Felbinac-containing external patch

Abstract

Provided is a felbinac-containing external patch which can exhibit high drug release properties, low skin irritation, and high drug stability, wherein felbinac having an average particle diameter of 5 μm or more and less than 100 μm is dispersed and mixed in an adhesive base including a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, a softener, and diethyl sebacate, and does not contain L-menthol. Specifically, in the felbinac-containing external patch, 0.1 to 10% by weight of felbinac having an average particle diameter of 5 μm or more and less than 100 μm is dispersed and mixed in an adhesive base including 10 to 30% by weight of a styrene-isoprene-styrene block copolymer, 10 to 50% by weight of an alicyclic saturated hydrocarbon resin, 10 to 75% by weight of a softener, and 0.1 to 10% by weight of diethyl sebacate.

Claims

1. A felbinac-containing external patch wherein 0.1 to 10% by weight of felbinac, having an average particle diameter of 5 μm or more and less than 100 μm, is dispersed and mixed in an adhesive base comprising: 10 to 30% by weight of a styrene-isoprene-styrene block copolymer, 10 to 50% by weight of an alicyclic saturated hydrocarbon resin, 10 to 75% by weight of a softener, and 0.1 to 10% by weight of diethyl sebacate, wherein the patch does not contain L-menthol, wherein the weight ratio of felbinac to diethyl sebacate is in the range of 1:0.1 to 1:15, and wherein the % by weight of said components are relative to the weight of the adhesive base.

Description

EXAMPLES

(1) Hereinafter, the present invention will be specifically described in detail with reference to Examples. However, the present invention is not limited to these examples.

(2) In each Table in Examples and Comparative Examples, the amount of added component is represented by % by weight unless otherwise specified.

Example 1

(3) SIS, polybutene, liquid paraffin, and dibutyl hydroxy toluene were kneaded under a heating condition of 170° C. and dissolved. Then, an alicyclic saturated hydrocarbon resin was added, and the mixture was kneaded under a heating condition of 130° C. and mixed to prepare an adhesive base.

(4) Separately, felbinac having an average particle diameter of 5 μm or more and less than 100 μm was uniformly dispersed in a mixing liquid of diethyl sebacate and an appropriate amount of liquid paraffin under stirring to prepare a felbinac dispersion solution. The felbinac dispersion solution was added to the adhesive base, and the mixture was kneaded until the felbinac was uniformly dispersed, to prepare an adhesive. The adhesive was spread to a silicone-treated polyethylene terephthalate film so that the thickness was 100 μm, and a polyester woven fabric was laminated thereon to obtain a test preparation.

Examples 2 to 16

(5) Each target patch of the present invention was produced from component compositions shown in Tables 1 to 3 in the same manner as in Example 1.

(6) TABLE-US-00001 TABLE 1 Example Component 1 2 3 4 5 SIS 15 17 20 12 25 Polybutene 5 10 8 4 10 Liquid Paraffin 36 40 33.5 35 39 Dibutylhydroxytoluene 1 1 1 1 1 Alicyclic Saturated hydrocarbon Resin 35 25 30 45 15 Felbinac 4 5 0.5 2 3 Diethyl Sebacate 4 2 7 1 7 Average Particle Diameter of Felbinac 30 30 30 30 30 (μm)

(7) TABLE-US-00002 TABLE 2 Example Component 6 7 8 9 10 SIS 20 15 20 13 16 Polybutene 15 6 9 2 4 Liquid Paraffin 20 34 36 35 34.5 Dibutylhydroxytoluene 1 2 2 2 0.5 Alicyclic Saturated hydrocarbon Resin 40 37 20 42 37 Felbinac 1 3 6 2 5 Diethyl Sebacate 3 3 7 4 3 Average Particle Diameter of Felbinac 30 30 30 30 30 (μm)

(8) TABLE-US-00003 TABLE 3 Example Component 11 12 13 14 15 16 SIS 30 10 26 18 14 15 Polybutene 4 3 3 6 7 5 Liquid Paraffin 37 28 50 33.5 33 36 Dibutylhydroxytoluene 1 2 0.5 2 1 1 Alicyclic Saturated Hydrocarbon 20 50 15 33 38 35 Resin Felbinac 2 6 5 3.5 3.5 4 Diethyl Sebacate 6 1 0.5 4 3.5 4 Averge Particle Diameter of 30 30 30 30 30 18 Felbinac (μm)

Comparative Examples 1 to 7

(9) Each external patch of Comparative Examples was produced in the same manner as in Example 1 except that component compositions shown in Table 4 were used.

(10) In the preparation of Comparative Example 7, felbinac as an active pharmaceutical ingredient was aggregated during the production (preparation of adhesive), and as a result, the preparation had an uneven surface. For this reason, the preparation was not subjected to the following preparation evaluation tests.

