Oxymorphone transdermal patch

Abstract

The present invention relates to a transdermal patch comprising 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 having a drug-containing layer comprising oxymorphone, or a pharmaceutically acceptable salt thereof, a penetration enhancer, and a pharmaceutically acceptable pressure sensitive adhesive, wherein the oxymorphone is present at an amount of 1-10% w/w in the drug-containing layer; wherein the penetration enhancer is present in an amount of 2-12% w/w of the drug-containing layer; wherein the total amount of adhesive constitutes between 58 and 99% w/w of the drug-containing layer; and wherein the drug containing layer has a first surface that contacts a backing membrane and a second opposing surface that contacts the skin during use.

2. A transdermal patch according to claim 1, wherein the oxymorphone is present at an amount of 4-7% w/w in the drug-containing layer.

3. A transdermal patch according to claim 1, wherein the oxymorphone is present in a non-salt form, e.g. as a free base.

4. A transdermal patch according to claim 1, wherein the adhesive is selected from acrylate/polyacrylate materials, rubbers and silicones or mixtures thereof.

5. A transdermal patch according to claim 1, wherein the adhesive is a mixture of an acrylate/polyacrylate adhesive and a silicone adhesive.

6. A transdermal patch according to claim 1, wherein the penetration enhancer is oleic acid or ethyl oleate.

7. A transdermal patch according to claim 1, wherein the drug-containing layer comprises a second penetration enhancer.

8. A transdermal patch according to claim 7, wherein the second penetration enhancer is oleyl alcohol.

Description

MATERIALS AND PROCEDURES

(1) Chemicals

(2) The various chemicals used throughout these examples are as follows:

(3) TABLE-US-00002 Chemical Manufacturer Part # CAS Lot # Oxymorphone Mallinckrodt Inc. 079006 357-07-3 1304000913 hydrochloride, USP Potassium phosphate, Fisher Scientific BP362-500 7778-77-0 132450 monobasic Potassium phosphate Acros Organics AC20593- 16788-57-1 A0331382 dibasic trihydrate 5000 Propylene glycol, USP Spectrum Chemicals PR130-500mL 57-55-6 2BG0259 Ethanol, 200 proof, Sigma Aldrich 493546- 64-17-5 SHB04820V USP 500mL Alcohol (ethyl alcohol) Spectrum ET108 64-17-5, 7732-18-5 2CD0092 190 proof USP Ethyl acetate, NF Fisher Scientific E124-20 141-78-6 134168 Myristic acid myristyl MP Biomedicals 0215575591 3234-85-3 155755 ester Oleic acid, NF Spectrum Chemicals OL103-1LTGL 112-80-1 Myristic acid, reagent Spectrum Chemicals MY110- 544-63-8 WV3017 100GM BIO-PSA AC7-4302 Dow Corning 3275205 238094-36-5, 141-78- 0006099302 6, 1330-20-7 BIO-PSA 7-4202 Dow Corning 000015563317 238094-36-5, 141-78- 0006001327 6, 1330-20-7 Duro-Tak 2054 Henkel 387-2054 200-661-7, 205-500-4, 2Q939447717 203-624-3, 203-625-9, 237-741-6, 203-806-2, 205-480-7 Duro-Tak 608A Henkel 1214080 142-82-5, 9003-27-4 20382-12 Duro-Tak 4098 Henkel 1219326 141-78-6, 108-05-4 OH31424641 Duro-Tak 9301 Henkel 1428620 141-78-6 OH14495473 Duro-Tak 202A Henkel 87-202A 141-78-6, 67-63-0, 67- OH90213550 56-1 Klucel EF PH Hercules Incorporated NA 9004-64-2 99860 Aqualon EC-N50 PH Hercules Incorporated NA 9004-57-3 42118 Polyvinylpyrollidone Spectrum Chemicals P1454 9003-39-8 XQ0602 (PVP-K30) Polyvinylpyrollidone Sigma Aldrich 190845-250g 25086-89-9 MKBC1985 vinyl acetate Chloroform J T Baker 9182-01 67-66-3 J02B18 Sodium hydroxide J T Baker 3722-01 1310-73-2 J20K52 Sodium chloride Fisher Scientific M-11624 7647-14-5 102040 Acetonitrile, HPLC Fisher Scientific A998-4 75-05-8 138059 grade Methanol, HPLC grade Fisher Scientific A452-4 67-56-1 124875
Supplies

