TRANSDERMAL THERAPEUTIC SYSTEMS CONTAINING 4-N-BUTYL-RESORCINOL

Abstract

A method for the treatment of a local pigmentation disorder comprises applying to skin affected by the disorder a transdermal therapeutic system which comprises 4-n-butylresorcinol as an active ingredient.

Claims

1. A method for the treatment of a local pigmentation disorder, wherein the method comprises applying to skin affected by the disorder a transdermal therapeutic system which comprises 4-n-butylresorcinol as an active ingredient.

2. The method of claim 1, wherein the local pigmentation disorder comprises local hyperpigmentation.

3. The method of claim 1, wherein the local pigmentation disorder comprises age spots.

4. The method of claim 1, wherein the local pigmentation disorder comprises freckles.

5. The method of claim 1, wherein the local pigmentation disorder comprises post-inflammatory hyperpigmentation.

6. The method of claim 1, wherein the local pigmentation disorder comprises melasma.

7. The method of claim 1, wherein the transdermal therapeutic system is employed in the form of a self-adhesive flat bandage.

8. The method of claim 1, wherein the transdermal therapeutic system is employed in the form of at least one of a cosmetic plaster and a medicinal plaster.

9. The method of claim 1, wherein the transdermal therapeutic system is employed in the form of a matrix system.

10. The method of claim 9, wherein the matrix is selected from nonpolar matrices based on synthetic and natural rubber, polar wet adhesive films based on polyacrylic acid/polyvinyl alcohol, nonpolar matrices based on polyacrylic acid copolymers, polar anhydrous gel matrices based on polyacrylic acid/polyvinylpyrrolidone, nonpolar polyisobutylene matrices, and polar water gel matrices based on agar agar/polyacrylic acid.

11. The method of claim 9, wherein the matrix is selected from polyisobutylene matrices.

12. The method of claim 9, wherein the matrix is selected from water gel matrices based on agar agar/polyacrylic acid.

13. The method of claim 1, wherein the transdermal therapeutic system comprises from 0.001% to 10% by weight of 4-n-butylresorcinol, based on a total weight of the system.

14. The method of claim 1, wherein the transdermal therapeutic system comprises from 0.01% to 1% by weight of 4-n-butylresorcinol.

15. The method of claim 11, wherein the matrix has a layer thickness of from 0.15 mm to 1.00 mm.

16. The method of claim 12, wherein the matrix has a layer thickness of from 0.15 mm to 1.00 mm.

17. The method of claim 11, wherein the matrix has a layer thickness of from 0.20 mm to 0.50 mm.

18. The method of claim 12, wherein the matrix has a layer thickness of from 0.20 mm to 0.50 mm.

19. The method of claim 1, wherein the transdermal therapeutic system comprises from 0.001% to 10% by weight of one or more penetration accelerators.

20. The method of claim 19, wherein the one or more penetration accelerators comprise at least one of isopropyl palmitate and isopropyl myristate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0031] To produce an effective self-adhesive plaster comprising 4-butylresorcinol with optimized release for the treatment of pigment disorders of the skin, various self-adhesive matrix systems with 1% of the active ingredient were produced and investigated with regard to their release properties after 24 hours on pig skin by means of Franz cells:

[0032] A nonpolar matrix based on synthetic and natural rubber (KA)

[0033] A polar wet adhesive film based on polyacrylic acid/polyvinyl alcohol (FKF)

[0034] A nonpolar matrix based on a polyacrylic acid copolymer (PAC)

[0035] A polar anhydrous gel matrix based on polyacrylic acid/polyvinylpyrrolidone (WFG)

[0036] A nonpolar polyisobutylene matrix (PIB)

[0037] A polar water gel matrix based on agar agar/polyacrylic acid (WG)

[0038] Results of the active ingredient release of different matrix systems:

TABLE-US-00001 (KA) (FKF) (PAC) (WFG) (PIB) (WG) 7.4% 17.8% 18.1% 20.6% 22.2% 34.0%

[0039] Based on the above first results, the nonpolar polyisobutylene matrix and the polar water gel matrix were selected for further optimization experiments with regard to the release of 4-n-butylresorcinol.

[0040] The active ingredient release can advantageously be controlled by virtue of the layer thickness of the TTS.

[0041] For both systems, PIB and WG, in each case samples with a layer thickness of 1.00; 0.75; 0.50; 0.30 and 0.15 mm were produced and investigated.

[0042] Results of the active ingredient release of different matrix layer thicknesses:

TABLE-US-00002 1.00 mm 0.75 mm 0.50 mm 0.30 mm 0.15 mm (PIB) 22.2% 27.4% 26.7% 42.7% 46.4% (WG) 34.0% 48.3% 41.8% 66.2% 56.8%

[0043] As a compromise between percentage active ingredient release, absolute released amount of active ingredient and handlability of the finished self-adhesive plaster, for both matrix systems, a layer thickness between 1.00 mm and 0.01 mm, preferably 0.50 and 0.20 mm and very particularly preferably of 0.30 mm is considered. In particular, the self-adhesive patch based on a polar water gel according to the invention exhibits, with around 65% of the active ingredient, a surprisingly high release compared to customary plaster applications.

[0044] In order to likewise bring the PIB matrix system into this active ingredient release range, further experiments were carried out by means of incorporating customary additives for increasing the hydrophilicity of the matrix, and also customary penetration accelerators.

[0045] The incorporation of 35% cellulose into the PIB matrix revealed no significant difference in the active ingredient release compared with a matrix not filled with cellulose.

