METHODS FOR THE TREATMENT OF ROSACEA

Abstract

The present invention relates to pharmaceutical compositions for topical use (including also dermatological compositions), for treating skin conditions and afflictions, such as rosacea and symptoms and conditions associated there from.

Claims

1. A composition for the topical treatment of rosacea, comprising as a sole pharmaceutical active agent benzoyl peroxide in solid form, wherein the composition comprises 5% by weight of said benzoyl peroxide and said composition is an oil-in-water emulsion; wherein said solid benzoyl peroxide is encapsulated as the core of a microcapsule having a shell comprising between 5-100 layers of metal oxide, and wherein said composition has a dissolution rate of less than 80% weight/h as measured in a medium of 55%:45% mixture of water and acetonitrile at ambient temperature.

2. The composition of claim 1, wherein said benzoyl peroxide has a dissolution rate of less than about 60% weight/h.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0158] In order to understand the disclosure and to see how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0159] FIG. 1 is a graph presenting the mean IGA per time of BPO composition of the invention (1% and 5% encapsulated BPO as described in example 1) as compared with vehicle alone over a period of time of 12 weeks.

[0160] FIG. 2 is a graph presenting the is the mean inflammatory lesion count per time of BPO composition of the invention (1% and 5% encapsulated BPO as described in example 1) as compared with vehicle alone over a period of time of 12 weeks.

[0161] FIG. 3 is a graph presenting the dissolution rate of BPO over a period of 60 minutes of a composition of the invention (5% E-BPO, produced according to Example #3), and Benzac AC 5% BPO and NeoBenz Micro 5.5%.

DETAILED DESCRIPTION OF EMBODIMENTS

Example 1: Encapsulation of BPO

[0162] Step 1: Milling:

[0163] 110 g. of hydrous BPO 75% (USP grade from Sigma) were suspended in 152 g. of 0.4% CTAC solution containing 0.001% silicon antifoam. The BPO was milled using a stator rotor mixer (Kinematika polytron 6100 operated at 15,000 rpm/25 m/s). The milling was stopped when the particle size distribution (PSD) of the suspension was d(0.9)<35 m or the temperature has reached 50 C. The final suspension was cooled to room temperature.

[0164] Step 2a: Coating Option #1:

[0165] During the coating procedure the suspension was stirred with a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of the milled BPO suspension was corrected to 8 using NaOH 5N solution. A portion of 1 g of 15% sodium silicate solution (15% w/w as SiO.sub.2) was added and the suspension was stirred for 5 min. A portion of 1 g of 3% Polyquaternium 7 was added and the suspension was stirred for 5 min. pH was adjusted to 6-7 using 5N HCl solution.

[0166] This procedure was repeated for 5-100 times in order to create a series of silica layers around BPO having different thickness.

[0167] Step 2b: Coating Option #2:

[0168] During the coating procedure the suspension was stirred with a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of the milled BPO suspension was corrected to 8 using NaOH 5N solution. A portion of 2.5 g of 15% sodium silicate solution (15% w/w as SiO.sub.2) was added and the suspension was stirred for 5 min. A portion of 2.5 g of 3% Polyquaternium 7 was added and the suspension was stirred for 5 min. pH was adjusted to 6-7 using 5N HCl solution.

[0169] This procedure was repeated for 5-100 times in order to create a series of silica layers around BPO having different thickness.

[0170] The Aging Step:

[0171] The coated BPO suspension at pH 6.5 was kept for aging at room temperature (25 C+/2) under gentle agitation for 24 hrs.

Example 2: Preparation of Encapsulated BPO (15% E-BPO Water Suspension)

[0172] a) Preparation of Benzoyl Peroxide Dispersion and Acid Cocktail

[0173] A benzoyl peroxide (BPO) dispersion was prepared by mixing 125.67 grams of CTAC CT-429 (Cetrimonium Chloride 30%), 3008 grams of hydrous benzoyl peroxide, and 5200 grams water under high shear. The dispersion was homogenized for 60 minutes at 33 C. (no more than 45 C.), and then the pH of the dispersion was adjusted to 7.0 using sodium hydroxide solution (20%).