(4) Supplies used throughout these examples are as follows: 1) XBridge C18 column; 5 m, 4.6250 mm, Waters Corporation, part number 186003117, serial number 0151323062 2) Clear target DP HPLC vials with pre-slit tef/white silicone septa caps; 100/pk, National Scientific, part number C4000-95P 3) Scintillation vials and caps; 20 mL low background borosilicate glass vial, polypropylene cap with metal foil liner; Research Products International Corp., part number 121000W0 4) Nylon membrane filter; Millipore, 0.2 m GNWP, part number GNWP04700
Equipment

(5) The equipment used throughout these examples is as follows: 1) INST-004 2695 Alliance separations module, Waters Corporation 2) INST-005 2487 Dual wavelength absorbance detector, Waters Corporation 3) INST-006 Column heater, Waters Corporation 4) INST-021 Retriever IV fraction collector, Isco 5) INST-025 Retriever IV fraction collector, Isco 6) INST-033 Retriever IV fraction collector, Isco 7) INST-023 Heated water bath, Thermo 8) INST-027 Heated water bath, Thermo 9) INST-031 Heated water bath, Thermo 10) INST-026 Heated circulating water bath, Fisher Scientific 11) INST-030 Heated circulating water bath, VWR International 12) INST-028 16 channel pump, Watson Marlow 13) INST-032 16 channel pump, Watson Marlow 14) INST-034 16 channel pump, Watson Marlow 15) INST-064 Model S slimline dermatome, Integra Life Sciences 16) INST-072 Balance, Sartorius 17) INST-078 Pump, KNF Laboport 18) INST-083 Caliper spring micrometer, Mitutoyo Corporation 19) INST-088 Dlamond UV/UF NANOpure system, Barnstead International 20) INST-116 AB15 pH meter, Fisher Scientific
Opioid Preparation

(6) Oxymorphone base was obtained from commercial oxymorphone hydrochloride by reacting an aqueous solution of the oxymorphone hydrochloride with an aqueous solution of sodium hydroxide. The resulting precipitate was filtered off, washed twice with water and dried overnight under high vacuum.

(7) Receiver Fluids

(8) Isotonic phosphate buffer pH 6.3 was prepared by combining 1600 mL of a 0.067 M potassium phosphate, monobasic solution to 400 mL of a 0.13 M potassium phosphate, dibasic trihydrate solution. 4.4 g/L sodium chloride was then added to the buffer. The resulting mixture had a measured pH of 6.3. The water was obtained from a NANOpure Diamond Life Science (UV/UF) ultrapure water system. The phosphate buffer was filtered (0.2 m nylon membrane filter) and placed in a 2 L glass bottle.

(9) A 10% ethanol in water receiver solution was prepared by adding 210 mL of ethyl acohol (190 Proof) to 1790 mL NANOpure water. The receiver solution was then filtered (0.2 m nylon membrane filter) and placed in a 2 L glass bottle.

(10) Skin Preparation

(11) Full thickness abdominal tissue with attached fat, harvested from abdominoplasty, was received. Skin was dermatomed (Model S slimline dermatome) to a thickness of 250 m. Dermatomed skin was stored at 20 C. until used for the permeation studies.

(12) Permeation Studies

(13) A PermeGear flow-through (In-Line, Hellertown, Pa.) diffusion cell system with supports was used for the skin permeation studies. The following protocol was used:

(14) Diffusion cells were kept at 32 C. with a heated circulating water bath. The transdermal drug delivery system circular disc was placed on the skin and pressed down to ensure secure contact with the skin. Human skin was arranged in the diffusion cell with epidermis (upper layer of skin) facing the donor compartment. Each cell was charged with a circular disc cut (0.95 cm.sup.2) from the respective transdermal drug delivery system. Permeation area of the skin was 0.95 cm.sup.2. Diffusion cells remained uncovered to mimic clinical conditions for the duration of the study. Data was collected from a single human skin donor with 3-4 diffusion cells per formulation.

