TRANSDERMAL PATCH

Abstract

The present invention relates to a transdermal patch for the for the transdermal administration of oxymorphone. The present invention also relates to processes for the preparation of the transdermal patches defined herein, as well as to the use of these patches for the treatment of pain.

Claims

1. A transdermal patch comprising an oxymorphone layer, which comprises: 1-6% w/w of oxymorphone, wherein the oxymorphone is present in a non-salt form; 82-97% w/w of a pharmaceutically acceptable pressure sensitive polyacrylate adhesive comprising a plurality of hydroxyl functional groups; and 2-12% w/w of a penetration enhancer selected from oleic acid or linoleic acid; wherein the oxymorphone layer has a first surface that contacts a backing film and a second opposing surface that contacts the skin during use.

2. A transdermal patch according to claim 1, wherein oxymorphone is present at an amount of 2-4% w/w.

3. A transdermal patch according to claim 2, wherein oxymorphone is present at an amount of 2%, 2.5% or 3% w/w.

4. A transdermal patch according to claim 1, wherein the total amount of adhesive will constitute between 87 and 95% w/w.

5. A transdermal patch according to claim 4, wherein the total amount of adhesive will constitute between 92 and 95% w/w.

6. A transdermal patch according to claim 1, wherein the pressure sensitive polyacrylate adhesive has a viscosity of between 1600 and 19000 mPa-s.

7. A transdermal patch according to claim 6, wherein the pressure sensitive polyacrylate adhesive has a viscosity of between 7000 and 18000 mPa-s.

8. A transdermal patch according to claim 6, wherein the pressure sensitive polyacrylate adhesive has a viscosity of between 7500 and 8500 mPa-s.

9. A transdermal patch according to claim 1, wherein the pressure sensitive polyacrylate adhesive comprises a plurality of hydroxyl functional groups and has a viscosity of between 1600 and 19000 mPa-s.

10. A transdermal patch according to claim 9, wherein the pressure sensitive polyacrylate adhesive comprises a plurality of hydroxyl functional groups and an acrylate-vinyl acetate, has a viscosity of between 7500 and 8500 mPa-s and is devoid of any crosslinker.

11. A transdermal patch according to claim 1, wherein the penetration enhancer is linoleic acid.

12. A transdermal patch according to claim 1, wherein the penetration enhancer is present in an amount of 4-6% w/w of the oxymorphone layer.

13. A method of treating a condition selected form the group consisting of opioid dependence, alcohol dependence, polydrug addiction, pain, cocaine addiction, eating disorders and treatment-resistant depression in a subject in need of such treatment, said method comprising administering a transdermal patch according to claim 1 to the skin of the subject.

14. The method of claim 13, wherein the eating disorder is binge eating.

Description

Materials and Procedures

Chemicals

[0111] The various chemicals used throughout these examples are as follows:

TABLE-US-00002 Chemical Manufacturer Lot/Batch CAS Oxymorphone base Mallinckrodt Inc. 1310000735 76-41-5 DURO-TAK 87- Henkel Corporation ZQ62566751 4287 ® (PSA) Linoleic acid Spectrum ZR1141 60-33-3 Oleic acid Croda 896947 112-80-1 Ethyl acetate 2DE0179 141-78-6

Procedures

Permeation Studies

Skin Permeation

[0112] Dermatomed/split thickness skin dermatomed to a thickness of about 375 μm from leg (left posterior leg or right posterior leg) was received from Skin Bank. Skin was stored at −5° C. until used for the permeation studies.

Permeation Studies

[0113] Franz Diffusion Cells were used for the skin permeation studies, with the following protocol used.

[0114] Diffusion cells were kept at 37° C. with a heated circulating water bath. Skin was cut 3 cm×3 cm and mounted on the top of the receptor of the Franz cells facing stratum corneum/epidermis layer up and dermis layer facing down towards the receptor. The release liner was removed from the transdermal patch (10.5 cm.sup.2 or 10.75 cm.sup.2) and the exposed adhesive layer was applied to the stratum corneum layer with slight pressure. The donor cap was clamped to the receptor compartment. The permeation area of the skin was 1.767 cm.sup.2. The samples were collected from 3 to 5 cells per formulation. The receptor/receiver solution was PBS (phosphate buffer saline) pH 7.4 solution. Entire samples were withdrawn from the receptor compartment at predetermined time points at 4, 20, 24, 28, 44, 48, 72 and 96 hours and replaced the same volume with fresh PBS solution. The samples were placed screw cap test tubes and refrigerated until ready for HPLC analysis.

Extraction Studies

In Ethanol:

[0115] Oxymorphone or Naltrexone patches (10.5 cm.sup.2) were placed on a polypropylene mesh and placed in a 250 mL glass stoppered conical flask with 100 mL of ethanol. The patches were extracted for 24 hours and the amount of Oxymorphone or Naltrexone was determined, typically by HPLC.

