Staple Stable, aqueous gel vehicles are provided for the topical application to the skin of irritating active ingredients such as retinoids, particularly tretinoin, with slow release of the active ingredient and minimal irritancy to the skin. The vehicles include a gelling agent effective to form a gel and hold the active ingredient in the aqueous medium for slow release on the skin, and an effective amount of an antioxidant to retard decomposition of the active ingredient. The vehicles and formulations are preferably aqueous emulsions which contain a solubilizing agent for the generally non-water soluble active ingredients, as well as usually an emulsifying agent and/or surfactant. Chelating agents, emollients, preservatives and other adjuvants and additives may also be included in the vehicles and formulations.
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1. A stable, aqueous retinoid composition for topical application to the skin with slow release of the retinoid and minimal irritancy to the skin, comprising:
(a) an aqueous medium such that the composition is at least about 40 weight percent water;
(b) an amount of retinoid effective for topical treatment of a skin condition, wherein said retinoid is tretinoin;
(c) an amount of a high molecular weight polyacrylic acid gelling agent neutralized to a ph of about 3 to 7 effective to form a gel and hold said retinoid for slow release in said aqueous medium; and
(d) an amount of antioxidant effective to retard decomposition of said retinoid in said aqueous medium.
0. 16. A method for topical treatment of a skin condition with tretinoin with minimal irritancy to the skin, comprising providing the tretinoin in a stable, aqueous composition for slow release of the tretinoin, the composition comprising:
(a) an aqueous medium such that the composition is at least about 40 weight percent water;
(b) an amount of tretinoin effective for topical treatment of a skin condition;
(c) an amount of a high molecular weight polyacrylic acid gelling agent neutralized to a ph of about 3 to 7 effective to form a gel and hold the tretinoin for slow release in said aqueous medium; and
(d) an amount of antioxidant effective to retard decomposition of the tretioin in said aqueous medium;
and topically applying the composition to the skin to be treated.
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Further, the formulation may contain up to about 10 weight percent of a lipophilic or hydrophobic agent, which may serve as an emollient or anti-irritant, as an additional help in relieving any irritation caused from the retinoid. Examples of such lipophilic agents include fatty materials such as fatty alcohols of about 12 to 20 carbon atoms, fatty acid esters having about 12 to 20 carbon atoms in the fatty acid moiety, petrolatum, mineral oils, and plant oils such as soybean oil, sesame oil, almond oil, aloe vera gel, and allantoin.
The formulations and vehicles of the present invention may further contain about 0.05 to 2 weight percent of a preservative or anti-microbial or anti-bacterial agent which prevents bacterial or microbial growth in the gel. Preferred preservatives include the parabens, preferably methyl paraben and ethyl paraben, and sorbitol. However, other conventional preservatives commonly used in pharmaceutical compositions will be readily recognized by those skilled in the art.
Finally, the vehicles and formulations of the present invention may optionally contain minor amounts of such other commonly used cosmetic adjuvants or additives as dyes, perfumes, sunscreens, etc., as will be readily recognized by those skilled in the art. In addition, it is also contemplated that the compositions of the invention may contain other topical active medicaments such as vitamins, lipids, hormones or anti-inflammatory agents, such as corticosteroids.
The invention will now be illustrated in more detail with reference to the following specific, non-limiting examples. The following formulation examples were tested for their particular effectiveness in preventing the oxidation of tretinoin. The formulations may contain varying amounts of tretinoin, such as 0.01, 0.025 or 0.05 weight percent. The results of these tests are set forth in Table II below, which shows the percent decomposition of tretinoin in the formulation vehicle after 10 months. Additional decomposition results for formulation Example 2 are set forth after Table II.