(15) Receiver solution was initially a pH 6.3 isotonic phosphate buffer but was later switched to 10% aqueous ethanol. The flow rate was set to 1.1 mUh in order to help maintain sink conditions.

(16) Samples were collected into scintillation vials at 8, 16, 24, 32, 40, 48, 56, 64 and 72 hour time points.

(17) At the end of the 72 hour experiment, the skin concentrations were determined and patches were extracted.

(18) The diffusion samples were analysed the day of collection or the following day.

(19) Dose Administration

(20) A 0.95 cm.sup.2 circular disc from the respective transdermal drug delivery system was cut to fit the In-line diffusional area. The 0.95 cm.sup.2 transdermal drug delivery system circular disc was placed on the skin and pressed down to ensure secure contact with the skin. Once cells were equilibrated, the study was initiated by starting the fraction collector and collecting fractions for the respective time increments.

(21) Analytical Methods

(22) Quantification of oxymorphone was done by high performance liquid chromatography (HPLC). Briefly, HPLC was conducted on a Waters 2695 Alliance separations module and column heater with a 2487 dual wavelength absorbance detector. The solvent system consisting of 35% A) acetonitrile and 65% B) phosphate buffer, pH 8.0 was run through a Waters XBridge C18 5 m, 4.6250 mm column at a flow rate of 1.0 mL/min. 50 L of the diffusion samples and 20 L for the skin samples were injected onto the HPLC column. The limit of detection was 0.043 g/mL. Samples were analysed the day of collection or the following day.

Example 1

Opioid Layer

(23) Typical Preparation of Oxymorphone Formulations

(24) The following series of steps provide a typical protocol for the preparation of the oxymorphone formulations forming part of the invention (in this specific example, the preparation of a 5% oxymorphone matrix layer (1 kg)). Materials and amounts may vary depending on specific composition of formulations. 1. Weigh 50 g oxymorphone base into a mixing vessel (5% w/w). 2. Tare weight and add 100 g of oleic acid, NF to the vessel (10% w/w). 3. Pipet 60 mL of ethanol (200 proof) into the vessel. 4. Pipet 260 mL of ethyl acetate into the vessel. 5. Begin mixing and blend until and oxymorphone is completely dissolved. 6. Add 242.1 g Duro-Tak 9301 (non-volatile content (NVC=41.3%) (10% w/w). 7. Add 1219.5 kg Dow BIO-PSA 7-4302 (non-volatile content (NVC=61.5%) (75% w/w). 8. Blend until a homogenous viscous solution is achieved. 9. Extrude at 20 mil wet thickness onto 3M Scotchpak 1022 release liner and air dry for 15 minutes at 25 C. 10. Oven dry at 90 C. for 15 minutes. 11. Laminate with 3M Scotchpak 1022 release liner and reroll for the complete patch assembly. 12. Store desiccated until ready for use.
Oxymorphone Formulations

(25) The composition of exemplary oxymorphone formulations are summarized below. Formulations were prepared on a 1 gram scale. Addition of solvent, ethanol and ethyl acetate were added to enhance solubility and mixing of solid excipients.