[0174] An acid cocktail was prepared using 493 grams Hydrochloric acid (37%), 98 grams anhydrous Citric Acid, 147 grams Lactic Acid (90%), and 794 grams water.

[0175] b) Coating Cycle

[0176] The coating cycle was started by adding 38 grams sodium silicate solution extra pure (28%) to the benzoyl peroxide dispersion prepared in step a) under high shear, followed by adding the acid cocktail prepared in step (a) to adjust the pH to be lower than 6.8, and followed by adding 57 grams PDAC (3%) solution to the mixture. The cycle was repeated 50 times while the mixture was stirred under high shear for 17 hours. After the 50 cycles, the pH of the mixture was adjusted to 5.0 using the acid cocktail, and water was added to complete the total weight of the mixture to 15 kilograms. The composition of the final BPO water suspension product is shown in Table 1.

TABLE-US-00001 TABLE 1 Composition of the encapsulated BPO 15% water suspension Ingredient % of ingredient in the suspension Polyquarternium-7 0.53 Hydrochloric Acid 0.87 Citric Acid, Anhydrous 0.46 Lactic Acid 0.63 Silicon Dioxide 3.42 Sodium hydroxide 0.01 Cetrimonium Chloride 0.25 Hydrous Benzoyl Peroxide 15.00 Sterile Water for Irrigation Up to 100%

Example 3: Preparation of Formulation of Encapsulated BPO (5%) Gel (Formulation I)

[0177] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of Glyceryl Monosterate were mixed at 70 C. Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt were dissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%) were added to the solution. After the solution was heated to 70 C., 72.0 grams of Carbopol 980 NF were added and the resulting mixture was homogenized at 3300 rpm for 10 minutes to ensure that all materials completely melted and dissolved. 76.5 grams if sodium hydroxide (20%) were then added and the mixture was stirred under high shear for 10 minutes at no less than 70 C.

[0178] The oil phase was added to the water phase under high shear at 78 C., and the resulting emulsion was homogenized at 3300 rpm for 10 minutes. 72.0 grams of Citric Acid and 6,000 grams of encapsulated BPO 15% water suspension made as described in Example 2 were mixed. The resulting mixture was added to the emulsion at 65 C. and mixed at 1400 rpm for 10 minutes. The emulsion was cooled to 35 C. and the pH of the emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion was stirred at 1400 rpm for 10 minutes and then water was added until the total weight of the emulsion reached 18 kilograms. The composition of the formulation prepared in this example is shown in Table 2.

TABLE-US-00002 TABLE 2 Composition of Formulation I Ingredient % of pure ingredient in the composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1 Hydrous Benzoyl Peroxide 5.00 Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Water for Irrigation up to 100%

Example 4: Preparation of Placebo of Encapsulated BPO Water Suspension

[0179] a) Preparation of Placebo Dispersion and Acid Cocktail

[0180] A placebo dispersion was prepared by mixing 125.67 grams of CTAC CT-429 (Cetrimonium Chloride 30%), and 5200 grams and then the pH of the solution was adjusted to 7.0 using sodium hydroxide solution (20%).

[0181] An acid cocktail was prepared using 493 grams Hydrochloric acid (37%), 98 grams anhydrous Citric Acid, 147 grams Lactic Acid (90%), and 794 grams water.

[0182] b) Coating Cycle

[0183] The coating cycle was started by adding 38 grams sodium silicate solution extra pure (28%) to the placebo solution prepared in step a) under high shear, followed by adding the acid cocktail prepared in step (a) to adjust the pH to be lower than 6.8, and followed by adding 57 grams PDAC (3%) solution to the mixture. The cycle was repeated 50 times while the mixture was stirred under high shear for 17 hours. After the 50 cycles, the pH of the mixture was adjusted to 5.0 using the acid cocktail, and water was added to complete the total weight of the mixture to 15 kilograms. The composition of the final placebo water suspension product is shown in Table 3.