In pH 6.3 buffer:

[0116] Oxymorphone or Naltrexone patches (10.5 cm.sup.2) were placed on a polypropylene mesh and placed in a 250 mL glass stoppered conical flask with 100 mL of pH 6.3 phosphate buffer. The patches were extracted for 24 hours and the amount of Oxymorphone or Naltrexone was determined, typically by HPLC.

Results

Transdermal Patches

Adhesive

[0117] Adhesive transdermal patches were firstly prepared using 3% oxymorphone in various adhesives and determined the corresponding flux values through Male skin age 45 (skin bank JL102114) using Phosphate buffered saline at pH of 7.4. The corresponding flux values are detailed in Table 1 below.

TABLE-US-00003 TABLE 1 Flux values of Oxymorphone through Male skin for transdermal patches comprising various adhesives Flux - Experiment Adhesive Adhesive Functional Vinyl Cross t 24 to 72 Number Used Type Group Acetate Linker μg/cm.sup.2/h 1 DURO-TAK Polyacrylate None VA None 2.72 ± 0.42 87-4098 Present 2 DURO-TAK Polyacrylate Hydroxyl VA Present 4.69 ± 0.44 87-2516 (—OH) Present 3 DURO-TAK Polyacrylate Carboxyl VA None 0.11 ± 0.03 87-2051 (—COOH) Present 4 DURO-TAK Polyacrylate Carboxyl VA Present 0.36 ± 0.12 87-2054 (—COOH) Present 5 DURO-TAK Polyacrylate Hydroxyl None None 2.66 ± 0.42 87-2510 (—OH) 6 DURO-TAK Polyacrylate None None None 1.65 ± 0.27 87-9088 7 DURO-TAK Polyacrylate Carboxyl VA Present 0.15 ± 0.05 87-2194 (—COOH) Present 8 DURO-TAK Polyacrylate Hydroxyl VA None 3.74 ± 0.23 87-4287 (—OH) Present 9 BIO-PSA Silicone 0.78 ± 0.11 7-4302 10 Silac Silicone + 1.23 ± 0.21 Hybrid Polyacrylate 7-6302 11 DURO-TAK Polyisobutylene 0.05 ± 0.02 87-6918

[0118] Table 1 illustrates the dramatic and unexpected increase in Oxymorphone flux in using polyacrylate adhesives comprising a plurality of hydroxyl functional groups.

Penetration Enhancer

[0119] Adhesive transdermal patches comprising oxymorphone (3% w/w) in DURO-TAK 87-4287 adhesive were prepared using 5 different penetration enhancers (5% w/w) (Oleic acid; oleyl alcohol; oleyl alcohol; lauryl lactate; lauryl alcohol and linoleic acid). Also prepared was a transdermal patch containing oxymorphone (3% w/w) in in DURO-TAK 87-2516 adhesive only. Flux values through Male white skin age 62 (skin bank KMG032615) using Phosphate buffered saline at pH of 7.4 were then determined. The corresponding flux values are in Table 2 below.

[0120] It was shown that in all cases, the addition of a penetration enhancer increased Oxymorphone flux through the skin. Penetration enhancers linoleic acid and oleic acid were shown to give substantially increased Oxymorphone flux.

TABLE-US-00004 TABLE 2 Flux values of Oxymorphone through Male skin for transdermal patches comprising various penetration enhancers Flux - Adhesive Adhesive Functional Vinyl Cross Penetration t 24 to 72 Used Type Group Acetate Linker Enhancer μg/cm.sup.2/h DURO-TAK Polyacrylate Hydroxyl Present No None 3.15 ± 0.88 87-4287 DURO-TAK Polyacrylate Hydroxyl Present No Oleic Acid 4.21 ± 0.68 87-4287 DURO-TAK Polyacrylate Hydroxyl Present No Oleyl Alcohol 2.33 ± 0.66 87-4287 DURO-TAK Polyacrylate Hydroxyl Present No Lauryl Lactate 2.27 ± 0.48 87-4287 DURO-TAK Polyacrylate Hydroxyl Present No Lauryl Alcohol 3.53 ± 0.19 87-4287 DURO-TAK Polyacrylate Hydroxyl Present No Linoleic Acid 3.62 ± 0.76 87-4287

Flux and Extraction Studies

[0121] Oxymorphone flux and extraction in ethanol was determined for the transdermal patches of the present invention. The results are summarised in Table 3 below.