(26) TABLE-US-00003 OM-2014-01-001 OM-2014-01-002 3% Oxymorphone 3% Oxymorphone 97% Dow Corning BIO-PSA 7-4502 97% Dow Corning BIO-PSA 7-4302 (amine 100 L Ethanol compatible) 100 L Ethanol OM-2014-01-003 OM-2014-01-004 8% Oxymorphone 3% Oxymorphone 92% Duro-Tak 2054 Acrylic (COOH functional 97% Duro-Tak 4098 Acrylic (non-functional group) group) 100 L Ethanol 100 L Ethanol OM-2014-01-005 OM-2014-01-006 3% Oxymorphone 6% Oxymorphone 97% Duro-Tak 608A Polyisobutylene [PIB] 94% Duro-Tak 202A Acrylic (OH functional group) 100 L Ethanol 100 L Ethanol OM-2014-01-007 OM-2014-01-008 5% Oxymorphone 5% Oxymorphone 95% Dow Corning BIO-PSA 7-4302/Duro-Tak 2054 89% Dow Corning BIO-PSA 7-4302/Duro-Tak 2054 Acrylic (80:20) Acrylic (80:20) 150 L Ethanol 6% Lactic acid 150 L Ethanol OM-2014-01-009 OM-2014-01-010 5% Oxymorphone 5% Oxymorphone 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 7.5% Myristic acid 5% Myristic acid 70.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 7.5% Myristyl myristate 4202 (75:25) 65.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 7% Duro-Tak 9301 4202 (75:25) 60 L Ethanol 7% Duro-Tak 9301 260 L Ethyl acetate 60 L Ethanol 260 L Ethyl acetate OM-2014-01-011 OM-2014-01-012 5% Oxymorphone 5% Oxymorphone 2.5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 7.5% Oleic acid 7.5% Oleic acid 10% Propylene glycol 5% Propylene glycol 65.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 70.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 4202 (75:25) 4202 (75:25) 7% Duro-Tak 9301 7% Duro-Tak 9301 60 L Ethanol 60 L Ethanol 260 L Ethyl acetate 260 L Ethyl acetate OM-2014-01-013 OM-2014-01-014 5% Oxymorphone 5% Oxymorphone 2.5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 7.5% Oleic acid 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 87.5% Dow Corning BIO-PSA 7-4302 7.5% Myristic acid 60 L Ethanol 5% Propylene glycol 260 L Ethyl acetate 70.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 4202 (75:25) 7% Duro-Tak 9301 60 L Ethanol 260 L Ethyl acetate OM-2014-01-015 OM-2014-01-016 5% Oxymorphone 5% Oxymorphone 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 7.5% Oleic acid 7.5% Oleic acid 82.5% Dow Corning BIO-PSA 7-4302 7.5% Propylene glycol 60 L Ethanol 75% Dow Corning BIO-PSA 7-4302 260 L Ethyl acetate 60 L Ethanol 200 L Ethyl acetate OM-2014-01-017 OM-2014-01-018 5% Oxymorphone 5% Oxymorphone 5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 2.5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 7.5% Oleic acid 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 7.5% Propylene glycol 5% Oleic acid 75% Dow Corning BIO-PSA 7-4302 7.5% Propylene glycol 60 L Ethanol 77.5% Dow Corning BIO-PSA 7-4302 200 L Ethyl acetate 60 L Ethanol 200 L Ethyl acetate OM-2014-01-019 OM-2014-01-020 5% Oxymorphone 5% Oxymorphone 2.5% Polyvinylpyrollidone [PVP-K30] (MW 30,000) 7.5% Oleic acid 2.5% Polyvinylpyrollidone vinyl acetate [PVP-VA] 87.5% Dow Corning BIO-PSA 7-4302 5% Oleic acid 50 L Ethanol 7.5% Propylene glycol 150 L Ethyl acetate 67.5% Dow Corning BIO-PSA 7-4302:BIO-PSA 7- 4202 (75:25) 10% Duro-Tak 9301 60 L Ethanol 200 L Ethyl acetate OM-2014-01-021 OM-2014-01-022 5% Oxymorphone 5% Oxymorphone 7.5% Oleic acid 7.5% Oleic acid 2.5% Propylene glycol 77.5% Dow Corning BIO-PSA 7-4302 75% Dow Corning BIO-PSA 7-4302 10% Duro-Tak 9301 10% Duro-Tak 9301 60 L Ethanol 50 L Ethanol 200 L Ethyl acetate 150 L Ethyl acetate OM-2014-01-023 OM-2014-01-024 5% Oxymorphone 3.5% oxymorphone 7.5% Oleic acid 7.5% oleic acid 2.5% Propylene glycol 77.5% Dow Corning BIO-PSA 7-4302 77.5% Dow Corning BIO-PSA 7-4302 11.5% Duro-tak 9301 10% Duro-Tak 9301 60 ul Ethanol 60 L Ethanol 200 ul ethyl acetate 200 L Ethyl acetate OM-2014-01-025 OM-2014-01-028 5% oxymorphone 5% Oxymorphone 8.5% myristic acid 10% oleic acid 76.5% Dow Corning BIO-PSA 7-4302 75% Dow Corning BIO-PSA 7-4302 10% Duro-tak 9301 10% Duro-tak 9301 60 ul Ethanol 60 ul Ethanol 200 ul ethyl acetate 260 ul ethyl acetate OM-2014-01-030 OM-2014-01-043 5% Oxymorphone 5% oxymorphone 10% oleic acid 7.5% oleyl alcohol 75% Dow Corning BIO-PSA 7-4302 5% PVP K30 10% Duro-tak 9301 82.5% Duro-Tak 4098 155 ul Ethanol 400 ul ethanol 155 ul ethyl acetate 100 ul EtOAc OM-2014-01-046 OM-2014-01-047 5% Oxymorphone 5% Oxymorphone 10% (1:1 oleic acid:oleyl alcohol) 10% (1:1 ethyl oleate:oleyl alcohol) 5% PVP-K30 5% PVP-K30 80% Duro-tak 4098 80% Duro-tak 4098 OM-2014-01-048 5% Oxymorphone 10% (1:1 oleyl oleate:oleyl alcohol) 5% PVP-K30 80% Duro-tak 4098
Oxymorphone Formulation Test Data

