ADMINISTRATION REGIMEN FOR A PHARMACEUTICAL PATCH COMPRISING LIDOCAINE AND DICLOFENAC

Abstract

The invention relates to a pharmaceutical patch comprising a Lidocaine constituent and a Diclofenac constituent, wherein the relative weight content ratio of the Lidocaine constituent to the Diclofenac constituent is within the range of from about 7:1 to about 4:1, based on the equivalent weight of the non-salt form of Lidocaine and of Diclofenac, for use in the local treatment or prevention of pain. The pharmaceutical composition is suitable for topical administration and local pharmacological action via delivery of Lidocaine and Diclofenac into the skin and possibly also through and to other deeper tissues such as the synovial fluid without significant systemic exposure.

Claims

1-68. (canceled)

69. A pharmaceutical patch comprising a Lidocaine constituent and a Diclofenac constituent, wherein the relative weight ratio of the Lidocaine constituent to the Diclofenac constituent is within the range of from about 7:1 to about 4:1, based on the equivalent weight of the non-salt form of Lidocaine and of Diclofenac, for topical use in the local treatment or prevention of pain, wherein the pharmaceutical patch is applied and remains applied to an area of the skin of a patient for an application period of more than about 12 hours; wherein after expiry of the application period, the pharmaceutical patch is removed from the skin, and no other pharmaceutical patch is applied to the area of the skin for an interruption period of at least about 1 hour.

70. The pharmaceutical patch for use according to claim 69, wherein the Diclofenac constituent comprises Diclofenac epolamine.

71. The pharmaceutical patch for use according to claim 69, wherein the Lidocaine constituent comprises Lidocaine in its non-salt form.

72. The pharmaceutical patch for use according to claim 69, wherein the relative weight ratio of the Lidocaine constituent to the Diclofenac constituent is within the range of from about 6.5:1 to about 4.5:1, based on the equivalent weight of the non-salt form of Lidocaine and of Diclofenac.

73. The pharmaceutical patch for use according to claim 69, wherein the total dose of the Lidocaine constituent is within the range of from about 600 mg to about 800 mg, based on the weight of the non-salt form of Lidocaine.

74. The pharmaceutical patch for use according to claim 69, wherein the total dose of the Diclofenac constituent is within the range of from about 85 mg to about 200 mg, based on the weight of the non-salt form of Diclofenac.

75. The pharmaceutical patch for use according to claim 69, which comprises a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.

76. The pharmaceutical patch for use according to claim 75, wherein the adhesive layer is a hydrogel or contains a hydrogel comprising at least a portion of the Lidocaine constituent and at least a portion of the Diclofenac constituent.

77. The pharmaceutical patch for use according to claim 69, wherein the pain is low back pain, pain due to osteoarthritis, visceral pain, rheumatoid pain, musculoskeletal pain, joint pain, gout pain, or inflammatory pain.

78. The pharmaceutical patch for use according to claim 69, wherein the application period is less than about 24 hours.

79. The pharmaceutical patch for use according to claim 69, wherein the interruption period is about 6 hours.

80. The pharmaceutical patch for use according to claim 69, wherein the application period lasts about 18 hours and the interruption period lasts about 6 hours.

81. The pharmaceutical patch for use according to claim 69, wherein the pharmaceutical patch is applied to the skin of the breast, or the skin of the knee, or the skin of the elbow, or the skin of the hip, or the skin of the hand, or the skin of the spine, or the skin of the back, particularly of the lower back.

82. A kit comprising a plurality of pharmaceutical patches as defined in claim 69 for use in the local treatment or prevention of pain, wherein a first pharmaceutical patch is applied and remains applied to an area of the skin of a patient for a first application period of more than about 12 hours, wherein after expiry of the first application period, the first pharmaceutical patch is removed from the skin, and no other pharmaceutical patch is applied to the area of the skin for a first interruption period of at least about 1 hour; wherein after expiry of the first interruption period, a second pharmaceutical patch is applied and remains applied to the area of the skin of the patient for a second application period of more than about 12 hours, wherein after expiry of the second application period, the second pharmaceutical patch is removed from the skin, and no other pharmaceutical patch is applied to the area of the skin for a second interruption period of at least about 1 hour.

