Topical pharmaceutical formulations containing a low concentration of benzoyl peroxide in suspension in water and a water-miscible organic solvent

Abstract

An aqueous formulation for topical application to the skin comprising water, a water-miscible organic solvent, and benzoyl peroxide, wherein the concentration of the organic solvent is sufficient to provide a stable suspension of benzoyl peroxide in the aqueous formulation without the inclusion of a surfactant in the formulation, wherein the ratio of concentrations of water and organic solvent in the formulation is sufficient to maintain the benzoyl peroxide in saturated solubility in the formulation following application to the skin, and wherein the concentration of benzoyl peroxide in the formulation is less than 5.0% and at least 1.0% w/w. The formulation may further contain a chemical compound in addition to benzoyl peroxide that is effective in the treatment of acne. The aqueous formulations of the invention are useful in the treatment of acne and acne rosacea.

Claims

1. An aqueous formulation for topical application to the skin comprising about 3.75% w/w benzoyl peroxide, about 5.0% w/w propylene glycol, about 1.2% w/w clindamycin phosphate, about 1.75% w/w carboxyvinyl polymer gelling agent and about 87.8% w/w water.

2. The aqueous formulation according to claim 1, wherein benzoyl peroxide is distributed in the formulation as a uniform suspension.

3. The aqueous formulation according to claim 2, wherein the suspended benzoyl peroxide has a mean particle size of less than 100 microns.

4. The aqueous formulation according to claim 2, wherein the aqueous formulation is free of surfactant.

5. The aqueous formulation according to claim 2, wherein the aqueous formulation comprises a surfactant.

6. A method for treating acne comprising applying once a day for up to 12 weeks to the skin of a patient in need thereof an aqueous formulation according to claim 1.

7. The method according to claim 6, wherein the aqueous formulation is applied to the face, neck, back, or chest of the patient.

8. The method according to claim 6, wherein the aqueous formulation is free of surfactant.

9. The method according to claim 6, wherein the aqueous formulation comprises a surfactant.

10. A method for treating acne rosacea comprising applying to the skin of a patient in need thereof an aqueous formulation according to claim 1 one or more times daily for a time sufficient to ameliorate the signs and symptoms of acne rosacea.

11. The method according to claim 10, wherein the aqueous formulation is free of surfactant.

12. The method according to claim 10, wherein the aqueous formulation comprises a surfactant.

Description

EXAMPLE 1EXEMPLARY FORMULATION OF THE INVENTION

(1) A pharmaceutical formulation of the invention was made containing the following components as shown in Table 1.

(2) TABLE-US-00001 TABLE 1 COMPONENT % w/w Benzoyl peroxide 2.5 Propylene glycol 5.0 Carbopol 980? 1.75 Potassium hydroxide 0.5 Water QS 100 (90.25)

EXAMPLE 2ADDITIONAL EXEMPLARY FORMULATIONS OF THE INVENTION

(3) Two pharmaceutical formulations of the invention containing an anti-acne medication in addition to benzoyl peroxide was made containing the following components as shown in Table 2.

(4) TABLE-US-00002 TABLE 2 Formulation A Formulation AA COMPONENT (% w/w) (% w/w) Benzoyl peroxide 2.5 3.75 Propylene glycol 5.0 5.0 Clindamycin phosphate 1.2* 1.2 Carbopol 980? 1.75 1.75 Potassium hydroxide 0.5 0.5 Water QS 100 (89.05) QS 100 (87.8) *equivalent to 1.0% clindamycin

EXAMPLE 3COMPARATIVE EFFICACY

(5) The aqueous gel formulation of Example 2 containing 2.5% benzoyl peroxide, 5% propylene glycol, 89% water, and 1% clindamycin was tested for efficacy in the treatment of acne lesions in a large clinical study in which 399 patients were treated. This formulation of the invention is Formulation A. A similar aqueous gel formulation containing 5.0% benzoyl peroxide, 10% propylene glycol, 82.5% water, and 1.0% clindamycin was made and tested for efficacy in the treatment of acne lesions in a second clinical study of very similar design. This formulation, which is not of the invention, is Formulation B. These results were compared with data provided in the prescribing information on the efficacy of an aqueous gel commercial product containing 5.0% benzoyl peroxide, 1% clindamycin, dioctyl sodium sulfosuccinate (surfactant), and water (BenzaClin? Topical Gel, Dermik Laboratories, Bridgewater, N.J.). This prior art formulation is Formulation C. Formulations A and B contained no surfactant. Formulation A was applied only once daily whereas Formulations B and C, each of which contain 5.0% benzoyl peroxide, were applied twice daily during the 12 week treatment period. Formulation A was tested after 12 weeks of application. The data for Formulations B and C is following 10 weeks of application. A formulation containing 3.75% benzoyl peroxide, Formulation AA, was also tested according to the procedure for Formulation A. Formulation AA also contained propylene glycol (5.0% w/w), clindamycin phosphate (1.2% w/w), Carbopol 980? (1.75% w/w), potassium hydroxide (0.5% w/w), and water (QS 100%). Formulation AA contained no surfactant.