(27) FIG. 1 and Table 1 below provide permeation data of oxymorphone formulation OM-2014-01-011 (n=3) with pH 6.3 isotonic phosphate buffer receiver solution.

(28) TABLE-US-00004 TABLE 1 Permeation data of oxymorphone formulation OM-2014-01-011 (n = 3) with pH 6.3 isotonic phosphate buffer receiver solution* 72 h 72 h skin concentration cumulative Flux Compound (mol/g) amount (g) (g/cm.sup.2/h) OM-2014-01-011 2.2 0.2 544.3 113.8 7.6 2.0 *One cell was removed from data set (outlier)

(29) FIG. 2 shows representative cumulative human skin permeation profile of oxymorphone formulation, OM-2014-01-011 (n=3). FIG. 3 shows representative time interval flux values of oxymorphone formulation, OM-2014-01-011 (n=3).

(30) Formulations OM-2014-01-012 and OM-2014-01-013 focused on decreasing propylene glycol (PG) content by 5% in both formulations while holding constant the PVP-K30, PVP-VA, and acid concentration. Reduction of PG to 5% decreased permeation as compared to formulation OM-2014-01-011. This reduction in PG content may have influenced the permeability of oxymorphone out of the matrix by creating a more non porous pathway due to an overall increase in solid content. Results are shown in Table 2 and FIGS. 4, 5, and 6 for OM-2014-01-012 and OM-2014-01-013.

(31) TABLE-US-00005 TABLE 2 Permeation data of oxymorphone formulation OM-2014-01-012 (n = 4) & OM-2014-01-013 (n = 4) with 10% aqueous ethanol receiver solution 72 h 72 h skin concentration cumulative Flux Compound (mol/g) amount (g) (g/cm.sup.2/h) OM-2014-01-012 ND 88.0 18.9 1.2 0.3 OM-2014-01-013 ND 95.2 39.4 1.3 0.7 ND = none determined

(32) Despite being viable opioid formulations, formulations OM-2014-01-016, OM-2014-01-017, and OM-2014-01-018 were not tested for inclusion in a transdermal patch due to non-uniform matrix formulation when cast onto the release liner and dried. Formulations OM-2014-01-014 and OM-2014-01-015 were whiter in appearance than other formulations when mixed and uniform casts prepared; however upon observation after drying, no solid particulates were observed. The addition of Duro-Tak 9301 to formulation OM-2014-01-019 provided enhanced solubility upon mixing; therefore a more transparent film was observed upon casting and drying. Results are shown in Table 3 and FIGS. 7, 8, and 9 for OM-2014-01-014, OM-2014-01-015, and OM-2014-01-019.

(33) TABLE-US-00006 TABLE 3 Permeation data of oxymorphone formulation OM-2014-01-014 (n = 4), OM-2014-01-015 (n = 4), & OM-2014-01-019 (n = 4) with 10% aqueous ethanol receiver solution 72 h 72 h skin concentration cumulative Flux Compound (mol/g) amount (g) (g/cm.sup.2/h) OM-2014-01-014 22.7 8.8 263.5 82.8 3.7 1.3 OM-2014-01-015 7.5 1.1 147.4 19.8 2.1 0.4 OM-2014-01-019 14.2 5.0 355.2 47.2 4.9 0.8

(34) Based on initial positive results, formulation OM-2014-01-014 was repeated on a different skin donor to confirm the flux value. Even though OM-2014-01-019 had a higher flux value compared to OM-2014-01-014, OM-2014-01-019 was not repeated due to the relative complexity of the formulation. Results are shown in Table 4 and FIGS. 10, 11, and 12 for OM-2014-01-014.