83. The kit according to claim 82, wherein the first application period and the second application period are each about 18 hours, and wherein the first interruption period and the second interruption period are each about 6 hours.

Description

EXAMPLES

[0186] An interaction study was performed as a single dose study in the CFA-hindpaw inflammation, paw pressure test.

Part AIntraperitoneal Injection

[0187] In comparative example 1 and inventive examples 1 to 4 described below, a compound or combination of compounds was administered by intraperitoneal injection (FIGS. 1 to 9).

Comparative Example 1Separate Administration

[0188] A dose dependent efficacy of both compounds was observed when they were administered alone. Lidocaine showed dose dependent efficacy at a dose range of from 10 mg/kg to 46.4 mg/kg; ip (FIG. 1) and Diclofenac showed dose dependent efficacy at a dose range of from 21.5 mg/kg to 100 mg/kg; ip (FIG. 2).

Inventive Example 1Combined Administration (Ratio Lidocaine:Diclofenac=1:3.17)

[0189] A combination of Lidocaine:Diclofenac (21.5 mg/kg:68.1 mg/kg) was tested: [0190] Lidocaine/Diclofenac in CFA-PPT (% change to prevalue) [0191] Dose ratio (Lidocaine/Diclofenac): 21.5 mg/kg:68.1 mg/kg=1:3.17

[0192] The results for the time window of 0 to 90 min after administration are shown in FIG. 3. The results for the time window of 90 to 240 min after administration are shown in FIG. 4.

[0193] The experiment revealed that, under the given conditions, the intraperitoneal administration of Diclofenac (68.1 mg/kg; ip) and Lidocaine (21.5 mg/kg, ip) showed similar efficacy in the range of 20-25% when given alone. The combination of Diclofenac and Lidocaine showed additive interaction from 15 to 60 min post administration and showed a supra-additive (i.e. synergistic) effect at 90 min. This study showed again synergistic action 90 min after administration and probably 120 min after administration.

Inventive Example 2Combined Administration (Dose Ratio Lidocaine:Diclofenac=1:2.16)

[0194] A combination of Lidocaine:Diclofenac (31.6 mg/kg:68.1 mg/kg) was tested: [0195] Lidocaine/Diclofenac in CFA-PPT (% change to prevalue) [0196] Dose ratio (Lidocaine/Diclofenac): 31.6 mg/kg:68.1 mg/kg=1:2.16

[0197] The results are shown in FIG. 5. The combination of Lidocaine:Diclofenac in a ratio of 31.6 mg/kg:68.1 mg/kg=1:2.16 showed synergistic action 60 min, 90 min, 120 min and 180 min after administration.

Inventive Example 3Combined Administration (Dose Ratio Lidocaine:Diclofenac=2.16:1)

[0198] A combination of Lidocaine:Diclofenac (46.4 mg/kg:21.5 mg/kg) was tested: [0199] Lidocaine/Diclofenac in CFA-PPT (% change to prevalue) [0200] Dose ratio (Lidocaine/Diclofenac): 46.4 mg/kg:21.5 mg/kg=2.16:1

[0201] The results are shown in FIG. 6. Lidocaine:Diclofenac in a dose ratio of 46.4 mg/kg:21.5 mg/kg=2.16:1 showed synergistic action 90 min and 120 min after administration.

Inventive Example 4combined administration (ratio Lidocaine:Diclofenac=1:1.47)

[0202] A combination of Lidocaine:Diclofenac (31.6 mg/kg:46.4 mg/kg) was tested: [0203] Lidocaine/Diclofenac in CFA-PPT (% change to prevalue) [0204] Dose ratio (Lidocane/Diclofenac): 31.6 mg/kg:46.4 mg/kg=1:1.47

[0205] The results are shown in FIG. 7. Lidocaine:Diclofenac in a dose ratio of 31.6 mg/kg:46.4 mg/kg=1:1.47 showed synergistic action 90 min and 120 min after administration.