TABLE-US-00005 TABLE 3 The extraction and flux data for optimised oxymorphone layer OXY FLUX flux determined using male Coating white skin age 62 Formulation gap Extraction Data Section RPL (μg/cm.sup.2/h) 3% oxymorphone in 0.600 mm OXYMORPHONE ASSAY Average flux 24-72 hrs = DURO-TAK 87-4287 1.sup.st extraction in ethanol = 4.20 mg 6.52 and 5% oleic acid 2.sup.nd extraction in ethanol = 0.12 mg total mg/patch = 4.32 mg 1.sup.st extraction in buffer pH 6.3 = 1.72 2.sup.nd extraction in ethanol = 2.17 mg total mg/patch = 3.89 mg 3% oxymorphone in 0.600 mm OXYMORPHONE ASSAY Average flux 24-72 hrs = DURO-TAK 87-4287 1.sup.st extraction in ethanol = 4.15 mg 6.96 and 5% linoleic acid 2.sup.nd extraction in ethanol = 0.12 mg Average flux 0-72 hrs = total mg/patch = 4.27 mg 6.27 1.sup.st extraction in buffer pH 6.3 = 1.65 mg 2.sup.nd extraction in ethanol = 2.01 mg total mg/patch = 3.66 mg

[0122] The results in Table 3 show that for the transdermal patches an excellent level of Oxymorphone flux is observed when both linoleic acid and oleic acid are used as the penetration enhancer.

[0123] Oxymorphone flux was then determined for the transdermal patches of the present invention at different coating thicknesses. The flux value are summarised in Tables 4 and 5 below.

TABLE-US-00006 TABLE 4 Flux values of Oxymorphone for transdermal patches comprising 3% Oxymorphone at different coating thicknesses. OXYMORPHONE Coating Permeation Flux Content DUROTAK gap enhance Skin Bank donor (t24-t72 hrs) 3% 87-4287 0.400 Linoleic M W (62) 3.62 +/− 0.76 acid (5%) MG032615) LPL 3% 87-4287 0.600 Linoleic M W (62) 6.96 acid (5%) MG032615 RPL 3% 87-4287 0.600 Linoleic M W (69) 6.98 acid (5%) MM041115 PT

TABLE-US-00007 TABLE 5 Further flux values of Oxymorphone for transdermal patches comprising 3% Oxymorphone at different coating thicknesses. Amount of FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 3% oxymorphone in 4.10 mg/10.5 cm.sup.2 5.4 mil 7.22 (a) SKIN DURO-TAK 87-4287 (15.6 mg/40 mg.sup.2) (0.6 mm) 6.74 (b) MM040002 and 5% linoleic acid 390 μg/cm.sup.2 7.11 (c) Age 69 6.88 (d) section pt 6.83 (e) Average of 5 6.95 μg/cm.sup.2/hr 3% oxymorphone in 4.24 mg/10.5 cm.sup.2 5.1 mil 6.81 (a) SKIN DURO-TAK 87-4287 (15.77 mg/40 mg.sup.2) (0.6 mm) 6.72 (b) JA040115 and 5% linoleic acid 404 μg/cm.sup.2 4.03 (c) Age 67 LPL Average of 3 5.86 μg/cm.sup.2/hr 3% oxymorphone in 5.32 mg/10.75 cm.sup.2 6.3 mil 7.14 (a) SKIN DURO-TAK 87-4287 (19.91 mg/40 mg.sup.2) (0.8 mm) 6.09 (b) JA040115 and 5% linoleic acid 498 μg/cm.sup.2 7.59 (c) Age 67 LPL Average of 3 6.94 μg/cm.sup.2/hr 3% oxymorphone in 6.87 mg/10.75 cm.sup.2 8.1 mil 7.17 (a) SKIN DURO-TAK 87-4287 (25.56 mg/40 mg.sup.2) (1.0 mm) 7.83 (b) JA040115 and 5% linoleic acid 639 μg/cm.sup.2 7.60 (c) Age 67 LPL Average of 3 7.54 μg/cm.sup.2/hr

Patches Comprising 2% and 2.5% Oxymorphone

Flux Values

[0124] Using patches comprising 2% and 2.5% Oxymorphone, the flux values of Oxymorphone through male white skin (67 years, skin bank JA040115) were determined. The results are summarised in Table 6 below.

TABLE-US-00008 TABLE 6 Flux values of Oxymorphone for transdermal patches comprising 2% and 2.5% Oxymorphone. Amount of FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 2.5% oxymorphone in 540 μg/cm.sup.2 0.5 mm + 7.56 (a) SKIN DURO-TAK 87-4287 0.5 mm 7.64 (b) JA040115 and 5% linoleic acid Total = 7.43 (c) Age 67 LPL 1.0 mm Average of 3 7.54 μg/cm.sup.2/hr 2% oxymorphone in 434 μg/cm.sup.2 0.5 mm + 4.31 (a) SKIN DURO-TAK 87-4287 0.5 mm 5.22 (b) JA040115 and 5% linoleic acid Total = 5.35 (c) Age 67 LPL 1.0 mm Average of 3 4.96 μg/cm.sup.2/hr

Effects of the Penetration Enhancer

[0125] Comparison of patches with and without penetration enhancer were next prepared. The results are summarised in Table 7 below.

