Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-09-28
2001-08-07
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S947000, C514S861000, C514S863000
Reexamination Certificate
active
06271219
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to topical pharmaceutical compositions comprising a pharmaceutically active agent, laurocapram, and one or more diols, particularly propylene glycol. The invention further relates to the use of the topical pharmaceutical compositions.
2. Related Art
A number of patents disclose compounds which enhance the penetration of physiologically active agents through the skin. See U.S. Pat. Nos. 4,122,170, 4,316,893, 4,444,762, 4,886,783, and 5,834,010.
U.S. Pat. No. 4,552,872 discloses topical pharmaceutical compositions comprising a pharmaceutically active corticosteroid together with a penetration enhancing vehicle containing a C
3
-C
4
diol, and a cell-envelope disordering compound such as oleic acid. The vehicle is substantially free of saturated, straight chain C
16
-C
20
alcohols and C
4
-C
20
mono- or dicarboxylic acids.
U.S. Pat. No. 4,557,934 discloses topical pharmaceutical compositions containing a pharmaceutically active agent, the penetrating enhancing agent 1-dodecylazacycloheptan-2-one (laurocapram), in combination with certain C
3
-C
4
diols. A preferred diol is propylene glycol. Preferred pharmaceutically active agents include corticosteroids such as triamcinolone acetonide, vitamins, antifungal agents, blood calcium regulators, etc.
U.S. Pat. Nos. 4,552,872, and 4,557,934 also teach that certain straight chain, saturated C
16
-C
20
normal fatty alcohols may interfere with penetration of the pharmaceutically active agents in the diol formulations, particularly, the propylene glycol formulations, and should be avoided if such interference is too great. In particular, the patents teach that cetyl (C
16
) and stearyl (C
18
) n-alcohols are capable of significant interference with the penetration enhancement of the formulation. In a preferred embodiment, the compositions are substantially free of such compounds and preferably contain less than 0.5% of cetyl or stearyl alcohol. Example 9 of the '934 patent shows that the skin penetration of the pharmaceutically active agent triamcinolone acetonide from a propylene glycol vehicle is reduced 39% upon the addition of cetyl alcohol at a concentration of 3% by weight.
Surprisingly, it has now been discovered that topical formulations comprising significant amounts of a pharmaceutically active agent such as a corticosteroid, cetyl alcohol, stearyl alcohol, laurocapram and a diol, preferably propylene glycol, are very effective in treating dermatological conditions.
SUMMARY OF THE INVENTION
The invention relates to a pharmaceutical composition for topical administration, comprising:
(a) a safe and pharmaceutically effective amount of a pharmaceutically active agent;
(b) about 15-97% by weight of a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and mixtures thereof;
(c) about 0.5-25% by weight of cetyl alcohol,
(d) about 0.1-25% by weight of glyceryl monostearate;
(e) about 0.9-5.0% by weight of laurocapram;
(f) about 0.5-25% by weight of stearyl alcohol;
(g) about 0.01-1.0% by weight of sodium lauryl sulfate; and
(h) water.
The invention also relates to a process for preparing a topical pharmaceutical composition, comprising:
(a) admixing water, a diol and sodium lauryl sulfate at about 70-80° C. at least until the diol and sodium lauryl sulfate dissolve to give an Aqueous Phase Mixture Part A, wherein said diol is selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and mixtures thereof;
(b) admixing laurocapram and a pharmaceutically active agent at about 70-80° C. at least until the agent dissolves to give an Agent/Laurocapram Premix Part B;
(c) admixing glyceryl monostearate, cetyl alcohol and stearyl alcohol at about 70-80° C. until at least the admixture melts;
(d) admixing with said melted admixture said Agent/Laurocapram Premix Part B at about 70-80° C. and mixing at least until thoroughly blended to give an Oil (non-aqueous) Phase Mixture Part C;
(e) emulsifying a mixture of Aqueous Phase Mixture Part A and the Oil (non-aqueous) Phase Mixture Part C at about 70-80° C.; and
(f) cooling to room temperature.
The pharmaceutically active agent may be added to the Aqueous Phase in step (a) or to the Oil (non-aqueous) Phase in step (d) depending upon the solubility of the pharmaceutically active agent.
The invention also relates to a pharmaceutical composition obtained by the process of the invention.
The invention also relates to a method of treating an inflammatory skin condition in an animal in need thereof, comprising administering an effective amount of the inventive pharmaceutical composition to said animal, wherein the pharmaceutically active agent in the composition is an anti-inflammatory agent, preferably, a corticosteroid, more preferably, triamcinolone, most preferably, triamcinolone acetonide.
The invention relates in part to the discovery that topical pharmaceutical compositions containing pharmaceutically active agents such as corticosteroids, and substantial amounts of cetyl alcohol and stearyl alcohol are very effective topical therapeutic agents, e.g., for treating dermatological conditions. The pharmaceutical composition of the invention comprising 0.05% triamcinolone acetonide as the pharmaceutically active agent was found to potently induce vasoconstriction, and to provide relief from the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The present invention provides for substantial cost savings due to a reduction in the required level of pharmaceutically active agent, results in a rapid onset of pharmacological effects, and is stable and non-irritating. In addition, preservatives are not required and the inventive compositions have acceptable cosmetic and aesthetic properties.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention relates to a pharmaceutical composition for topical administration, comprising:
(a) a safe and pharmaceutically effective amount of a pharmaceutically active agent;
(b) about 15-97% by weight of a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and mixtures thereof,
(c) about 0.5-25% by weight of cetyl alcohol;
(d) about 0.1-25% by weight of glyceryl monostearate,
(e) about 0.9-5.0% by weight of laurocapram;
(f) about 0.5-25% by weight of stearyl alcohol;
(g) about 0.01-1.0% by weight of sodium lauryl sulfate, and
(h) water.
The preferred diol is 1,2-propanediol, i.e., propylene glycol. The preferred source of glyceryl monostearate is CERASYNT® SD which is a non-compendial emulsifier available from Van Dyk & Co., Inc., although other self-emulsifying grades of glyceryl monostearate may be employed.
Examples of pharmaceutically active agents useful in the present invention include, without limitation, corticosteroids such as hydroxytriamcinolone, alpha methyl dexamethasone, dexamethasone acetate, betamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone, difluorosone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butylester, flucortolone, fluprednidine (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, 11-desoxycortisol, methylprednisolone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolene acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, clocortelone, clocortelone pivalate, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, paramethasone acetate, prednisolone
Allan Geoffrey
Gerhart Donald J.
Helmy Atef A.
Manning George N.
Vaidyanathan Rajaram
Jarvis William R. A.
Kim Vickie
Sterne Kessler Goldstein & Fox P.L.L.C.
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