TABLE-US-00003 TABLE 3 Composition of placebo of encapsulated BPO water suspension Ingredient % of ingredient in the suspension Polyquarternium-7 0.53 Hydrochloric Acid 0.87 Citric Acid, Anhydrous 0.46 Lactic Acid 0.63 Silicon Dioxide 3.42 Sodium hydroxide 0.01 Cetrimonium Chloride 0.25 Sterile Water for Irrigation Up to 100%

Example 5: Preparation of Formulation of Vehicle of Encapsulated BPO Gel (Formulation II)

[0184] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of Glyceryl Monosterate were mixed at 70 C.

[0185] Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt were dissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%) were added to the solution. After the solution was heated to 70 C., 72.0 grams of Carbopol 980 NF were added and the resulting mixture was homogenized at 3300 rpm for 10 minutes to ensure that all materials completely melted and dissolved. 76.5 grams if sodium hydroxide (20%) were then added and the mixture was stirred under high shear for 10 minutes at no less than 70 C.

[0186] The oil phase was added to the water phase under high shear at 78 C., and the resulting emulsion was homogenized at 3300 rpm for 10 minutes. 72.0 grams of Citric Acid and 6,000 grams of placebo of encapsulated BPO water suspension made as described in Example 4 were mixed.

[0187] The resulting mixture was added to the emulsion at 65 C. and mixed at 1400 rpm for 10 minutes. The emulsion was cooled to 35 C. and the pH of the emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion was stirred at 1400 rpm for 10 minutes and then water was added until the total weight of the emulsion reached 18 kilograms. The composition of the formulation prepared in this example is shown in Table 4.

TABLE-US-00004 TABLE 4 Composition of Formulation II Ingredient % of pure ingredient in the composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1 Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Water for Irrigation up to 100%

Example 6: Preparation of Formulation of Encapsulated BPO (1%) Gel (Formulation III)

[0188] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams of Glyceryl Monosterate were mixed at 70 C.

[0189] Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt were dissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%) were added to the solution. After the solution was heated to 70 C., 72.0 grams of Carbopol 980 NF were added and the resulting mixture was homogenized at 3300 rpm for 10 minutes to ensure that all materials completely melted and dissolved. 76.5 grams if sodium hydroxide (20%) were then added and the mixture was stirred under high shear for 10 minutes at no less than 70 C.

[0190] The oil phase was added to the water phase under high shear at 78 C., and the resulting emulsion was homogenized at 3300 rpm for 10 minutes. 72.0 grams of Citric Acid, 1200 grams of encapsulated BPO 15% water suspension made as described in Example 2 and 4800 grams of placebo of encapsulated BPO water suspension as described in Example 4 were mixed. The resulting mixture was added to the emulsion at 65 C. and mixed at 1400 rpm for 10 minutes. The emulsion was cooled to 35 C. and the pH of the emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion was stirred at 1400 rpm for 10 minutes and then water was added until the total weight of the emulsion reached 18 kilograms. The composition of the formulation prepared in this example is shown in Table 5.

TABLE-US-00005 TABLE 5 Composition of Formulation III Ingredient % of pure ingredient in the composition Polyquarternium-7 0.17 Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21 Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1 Hydrous Benzoyl Peroxide 1.00 Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Water for Irrigation up to 100%

Example 7: Efficacy Study of BPO in a Composition of the Invention

[0191] A multi-center, double-blind, randomized, vehicle-controlled, dose-range study was performed. Study duration was 12 weeks on mild to severe facial rosacea patients using encapsulated benzoyl peroxide gel, 1% (as described in Example 6) and 5% (as described in Example 3), and vehicle gel (as described in Example 5) once daily.

[0192] A total of 92 subjects were randomly assigned in a 1:1:1 ratio to 5% E-BPO Gel, 1% E BPO Gel, or Vehicle Gel.

[0193] The investigator performed the Investigator Global Assessment (IGA) and inflammatory lesion (papules and pustules) counts at Screening, Baseline, and Weeks 4, 8, and 12 (end of study).