(35) TABLE-US-00007 TABLE 4 Permeation data of oxymorphone formulation OM-2014-01-014 (n = 4), on a different skin donor for flux confirmation with 10% aqueous ethanol receiver solution (repeat study) 72 h 72 h skin concentration cumulative Flux Compound (mol/g) amount (g) (g/cm.sup.2/h) OM-2014-01-014 18.2 4.8 307.0 42.5 4.3 1.0

(36) Formulations OM-2014-01-020, OM-2014-01-021, OM-2014-01-022, and OM-2014-01-023 were prepared in order to investigate small differences in amounts of additional ethanol and ethyl acetate as well as the addition of PG and Duro-Tak 9301 into the formulation. Initially, formulations OM-2014-01-020 and OM-2014-01-021 were to be prepared with no addition of ethanol or ethyl acetate; however, mixing was difficult and a minimal amount was added. Both formulations were cast at 15 mil wet thickness compared to 20 mil wet thickness of all previous formulations and formulations, OM-2014-01-022 and OM-2014-01-023. Formulation OM-2014-01-022 showed the best results, with an average flux of 3.11.0 g/cm.sup.2/h. This formulation containing 10% Duro-Tak 9301 will provide better wear during therapy and was therefore selected for further studied along with OM-2014-01-014 for flux and with the abuse deterrent platform. Results are shown in Table 5 and FIGS. 13, 14, and 15 for OM-2014-01-020, OM-2014-01-021, OM-2014-01-022, and OM-2014-01-23.

(37) TABLE-US-00008 TABLE 5 Permeation data of oxymorphone formulation OM-2014-01-020 (n = 3), OM-2014-01-021 (n = 3), OM-2014-01-022 (n = 3) & OM-2014-01-023 (n = 3) with 10% aqueous ethanol receiver solution 72 h cumulative 72 h skin concentration amount Flux Compound (mol/g) (g/cm.sup.2) (g/cm.sup.2/h) OM-2014-01-020 12.4 1.9 83.0 12.6 1.2 0.3 OM-2014-01-021 9.7 4.9 83.0 9.7 1.2 0.2 OM-2014-01-022 10.1 13.2 225.6 71.5 3.1 1.0 OM-2014-01-023 2.6 1.3 135.0 40.9 1.9 0.6

(38) A variety of adhesive systems, enhancers and cosolvents were employed to observe permeation differences within these systems. In general, solubility in acrylic adhesives (i.e. Duro-Tak) was higher, and thus the driving force out of the patch would be relatively lower. Solubility in silicone adhesives was lower and thus provided a much higher driving constant out of the formulation and into the skin; however, due to the relatively lower solubility, a solubility enhancer that also assisted in solubilising the skin was utilized. Three acids (lactic acid (MW: 90.08, myristic acid (MW: 228.38) and oleic acid (MW: 282.47)) were screened for permeation and solubility enhancement. Oleic acid, the most hydrophobic acid screened, almost immediately dissolved 5% w/w OXY during formulation preparation and provided enhancement to obtain the desired permeation rate. Oleic acid is currently approved in 6 topical and transdermal formulations according to the FDA's inactive ingredient list. Owing to their fewer number of additives that may have a negative effect of cohesive properties, an opiate containing layer such as OM-2014-01-014 or OM-2014-01-022 provides preferred wear characteristics as well as delivery rates.

(39) For oxymorphone, the required therapeutic flux value is 3.97 g/cm.sup.2/h for a 42 cm.sup.2 transdermal drug delivery system (see Table 6 below). Currently with formulation OM-2014-01-014, the flux value is 4.01.2 g/cm.sup.2/h (n=8). The cumulative permeation of oxymorphone is 285.365.2 g/cm.sup.2 (n=8). Based on these results, a 42 cm.sup.2 transdermal drug delivery system would delivery at the therapeutic levels for 3 days. The estimated drug load per patch would be 38.2 mg for a 42 cm.sup.2 patch.