Summary of the Experiments with Intraperitoneal Administration

[0206] Intraperitoneal administration of Lidocaine (21.5 mg/kg, ip) and Diclofenac (68.1 mg/kg; ip) showed similar efficacy in the range of 20-25% when given alone. The combination of Lidocaine and Diclofenac showed additive interaction from 15 to 60 min post administration and showed a supra-additive (i.e. synergistic) effect at 90 min. As shown in FIG. 8, intraperitoneal administration of Lidocaine (21.5 mg/kg, ip) and Diclofenac (68.1 mg/kg; ip) showed similar efficacy in the range of 20-25% when given alone.

[0207] The combination of Diclofenac and Lidocaine showed additive interaction from 15 to 60 min post administration and showed a supra-additive effect at 90 min.

[0208] Lidocaine/Diclofenac in CFA-PPT (withdrawal thresholds) are shown in FIG. 9.

Part BTopical Application to the Skin

[0209] In comparative example 2 and inventive examples 5 to 8 as described below, a compound or combination of compounds was administered topically to the paw by means of an ointment or solution (FIGS. 10 to 18).

[0210] The efficacy was tested when a compound or a compositions of compounds was administered topically as an ointment or a solution. The study was performed on male albino rats (150-180 g body weight) to which an edema of paw was induced by injection of Complete Freunds Adjuvant (CFA). CFA is a composition of inactivated and dried Myobacteria tuberculoses, emulsified in mineral oil which is used as an immunopotentiator causing a painful reaction that lasts 7-8 days after subcutaneous injection.

[0211] The studies of comparative example 2 and inventive examples 5 to 8 were performed according to the following procedure: 50 L of CFA were injected sub plantar into the right hind paw, inducing mechanical-hyperalgesia after 24 hours. During a short anaesthesia an ointment comprising one compound or a combination of compounds was administered to the right hind paw and the paw was wrapped with polyethylene (PE)-foil and a smooth tape to prevent licking of the paw. The formulation of the vehicle was 4% hydroxypropylmethylcellulose (HPMC)/10% dimethylsulfoxide (DMSO) and aqua ini.

[0212] The pain was measured by pressing a pointer on the inflamed paw. The pointer exerts a force, increasing at a constant rate, monitored by a linear scale. Pain is deemed to be perceived one the rat starts to withdraw the paw. This value (withdrawal threshold in gram) is the pressure at which the animal feels pain (cut-off 450 g). Efficacy of the test compounds is expressed as a percent change of withdrawal threshold after compound administration to the pre-value (withdrawal threshold before compound administration).

Comparative Example 2Separate Administration

[0213] One hour was identified as an optimal incubation time (shown exemplary data for Lidocaine in FIG. 10). A dose dependent efficacy of both individual compounds was observed when topically administered. Lidocaine showed dose dependent efficacy at a dose range from 30 mg/ml to 60 mg/ml (FIG. 11) and Diclofenac showed dose dependent efficacy at a dose range from 40 mg/ml to 80 mg/ml (FIGS. 12 and 13).

Inventive Example 5Combined Administration (Concentration Ratio Diclofenac:Lidocaine=1.5:1)

[0214] A combination of Diclofenac:Lidocaine=1.5:1 (60 mg/ml: 40 mg/ml) was tested: [0215] Diclofenac/Lidocaine in CFA-PPT (% change to pre-value) [0216] Concentration ratio (Diclofenac/Lidocaine): 60 mg/ml: 40 mg/ml=1.5:1

[0217] The experiment revealed that under the given conditions topical administration of Diclofenac (60 mg/ml) and Lidocaine (40 mg/ml) after 90 min. showed similar efficacy in the range of 15-25% when given alone. The combination of Diclofenac and Lidocaine showed additive interaction from 90 to 120 min. post administration and showed a supra-additive (i.e. synergistic) effect from 120 to 180 min.

[0218] The results for the time window of 60 to 180 min after administration are shown in FIG. 14.