TABLE-US-00009 TABLE 7 Flux values of Oxymorphone for transdermal patches comprising either no penetration enhancer or 5% w/w linoleic acid at different coating thicknesses. Amount of FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 3% oxymorphone in 3.14 mg/10.5 cm.sup.2 3.7 mil (0.4 mm) 3.85 (a) SKIN DURO-TAK 87-4287 (11.96 mg/40 mg.sup.2) 3.42 (b) MG032615 299 μg/cm.sup.2 2.16 (c) Age 62 (white) Average of 3 section LPL 3.14 μg/cm.sup.2/hr 3% oxymorphone in 2.93 mg/10.5 cm.sup.2 4.2 mil (0.4 mm) 2.79 (a) SKIN DURO-TAK 87-4287 (11.16 mg/40 mg.sup.2) 3.78 (b) MG032615 and 5% linoleic acid 279 μg/cm.sup.2 4.28 (c) Age 62 LPL Average of 3 3.62 μg/cm.sup.2/hr 3% oxymorphone in 4.27 mg/10.5 cm.sup.2 0.6 mm 7.04 (a) SKIN DURO-TAK 87-4287 (16.27 mg/40 mg.sup.2) 7.74 (b) MG032615 and 5% linoleic acid 407 μg/cm.sup.2 7.07 (c) Age 62 (white) 6.98 (d) section RPL 6.48 (e) Average of 5 6.96 μg/cm.sup.2/hr 3% oxymorphone in 4.12 mg/10.5 cm.sup.2 5.4 mil (0.6 mm) 7.22 (a) SKIN DURO-TAK 87-4287 (15.61 mg/40 mg.sup.2) 6.74 (b) MM041115 and 5% linoleic acid 392 μg/cm.sup.2 7.11 (c) Age 69 6.88 (d) section pt 6.83 (e) Average of 5 6.95 μg/cm.sup.2/hr

Transdermal Patch Prepared by Double Coating Process

[0126] A transdermal patch containing a greater amount of Oxymorphone (greater thicknesses of Oxymorphone layer) was prepared and the flux of Oxymorphone through male white skin (69 years, skin bank MM041115) was determined. The patch was made in an identical manner to the other patches described hereinabove, albeit two coatings of the Oxymorphone layer were employed.

[0127] The flux values obtained for the ‘thicker’ patches are summarised in Tables 8 and 9 below.

TABLE-US-00010 TABLE 8 Flux values of Oxymorphone for a transdermal patch comprising 2.5% Oxymorphone. Amount FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 2.5% oxymorphone in 635 μg/cm.sup.2 0.6 mm + 4.93 (a) SKIN DURO-TAK 87-4287 0.6 mm 7.08 (b) MM041115 and 5% linoleic acid Total = 6.83 (c) Age 69 LPL 1.2 mm 7.46 (d) 7.18 (e) Average of 5 6.69 μg/cm.sup.2/h

TABLE-US-00011 TABLE 9 Amount FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 2.5% oxymorphone in 587 μg/cm.sup.2 1.2 mm (10.6 mil) 5.06 (a) SKIN DURO-TAK 87-4287 5.77 (b) JL080915 and 5% linoleic acid 2.58 (c) Age 52 RPL Average of 3 4.47 μg/cm2/h

Scale-Up Production

[0128] A total of 3755×10 cm.sup.2 transdermal patches were prepared, with each containing 1.72 mg of oxymorphone with a dry weight coating thickness of approximately 2.7 mil (using a coating gap of 0.340 mm).

[0129] The flux values for the ‘scale-up’ batch of transdermal patches are provided in Table 10 below.

TABLE-US-00012 TABLE 10 Flux values of Oxymorphone for a scale-up transdermal patch comprising 2.5% Oxymorphone Amount FLUX VALUE % Oxymorphone COATING (t 24-72 hrs; OXYMORPHONE per cm.sup.2 GAP (mm) units: μg/cm.sup.2/h) COMMENT 2.5% oxymorphone in 173 μg/cm.sup.2 0.340 mm 2.91 (a) SKIN DURO-TAK 87-4287 3.17 (b) CM120115 and 5% linoleic acid 2.98 (c) Age 48 2.92 (d) White Male 2.95 (e) LPL Average of 5 2.99 μg/cm.sup.2/h

[0130] While specific embodiments of the invention have been described for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.