Ingredient
Weight Percent
CARBOPOL 940
0.4
Ethanol
3.0
Propylene glycol
3.0
BHT
0.015
Parabens
0.05
Tetrasodium EDTA
0.001
Polyethylene glycol 400
0.05
Triethanolamine
0.05
Water
q.s. to
100
All of the following Formulation Examples 2 through
7 contains the following components in addition to
those listed
Parabens
0.05%
Tetra-sodium EDTA
0.001%
Polyethylene glycol 400
0.05%
Triethanolamine
0.05%
Ingredient
Weight Percent
CARBOPOL 940
0.50
Propylene glycol
1.00
Ethanol
2.00
BHT
0.015
Water
q.s. to
100
Ingredient
Weight Percent
CARBOPOL 940
1.60
Propylene glycol
6.00
Ethanol
10.00
BHT
0.03
Water
q.s. to
100
Ingredient
Weight Percent
CARBOPOL 940
0.4
Propylene glycol
20.0
Ethanol
20.0
BHT
0.01
Water
q.s. to
100
Ingredient
Weight Percent
CARBOPOL 940
0.5
Propylene glycol
10.0
Ethanol
20.0
BHT
0.1
Water
q.s. to
100
Ingredient
Weight Percent
CARBOPOL 940
0.4
Propylene glycol
3.5
Ethanol
10.0
BHT
0.1
Water
q.s. to
100
Ingredient
Weight Percent
CARBOPOL 940
0.3
Propylene glycol
1.20
Isopropyl alcohol
1.90
BHT
0.01
Water
q.s. to
100
TABLE II
Stability Test Results
Formulation
Percent Decomposition
Example No.
of Tretinoin (10 months)
1
11
2
5
3
8
4
11
5
3
7
13
Formulation Example No. 2 was additionally tested for decomposition and found to have 2% decomposition of tretinoin after one month and about 13% decomposition of tretinoin after one year.
In order to test and demonstrate the effectiveness of the vehicles of the present invention in delivering retinoids in a less irritating manner while retaining therapeutic efficacy, the following studies were performed.
In order to assess the bio-equivalency of tretinoin in an aqueous gel base according to the present invention, compared to the presently FDA approved formulation (RETIN-A), the Rhino mouse model was utilized. Thus, topical tretinoin produces a dose-dependent reduction in the size of the horn-filled utriculi in Rhino mouse epidermis. In this study, equivalent concentrations of tretinoin (0.025 weight percent) in the CARBOPOL gel formulation of Formulation Example No. 2 and in the RETIN-A cream vehicle were applied daily to the dorsal trunk skin of Rhino mice for up to two months. At two-week intervals, biopsies and photographs were taken to assess the effect of the tretinoin on histology, reduction of utriculi and general skin appearance. The resulting histology showed equivalent activity in the Rhino mouse epidermis treated with tretinoin in either the CARBOPOL gel formulation or the RETIN-A formulation.
Similar studies performed with Rhino mice skin at 0.05 percent and higher concentrations of tretinoin showed equivalent activity in both the CARBOPOL gel and RETIN-A formulations.
Seventy volunteer subjects participated in this study to assess the therapeutic efficacy as well as the irritancy potential of aqueous gel formulations of the present invention versus the RETIN-A cream formulation. These subjects had all previously reported that they could not use the presently available formulations of tretinoin without experiencing irritation sufficient to cause them to discontinue the use of the drug. Subjects were given either a 0.025% or 0.05% tretinoin formulation in the CARBOPOL gel formulation of Formulation Example No. 2 above and were asked to apply the gel twice daily. These subjects were followed for six months, and results were evaluated by the attending dermatologist as well as the patient.
Sixty-seven of the volunteers completed the study. As compared to the 100% irritation reported by these volunteers who had all previously used the commercial 0.025% tretinoin formulation of RETIN-A, only 10 reported irritation using the CARBOPOL gel formulation of Example 2 above. Of these, three reported mild irritation with the 0.025% gel formulation, six reported mild irritation with the 0.05% gel formulation, and only one reported moderate irritation with the 0.05% gel formulation. None of the subjects reported severe irritation with either concentration of the gel formulation.
These results demonstrate that the slow release CARBOPOL gel formulations of the present invention were less irritating than the standard RETIN-A cream formulation. Subjects sensitive to RETIN-A were able to tolerate equivalent and stronger concentrations of tretinoin in the gel formulation without as much irritation, and therefore they continued to use the tretinoin as prescribed.
Additional subjects have been tested in studies with 0.01% tretinoin in the gel formulations of the present invention, with similar results being obtained. In general, the slow release gel vehicles of the present invention appear to be an effective method of delivering tretinoin in a less irritating manner while still maintaining therapeutic efficacy.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification as indicating the scope of the invention.
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