Inventive Example 6Combined Administration (Concentration Ratio of Diclofenac:Lidocaine=2:1)

[0219] Two combinations of Diclofenac:Lidocaine=concentration ratio of 2:1 (60 mg/ml: 30 mg/ml and 80 mg/ml: 40 mg/ml) were tested: [0220] Diclofenac/Lidocaine in CFA-PPT (% change to prevalue) [0221] Concentration ratio (Diclofenac/Lidocaine): 60 mg/ml: 30 mg/ml=2:1 and 80 mg/ml: 40 mg/ml=2:1

[0222] The combination of Diclofenac:Lidocaine in a concentration ratio of 60 mg/ml: 30 mg/ml=2:1 showed synergistic action 60 min, 90 min, 120 min and 180 min after administration (FIG. 15). The combination of Diclofenac:Lidocaine in a ratio of 80 mg/ml: 40 mg/ml=2:1 showed synergistic action 150 min and 180 min after administration (FIG. 16).

[0223] The efficacy of the combination of Diclofenac:Lidocaine in a concentration ratio of 80 mg/ml: 40 mg/ml=2:1 at 150 min and 180 min was substantially higher with values from around 40% to 50%, compared to the administration of 80 mg/ml of Diclofenac alone or 40 mg/ml of Lidocaine alone in the same time window which both showed an efficacy of under 15%.

Inventive Example 7Combined Administration (Concentration Ratio Diclofenac:Lidocaine=2.7:1)

[0224] A combination of Diclofenac:Lidocaine=concentration ratio of 2.7:1 (80 mg/ml: 30 mg/ml) was tested: [0225] Diclofenac/Lidocaine in CFA-PPT (% change to prevalue) [0226] Concentration ratio (Diclofenac/Lidocaine): 80 mg/ml: 30 mg/ml=2.7:1

[0227] The results are shown in FIG. 17. Diclofenac:Lidocaine in a concentration ratio of 80 mg/ml: 30 mg/ml=2.7:1 showed synergistic action 150 min and 180 min after administration.

Inventive Example 8Combined Administration (Concentration Ratio Diclofenac:Lidocaine=1:1)

[0228] A combination of Diclofenac:Lidocaine=1:1 (40 mg/ml: 40 mg/ml) was tested: [0229] Diclofenac/Lidocaine in CFA-PPT (% change to prevalue) [0230] Ratio (Diclofenac/Lidocaine): 40 mg/ml: 40 mg/ml=1:1

[0231] The results are shown in FIG. 18. Diclofenac/Lidocaine: 40 mg/ml: 40 mg/ml=1:1 (concentration ratio) showed better efficacy 120 min after administration.

[0232] Summary of the Experiments with Topical Application to the Skin

[0233] When applied topically the combinations of Diclofenac/Lidocaine at concentration ratios of 1.5:1, 2.2 and 2.7:1 showed synergistic interaction. A supraadditive effect mostly occurred at later timepoints, i.e. after at least 120 min post administration.

[0234] The combination of Diclofenac and Lidocaine according to the invention unexpectedly provides significant therapeutic superiority compared to the single agents due to a pharmacological interaction. Surprisingly, the addition of increasing doses of Lidocaine bestowed both a long-term pharmacological potentiation of Diclofenac and a coalistic pharmacological effect (neither drug active individually) across the diverse experimental testing.

Inventive Example 8Pharmaceutical Patch

[0235] A typical pharmaceutical patch according to the invention has a contact surface to the skin of 140 cm.sup.2 and is composed of a surface layer (backing) of non-woven polyethylene terephthalate, an adhesive layer comprising the Diclofenac constituent and the Lidocaine constituent in a hydrogel, and a removable release liner.