(6) Test subjects were instructed to apply the formulation to the face, either twice daily for Formulations B and C or once daily for Formulations A and AA. After 10 weeks for Formulations B and C, and after 12 weeks for Formulations A and AA, the mean percent reduction in inflammatory lesions and non-inflammatory acne lesions was determined. The percentage reduction in inflammatory lesions (pustules and papules) was calculated by subtracting the total inflammatory lesion counts at the end of the study (10 or 12 weeks) from the baseline total inflammatory lesion counts, times 100, and divided by the baseline total inflammatory lesion counts. Non-inflammatory lesions comprised open comedones and closed comedones, and the percentage reduction in non-inflammatory lesions was calculated in the same way. The results of this acne study are shown in Table 3.

(7) TABLE-US-00003 TABLE 3 Formulation Formulation Formulation Formulation A B C AA Number of 399 481 215 253 Subjects Mean % 48.8 59.2 53.5 60.6 Reduction in Inflammatory Acne Lesions Mean % 42.6 51.0 36.1 51.6 Reduction in Non- inflammatory Acne Lesions

(8) The data of Table 3 shows that the efficacy of Formulation A containing only 2.5% benzoyl peroxide was similar to that of Formulations B and C. These results are especially surprising in view of the fact that Formulation A was applied only once daily whereas Formulations B and C were applied twice daily. Formulation AA containing 3.75% benzoyl peroxide and 1.2% clindamycin phosphate exhibited higher efficacy than the Formulation A containing 2.5% benzoyl peroxide and 1.2% clindamycin phosphate. Surprisingly, Formulation AA also exhibited higher efficacy than Formulations B and C containing 5% benzoyl peroxide.

EXAMPLE 4IRRITATION POTENTIAL

(9) Formulations A and B of Example 3, each containing benzoyl peroxide and 1.0% clindamycin, were tested to determine the comparative irritation potential of these two formulations. Formulation A of the invention contains 2.5% benzoyl peroxide, propylene glycol at two times the concentration of the benzoyl peroxide, and water at a concentration 17.8 times that of the propylene glycol. Formulation B contains 5.0% benzoyl peroxide, propylene glycol at two times the concentration of the benzoyl peroxide, and water at a concentration 8.25 times that of the propylene glycol.

(10) Gel formulations A and B were applied under separate occlusive patches to the backs of 33 healthy subjects three times a week for three weeks. Each application was observed 48 hours following each application for signs of irritation or inflammation by evaluators and assigned a score using a standardized grading system for irritation on a severity scale of 0 (no sign of irritation) to 4 (erythema with edema and blistering). Data from this study shows that use of Formulation A of the invention produced a 33% decrease in overall cumulative irritation score compared to use of Formulation B.

(11) In addition, Formula A and Formulation AA exhibited similar adverse event profiles. The expectation was that the number of subjects reporting adverse events (for example, redness, itching, and burning) would be higher for Formulation AA, having a higher concentration of benzoyl peroxide, than for Formulation A. The unexpected results of combination AA are shown in Table 4. The number of subjects reporting one or more adverse events were similar for Formulation A and Formulation AA, and both formulations were similar to vehicle.

(12) TABLE-US-00004 TABLE 4 Formulation Vehicle AA AA Formulation A Vehicle A Number of Subjects 243 236 386 188 Number of subjects who 54 of 243 57 of 236 106 of 386 50 of 188 reported one or more adverse (22.2%) (24.2) (27.5) (26.6) events Number of adverse events 4 of 68 7 of 71 5 of 139 4 of 78 related to or possibly related to (5.8%) (9.9%) (3.6%) (5.1%) study medication.sup.a .sup.aBased on total number of events.

(13) Further modifications, uses, and applications of the invention described herein will be apparent to those skilled in the art. It is intended that such modifications be encompassed in the above description and in the following claims.