[0194] Evaluation of Efficacy:

[0195] The first application of the test product was applied at the investigational site at the end of the Baseline visit (Day 0) under the supervision and instruction of the designated investigational site staff. The investigator performed the Investigator Global Assessment (IGA) and inflammatory lesion (papules and pustules) counts at Screening, Baseline, and Weeks 4, 8, and 12 (end of study) and erythema and telangiectasia assessments at Baseline, and Weeks 4, 8, and 12 (end of study). The evaluator also assessed local application site irritation (dryness, scaling, pruritus, stinging and burning) at Baseline and Weeks 2, 4, 8 and 12 (end of study). At selected investigational site(s), standardized photography of facial rosacea also was performed at Baseline and Week 8 and 12 (end of study). Information on adverse events (AEs) was collected at all visits.

[0196] Efficacy endpoints were: Proportion of subjects with the primary measure of success, defined as a 2-grade improvement in the IGA relative to Baseline at Week 12, with the Week 12 IGA of clear or almost clear. Change in inflammatory lesion count at Week 12.

[0197] Results:

[0198] Baseline Characteristics: The Baseline characteristics were similar among the treatment groups for IGA and telangiectasia. While the median inflammatory lesion counts were similar among the treatment groups, the mean inflammatory lesion count was numerically higher for 1% E-BPO Gel than for 5% E-BPO Gel and for 1% E-BPO Gel and 5% E-BPO Gel than for Vehicle Gel, and a numerically higher proportion of subjects in 1% E-BPO Gel than in 5% E-BPO Gel and 1% E-BPO Gel and 5% E-BPO Gel than in Vehicle Gel had severe inflammatory lesion erythema at Baseline. A numerically higher proportion of subjects in 1% E-BPO Gel and 5% E-BPO Gel than in Vehicle Gel had severe rosacea erythema

[0199] Primary Efficacy Analyses

[0200] For the Primary Efficacy Endpoints:

[0201] The proportions of subjects with the primary measure of success (defined as a 2-grade improvement in the IGA relative to Baseline at Week 12, with the Week 12 IGA of clear or almost clear) were 20.0% (6/30) for Vehicle Gel, 37.5% (12/32) for 1% E-BPO Gel, and 53.3% (16/30) for 5% E-BPO Gel. The improvement in mean IGA is described in FIG. 1.

[0202] The proportions of subjects with the 2.sup.nd primary measure of success (defined as mean inflammatory lesion count percent change from Baseline at Week 12) were about 30.0% for Vehicle Gel and more than 60% for 1% E-BPO Gel and 5% E-BPO Gel

[0203] The improvement in inflammatory lesion count is described in FIG. 2.

Example 8: Measuring the Dissolution Rate of BPO from a Composition of the Invention

[0204] Weighing of Samples

[0205] A sample was weighed according to its BPO content in amount equivalent to 40 mg of BPO. Examples for weight of samples are given in the table below.

TABLE-US-00006 Concentration of BPO in the sample (C.sub.0) 1% (w/w) 5% (w/w) 10% (w/w) Weight of sample, mg 3200-4800 640-960 320-480

[0206] Preparation of Samples and Measurement Procedure

[0207] The sample was weighed into a 250 mL Erlenmeyer flask, 200 mL of medium were added and a 3.0 cm length magnetic bar was inserted, the flask was placed on the stirrer and stirring at 400 rpm was started. 2 mL at specified time intervals were withdrawn and filtered through 0.2 m GHP Acrodisc syringe filter (first mL discarded). The concentration of BPO (in % w/w) dissolved in each time interval (C.sub.n) were calculated.

[0208] The medium was prepared by mixing 550 mL of water with 450 mL of acetonitrile, which were than equilibrated to ambient temperature.

[0209] The dissolution rate was measured according to the following formula:

The dissolution rate (%)=(C.sub.n/C.sub.0)*100%

[0210] Dissolution Rate of BPO in Compositions of the Invention

[0211] The dissolution rate of a composition of the invention comprising 5% E-BPO, produced according to Example #3, were compared with the dissolution of Benzac AC 5% BPO and NeoBenz Micro 5.5%. As can be seen from the results presented in FIG. 3, the dissolution rate of a composition of the invention was much lower than the dissolution of the above commercial products.