[0236] Typical ingredients of the adhesive paste forming the adhesive layer are compiled in the table here below:

TABLE-US-00004 Lidocaine (700 mg) Diclofenac epolamine (182 mg) methyl parahydroxybenzoate propyl parahydroxybenzoate propylene glycol sorbitol glycerol polyacrylic acid sodium polyacrylate sodium carmellose heavy kaolin aluminum glycinate sodium EDTA tartaric acid purified water urea

Inventive Example 9Pharmaceutical Patch

[0237] The relative systemic bioavailability of lidocaine and diclofenac of the patch according to inventive example 8 was compared to commercial patches only containing lidocaine (Versatis) and only containing diclofenac (Flector Tissugel). The relative systemic bioavailability of lidocaine and diclofenac after a single 18-hour application in the lumbar region of the fixed-dose combination patch containing lidocaine 5% and diclofenac epolamine 1.3% compared to Versatis and Flector Tissugel patches was assessed in healthy adult subjects. The clinical trial was designed as a randomized, single-site, open-label, single application, 3-way crossover, exploratory Phase I trial in healthy male and female subjects. The primary objective was to assess the relative systemic bioavailability of lidocaine and diclofenac released from the inventive patch and from the marketed patches Versatis and Flector Tissugel (diclofenac patch) following single application. Furthermore data were collected on skin irritation and patch adhesiveness. Bioequivalence assessment was not intended in this trial.

[0238] PK sampling was performed until 58 hours after patch application (=40 hours after patch removal). Subject dispositionsafety set: 22 subjects, PK set: 22 subjects. Enrollment VisitDay 1Allocation to treatment sequencesTreatment Period 1 (4 days), Treatment Period 2 (4 days) or Washout Phase 3-10 days between IMP applicationsTreatment Period 3 (4 days)Final Visit within 7-14 days after Treatment Period 3. In each treatment period, a single patch was applied for 18 hours, hospitalization from Day 1 until 40 hours after patch removal.

[0239] The mean plasma-concentration-time profiles of lidocaine following 18 h application of the patch according to the invention (T) and Versatis (R1)PK Set are shown in FIG. 19. It can be concluded that the time course of PK time profile for both patches was similar with an overall low exposure but continuously lower for the patch according to the invention.

[0240] The mean plasma-concentration-time profiles of 2,6-xylidine (metabolite of lidocaine) following 18 h application of the patch according to the invention (T) and Versatis (R1)PK Set are shown in FIG. 20. It can be concluded that the time course of PK time profile for both patches was similar with an overall low exposure but continuously lower for the patch according to the invention.

[0241] The mean plasma-concentration-time profiles of diclofenac following 18 h application of the patch according to the invention (T) and Flector (R2)PK Set are shown in FIG. 21. It can be concluded that the time course of PK time profile for both patches was similar with an overall low exposure but continuously lower for the patch according to the invention.

[0242] Summary of meanstandard deviation (coefficient of variation %, n) pharmacokinetic parametersPK-Set:

TABLE-US-00005 t.sub.max median (min-max C.sub.max AUC.sub.0-t AUC t.sub.1/2, z Compound Treatment range) [h] [ng/mL] [h*ng/mL] [h*ng/mL] [h] Lidocaine inventive 16.0 24.5 10.0 455 175 461 173 7.7 2.3 patch (8.00-22.0) (41%, 22) (39%, 22) (38%, 22) (30%, 22) Versatis 14.0 34.5 14.7 415 235 620 233 7.0 1.7 (10.0-22.0) (43%, 22) (38%, 22) (38%, 22) (25%, 22) 2,6-Xylidine inventive 21.0 1.6 0.7 39.5 17.7 51.7 16.0 13.0 2.3 patch (14.0-28.0) (44%, 22) (45%, 22) (31%, 15) (18%, 15) Versatis 20.0 2.2 0.9 54.3 21.9 68.2 17.8 12.6 4.0 (14.0-40.0) (41%, 22) (40%, 22) (26%, 17) (32%, 15) Diclofenac inventive 17.9 1.6 1.1 35.2 20.6 40.9 22.5 11.1 4.1 patch (10.0-24.0) (64%, 21) (59%, 21) (55%, 15) (37%, 15) Flector 17.9 3.4 1.8 63.5 30.7 62.1 35.9 8.4 2.8 (4.0-22.0) (53%, 22) (48%, 22) (58%, 15) (34%, 15)