10 10 Liquid paraffin 11 42 16 11 16.5 BHT 2 2 2 2 2 Isopropyl myristate 5 5 5 5 5 Fentanyl 6 10 1 6 0.5 Rosin resin/Fentanyl 0.5 0.8 6.0 5.8 6.0 (ratio by weight) Rosin resin/Whole 0.06 0.73 0.12 0.7 0.06 tackifier resin (ratio by weight)

(24) TABLE-US-00004 TABLE 3-2 Comp. Comp. Comp. Comp. Composition Ex. 6 Ex. 7 Ex. 8 Ex. 9 Styrene-isoprene-styrene 16 8 3 block copolymer Hydrogenated rosin 15 15 glycerol ester Alicyclic saturated 35 44.5 29.2 35 hydrocarbon resin Polybutene 10 Polyisobutylene 8 37.2 (low molecular weight) Polyisobutylene 13 8 26.6 (higher molecular weight) Liquid paraffin 36.7 24 BHT 2 2 Isopropyl myristate 5 5 5 Fentanyl 6 2 2 6 Aluminum silicate 0.8

Test Example 1: Rat Skin Penetration Test In Vitro

(25) The patches of Examples 1, 3, 4, 5, 6 and 7, Reference Examples 1 to 5 and Comparative Examples 3 to 8 were subjected to rat skin penetration test in vitro for fentanyl-release.

(26) A skin segment excised from the rat abdomen of removal of hairs was set on a Franz cell, the cell was filled with phosphate-buffered saline, and warm water at 37 C. was circulated through the water jacket. A circular sample (16 mm in diameter) was punched out from each preparation and applied to the rat excised skin, the receptor liquid was sampled with time, the amount of fentanyl that had permeated was determined by liquid chromatography, and permeation rate (4-12 hr) was calculated. The results thus obtained are shown in Table 4-1, Table 4-2 and Table 4-3.

(27) TABLE-US-00005 TABLE 4-1 Sample Ex. 1 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Fentanyl concentration (%) 6 6 6 2 6 6 Rate of release (g/cm.sup.2/hr) 8.7 8.3 9.3 4.3 9.0 11.7

(28) TABLE-US-00006 TABLE 4-2 Ref. Ref. Ref. Ref. Ref. Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Fentanyl concentration (%) 2 2 6 6 6 Rate of release (g/cm.sup.2/hr) 3.5 5.2 11.9 9.5 8.7

(29) TABLE-US-00007 TABLE 4-3 Comp. Comp. Comp. Comp. Comp. Comp. Sample Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Fentanyl 1 6 0.5 6 2 2 concentration (%) Rate of release 1.7 4.8 0.5 7.1 2.6 2.6 (g/cm.sup.2/hr)

Test Example 2: Stability Test

(30) The preparations of Examples 1, 2, 3 and 4 and Comparative Example 1 to 8 after 3 months of storage at room temperature were subjected to appearance observation by visual inspection; the results are shown in Table 5. The preparations showing precipitation of crystal were evaluated as X and the preparations showing no precipitation of crystal as O.

(31) TABLE-US-00008 TABLE 5 Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Observation result Comp. Comp. Comp. Comp. Comp. Comp. Comp. Comp. Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Observation X X X X result

Test Example 3: Adhesiveness Test

(32) The preparations of Examples 1, 2, 3, 4, 5, 6 and 7, Reference Examples 1 to 5 and Comparative Examples 1 to 8 were each subjected to 180 peeling-off test using a tensile tester (Rheometer CR500DX, product of Sun Scientific Co., Ltd.) to evaluate the adhesiveness. The results thus obtained are shown in Table 6-1, Table 6-2 and Table 6-3.

(33) TABLE-US-00009 TABLE 6-1 Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Adhesiveness (g) 305.3 256.8 522.1 420.0 346.3 688.3 220.1

(34) TABLE-US-00010 TABLE 6-2 Ref. Ref. Ref. Ref. Ref. Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Adhesiveness (g) 8.0 4.7 17.9 144.8 1072.6

(35) TABLE-US-00011 TABLE 6-3 Comp. Comp. Comp. Comp. Comp. Comp. Comp. Comp. Sample Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Adhesiveness 349.9 7.5 225.3 395.8 276.6 481.1 207.6 831.2 (g)

Test Example 4: Rabbit Skin Primary Irritation Test

(36) The patches of Examples 1, Example 2 and Comparative Example 8 were subjected to primary skin irritation testing on rabbits. Each patch was applied to the rabbit back of removal of hairs for 72 hours, and the irritation index (P.I.I.) was determined from the skin symptoms after 1 hour, 24 hours and 48 hours after peeling off. The evaluation criteria and the results are shown in Table 7-1 and Table 7-2, respectively.

(37) TABLE-US-00012 TABLE 7-1 (Evaluation criteria) P.I.I Stability class P.I.I = 0 Nonirritant 0 < P.I.I < 2 Weak irritant 2 P.I.I < 5 Medium irritant 5 P.I.I Strong irritant

(38) TABLE-US-00013 TABLE 7-2 (Result) Sample Ex. 1 Ex. 2 Ex. 5 Ex. 8 Irritation index (P.I.I) 1.8 1.6 2.2 3.0
Discussion
(1) The results shown in Table 4-1 to Table 4-3 revealed that patches of Examples of the present invention are excellent in drug-release. In particular, it was revealed that those patches are excellent in drug-release as compared with the comparative example patches identical in drug concentration. The patches of Comparative Examples 3 to 5, 7 and 8 are considerably inferior in drug-releasing characteristics to the patches of the examples according to the present invention.
(2) The data shown in Table 5 and Table 7-2 revealed that the patches of the examples according to the present invention are superior in stability and safety. Crystal precipitation was observed in Comparative Examples 1, 2, 6 and 8.
(3) Further, the results shown in Table 4-1 to Table 7-1 revealed that the preparations of Comparative Examples 1, 2 and 6 have the problem of principal agent crystallization in the preparation, that the preparations of Comparative Examples 3, 4 and 5 show low levels of main drug-release, and that the preparation of Comparative Example 7 is low in main drug-release and also low in adhesiveness. It was further revealed that the preparation of Comparative Example 8 is low in main drug-release, allows crystallization of the main drug therein and is high in skin irritation although it is high in adhesiveness.

Test Example 5: Rabbit Plasma Concentration Measurement Test

(39) The patch of Example 1 and a commercial product (reservoir-type patch containing fentanyl dissolved in ethanol) were subjected to rabbit plasma fentanyl concentration measurement (each dose being 5 mg). Each patch was applied to the depilated rabbit back for 72 hours, and blood samples were taken at timed intervals and subjected to liquid chromatography for plasma fentanyl concentration determination. The results thus obtained are shown in FIG. 1. It was revealed that the patch of the example according to the present invention is almost comparable to the commercial product in duration of action but shows a higher rate of initial increase in blood drug concentration.

INDUSTRIAL APPLICABILITY

(40) The fentanyl-containing patch for external use according to the present invention is excellent in the permeation of fentanyl through the skin, high in formulation stability during storage and lowly irritant to the skin, and can be used for relieving pain in cancer patients, and the like.