(40) The apparent lag time for all formulations ranged from 16-24 h based on point flux estimation calculations. That is, lag time was estimated from the point at which flux over time became statistically constant.

(41) Time increments of 8 h for 72 h duration were chosen for initial screening. Time increments as described in the proposal will be used for completing the in vitro permeation studies with the optimized formulation(s).

(42) TABLE-US-00009 TABLE 6 Comparison of parameters for opioids Parameters Oxycodone Oxymorphone Hydrocodone Hydromorphone Oral dose (mg/day) 80.0 40.0 80.0 45.5 Bioavailability 87% 10% 80% 24% Dose after first 69.6 4.0 64.0 10.9 pass effect (mg/day) Patch size 140 42 140 40 Required flux* 20.7 3.97 19.0 11.4 (g/cm.sup.2/h) *Required flux was derived from the following equation based on daily dose, bioavailability and a theoretical patch size

(43) $\mathrm{Required}\mathrm{Flux}\left(\frac{g}{{\mathrm{cm}}^2.Math.h}\right)=\frac{\mathrm{Dose}\left(\frac{\mathrm{mg}}{\mathrm{day}}\right)\mathrm{Bioavailability}\left(\%\right)}{\mathrm{Theoretical}\mathrm{patch}\mathrm{size}\left({\mathrm{cm}}^2\right)\mathrm{Time}\left(\frac{24h}{1\mathrm{day}}\right)}1000\frac{g}{\mathrm{mg}}$$\mathrm{Oxymorphone}\mathrm{Required}\mathrm{Flux}\left(\frac{g}{{\mathrm{cm}}^2.Math.h}\right)=\frac{40\left(\frac{\mathrm{mg}}{\mathrm{day}}\right)10\left(\%\right)}{42\left({\mathrm{cm}}^2\right)x\left(\frac{24h}{1\mathrm{day}}\right)}1000\frac{g}{\mathrm{mg}}$$\mathrm{Oxymorphone}\mathrm{Required}\mathrm{Flux}\left(\frac{g}{{\mathrm{cm}}^2.Math.h}\right)=3.97\frac{g}{{\mathrm{cm}}^2.Math.h}$
Dual Penetration Enhancer Formulations

(44) Formulations comprising dual penetration enhancers were investigated. Exemplified enhancers included combinations of oleyl alcohol and either (i) oleic acid; (ii) ethyl oleate and (iii) oleyl oleate. Formulations comprising dual enhancers include OM-01-043; OM-01-046; OM-01-047 and OM-01-048.

(45) All of the above formulations were cast and flux values were determined in pig skin and in human skin. The results are summarised in Table 7 and FIGS. 16 and 17. All the exemplified dual penetration enhancer formulations demonstrated marked increases in flux when compared to other exemplified formulations.

(46) TABLE-US-00010 TABLE 7 Summary of flux values for formulations OM-01-043: OM-01-046: OM-01-047 and OM-01-048 Flux Flux Compound (g/cm.sup.2/h) (PIG) (g/cm.sup.2/h) (human) OM-2014-01-043 4.2 1.11 n/a OM-2014-01-046 6.09 1.60 4.67 4.32 4.37 (65/w/f) (46/b/f) (59/w/f) OM-2014-01-047 6.05 1.12 n/a OM-2014-01-048 5.77 1.10 n/a

(47) Formulation (OM-01-046) was then subsequently tested in three different types of human skin. Three human donor skins were used. All skin donors were female.

(48) Skin donor one was white; aged 65 years. The flux was determined to be 4.67 ug/cm.sup.2/hr. The results are shown in FIG. 18.

(49) Skin donor two was black aged 46 years. The flux was determined to be 4.32 ug/cm.sup.2/hr. The results are shown in FIG. 19.

(50) Skin donor three was white aged 59 years. The flux was determined to be 4.37ug/cm.sup.2/hr. The results are shown in FIG. 20.

(51) It should be noted that for FIG. 20 there was a leakage in cell 3 at the end of the experiment. Flux values for 64 h and 72 h are artificially elevated. Instead of these data points, the average of 48 and 56 h values were used for the average flux calculations.

(52) Formulations OM-01-047 and OM-01-048 were also tested on human skin. The results are summarised in FIGS. 21 and 22.