[0046] As customary penetration accelerators, in each case 5% isopropyl palmitate (IPP) and 5% isopropyl myristate (IPM) were then incorporated into a corresponding PIB matrix, and the release of 4-n-butylresorcinol from the end products produced therefrom of layer thickness 0.30 mm was determined.

[0047] Results of the PIB matrix active ingredient release of different penetration accelerators:

TABLE-US-00003 PIB matrix PIB matrix plus 5% IPP plus 5% IPM Release of 4-n-butyl-resorcinol 33.2% 61.3%

[0048] Surprisingly, the addition of 5% IPM exhibited almost twice as high an active ingredient release from the PIB matrix as the addition of the homologous penetration accelerator IPP.

[0049] With around 61% release of 4-n-butylresorcinol from the nonpolar PIB matrix, it was possible to achieve an analogous order of magnitude as from the polar water gel matrix with around 65%.

[0050] Examples of the preparation of polar self-adhesive water gel matrices are described in DE 102 60 872.

[0051] Examples of the preparation of nonpolar self-adhesive PIB matrices are described in EP 1335755.

[0052] Suitable carrier materials for polar and nonpolar self-adhesive patches according to the invention with optimized active ingredient release for the treatment of pigment disorders of the skin are all customary flat layered materials such as, for example, woven fabrics, films, nonwoven fabrics etc. In the case of the last-mentioned carrier materials, in particular so-called non-wovens of small layer thickness are advantageous because these are barely noticeable in visual terms on the matrices against the skin. The use of very thin, layer thickness below 100 μm, flexible and transparent to translucent polymer films, in particular those polyurethane films produced from aqueous dispersion, is particularly advantageous.

[0053] However, it is also possible to use films from all other known polymer films, such as e.g. polyethylene, ethylvinylacetate etc. In the case of the polyisobutylene matrix, when using carrier materials with significantly different water vapor transmission rates (WVTR) of 5933.5 g/m.sup.2*24 h (viscose) via 1509.9 g/m.sup.2*24 h (polyurethane) to 25.7 g/m.sup.2*24 h (polyethylene), no significant differences could be established in the active ingredient release. The reason for this is the hydrophobicity of the PIB matrix as determining factor for the WVTR. When using hydrophilic fillers, such as e.g. cellulose or polyacrylic acid derivatives, in a PIB matrix, however, carrier materials of different WVTR can become relevant again as the determining factor of the active ingredient release.

[0054] In the case of the water gel, the active ingredient release can be significantly influenced by the WVTR of the carrier material used. Thus, e.g. samples with viscose carrier exhibited a 14% higher active ingredient release compared with samples with PU carriers.

[0055] Since the water gel matrices and also polyisobutylene matrices according to the invention are transparent to at most translucent, patches laminated with the above-described films as carrier materials are barely noticeable in visual terms and can therefore also be used inconspicuously over prolonged periods. As a result of appropriate coloring of the matrices or covering with a precolored carrier, a patch according to the invention, however, can also be produced in an inconspicuous skin shade.

[0056] Self-adhesive patches according to the invention can have any desired shape and size, e.g. round, rectangular, square etc. It is particularly advantageous that patches according to the invention based on PIB and on WG can be rightly cut by the user into any desired shape and size using standard commercial scissors in order to tailor the patch exactly to the desired treatment area.

[0057] It has been found that the water gel matrices and polyisobutylene matrices according to the invention have proven to be particularly easy to handle and effective particularly for the treatment of local hyperpigmentations such as age spots, freckles, post-inflammatory hyperpigmentations (e.g. as a consequence of Pseudofollikulitis barbae) if they are present in round to oval form with a diameter of ≦20 mm, preferably ≦15 mm, very particularly preferably ≦10 mm.

[0058] It has been found that the water gel matrices and also polyisobutylene matrices according to the invention have proven to be particularly easy to handle and effective particularly for the treatment of local hyperpigmentations such as melasma if they have an area ≧25 cm.sup.2, preferably ≧15 cm.sup.2, very particularly preferably ≧4 cm.sup.2.

EXAMPLES

Example 1: Wet Adhesive Film Based on Polyacrylic Acid/Polyvinyl Alcohol (FKF)

[0059]

TABLE-US-00004 % by weight Polyvinyl alcohol 68.0 Polyacrylic acid 16.5 Polyethylene glycol 400 9.5 Glycerol 5.0 4-n-Butylresorcinol 1.0

Example 2: Polar Anhydrous Gel Matrix, Polyacrylic Acid/Polyvinylpyrrolidone Base (WFG)

[0060]

TABLE-US-00005 % by weight Dexpanthenol 3.0 Propanediol 5.0 Polyethylene glycol 400 18.0 Polyacrylic acid 22.5 Polyvinylpyrrolidone 3.5 Silicon dioxide 4.0 Glycerol 43.0 4-n-Butylresorcinol 1.0

Example 3: Nonpolar Polyisobutylene Matrix (PIB)

[0061]

TABLE-US-00006 % by weight PIB 12 21.5 PIB 80 20.0 PIB 12 10.0 Cellulose 33.0 Isopropyl myristate 5.0 Decyl oleate 9.5 4-n-Butylresorcinol 1.0

Example 4: Polar Water Gel Matrix Based on Agar Agar/Polyacrylic Acid (WG)

[0062]

TABLE-US-00007 % by weight Water 49.1 Sorbitol 15.7 Agar agar 2.0 Glycerol 20.0 Polyacrylic acid 8.0 NaOH 45% 4.2 4-n-Butylresorcinol 1.0