(11) TABLE-US-00004 TABLE 4 Comparative Example Component 1 2 3 4 5 6 7 SIS 18 20 15 15 20 15 15 Polybutene 5 5 5 5 5 5 5 Liquid Paraffin 30 35 36 36 35 36 36 Dibutylhydroxytoluene 1 1 1 1 1 1 1 Alicyclic Saturated 35 35 30 35 35 Hydrocarbon Resin Rosin Ester Derivative 35 30 Felbinac 4 2 4 4 2 4 4 Diethyl Sebacate 4 4 4 Crotamiton 4 4 Isopropyl Myristate 4 Disopropyl adipate 4 L-Menthol 3 3 3 Average Particle Diameter of 30 30 30 30 30 3 100 Felbinac (μm)

Test Example 1

Skin Primary Irritation Test on Humans (Human Patch Test)

(12) The preparations in Examples 1 and 2 and Comparative Examples 1 and 2 were each punched to a diameter φ of 25 mm. Each preparation was applied to the inside of the upper arm in 15 healthy men for 24 hours. One hour and 24 hours after peeling off the preparation, skin irritation was judged.

(13) The results are shown in Table 5 below.

(14) TABLE-US-00005 TABLE 5 Number of Person who had Skin irritation at applied site 1 hr. after 24 hrs. after Test Preparation Peeling Off Peeling Off Example 1 0/15 0/15 Example 2 0/15 0/15 Comparative Example 1 3/15 2/15 Comparative Example 2 4/15 3/15

(15) As shown from the results in Table 5, the preparations in Examples 1 and 2 which are each the external patch of the present invention have low skin irritation as compared with Comparative Examples 1 and 2.

Test Example 2

Measurement of Amount of Felbinac Remaining in Used Patches

(16) The preparations in Example 1 and Comparative Examples 3 and 4 were each punched to 5 cm×7 cm. Each preparation was applied to the back in 6 healthy men for 12 hours. A drug remained in each of the collected preparations was extracted and the amount of the drug was measured by HPLC.

(17) The amount of the drug disappeared was calculated by subtracting the amount of drug remained from the amount of drug just before application. The results are shown in Table 6 below.

(18) TABLE-US-00006 TABLE 6 Mount of Drug (Felbinac) Disappeared from Preparation 12 hrs after Application Test Preparation (Mean of 6 Persons) Example 1 1.47 mg Comparative Example 3 0.96 mg Comparative Example 4 0.73 mg

(19) As shown from the results in Table 6, the preparation in Example 1 which is the patch of the present invention has a larger amount of drug disappeared and higher percutaneous absorption properties as compared with Comparative Examples 3 and 4.

Test Example 3

Stability Test

(20) Samples (7 cm×10 cm) in Example 1 and Comparative Examples 2 and 5 were stored at 40° C. for 3 months. After then, the drug in each of the test preparations was extracted and the felbinac content was measured.

(21) The felbinac content was compared with the felbinac content of each sample before the test (initial value). From the comparison, a percentage relative to the initial value (%) was calculated. The results are shown in Table 7.

(22) TABLE-US-00007 TABLE 7 After Storage at 40° C. for 3 months Test Preparation (Relative to Initial Value) Example 1 99.5% Comparative Example 2 96.5% Comparative Example 5 97.8%

(23) As shown from the results in Table 7, Example 1 which is the external patch of the present invention has excellent drug stability as compared with Comparative Examples 2 and 5.

Test Example 4

Release Test of Felbinac (Active Ingredient)

(24) The preparations in Examples 1 and 16 and Comparative Example 6 were each punched to a diameter φ of 20 mm, and attached to the inside of a 100-mL beaker with a double sided tape so that the adhesive side faced the inside of the beaker.

(25) The position of attached preparation was adjusted so that the lowest end of the preparation was located about 30 mm from the bottom of the beaker. After then, 100 mL of release solution (PBS buffer solution) was poured into the beaker, and was stirred with a magnetic stirrer. Ninety minutes after initiation of test, the felbinac content in the release solution was measured by high performance liquid chromatograph, and the release rate of Felbinac (active ingredient) was calculated. The results are shown in Table 8.

(26) TABLE-US-00008 TABLE 8 Release Rate 90 min after Test Preparation beginning of Test (UNIT: %) Example 1 95.8 Example 16 76.5 Comparative Example 6 47.9

(27) As shown from the results in Table 8, Examples 1 and 16 which are the external patch of the present invention have very excellent release properties of Felbinac (active ingredient) as compared with the preparation in Comparative Example 6.

INDUSTRIAL APPLICABILITY

(28) The present invention provides a felbinac-containing anti-inflammatory analgesic external patch which exhibits good drug release properties, low skin irritation, and high drug stability.

(29) The external patch of the present invention is useful for prevention and medical treatment for osteoarthritis, rheumatoid arthritis, low back pain, shoulder periarthritis, tendovaginitis, peritendinitis, lateral humeral epicondylitis (e.g., tennis elbow), myalgia, and swelling and pain after trauma, and is widely applied.