Acne is treated or prevented by the topical application of compositions containing an alkanolamine such as dimethylaminoethanol, tyrosine, and a sulfur ingredient such as lipoic acid or glutathione. Adjunct ingredients such as fatty acid esters of ascorbic acid, e.g., ascorbyl palmitate and .alpha.-hydroxy acids may be included in the formulations. Compositions of the invention may be used alone, or, in many preferable embodiments, in combination with conventional acne medications such as anti-acne products containing salicylic acid, benzoyl peroxide, or a retinoid. In these embodiments, alkanolamine compositions of the invention are applied to affected skin areas first, and then a conventional acne medication is applied. This maximizes the efficacy of the treatment while minimizing skin irritation caused by conventional medications.

BRIEF SUMMARY OF THE INVENTION

It is an objective of this invention to provide improved compositions and methods for the treatment of acne vulgaris, both during the active phase, and for acneform scars afterwards, and for the prevention of acne and pore size reduction. It is another objective of the invention to provide acne compositions and ingredients for compositions that can be used in combination with conventional acne medications to reduce inflammation and redness, and that follow, efficacious compositions illustrating the invention contain 2 to 3% DMAE.

DMAE and/or other structurally related alkanolamines are applied in compositions that contain tyrosine and a sulfur ingredient. Alkanolamine compositions of the invention typically contain from about 0.01% to about 6%, more narrowly from about 0.03% to about 5% by weight, and, in many embodiments, from about 0.2% to about 0.5% by weight tyrosine, based on the total composition. Compositions illustrated in the examples that follow contain from 0.1 to 0.5% tyrosine.

The sulfur ingredient includes, but is not limited to, sulfur, sulfacetamide, a combination of sulfur and resorcinol (often called "sulfur resorcinol" in the literature), a combination of sulfur and resorcinol monoacetate, lipoic acid, glutathione, and their biologically active derivatives. Sulfur ingredients are typically present in the alkanolamine compositions of the invention in amounts ranging from about 0.1% to 0.5% up to 15%, more narrowly from about 0.5% to 10% by weight. Sulfur (5%) and sodium sulfacetamide (10%) are active ingredients marketed as a Plexion.TM. suspension. Where sulfur and resorcinol or sulfur and resorcinol monoacetate are all are part of the sulfur ingredient, typical concentrations range from about 3% to about 8 to 10% by weight of the composition.

Lipoic acid is the sulfur ingredient used in some embodiments illustrated hereafter. The term "lipoic acid" encompasses thioctic acid (1,2-dithiolane-3-pentanoic acid; 1,2-dithiolane-3-valeric acid), C.sub.8H.sub.14O.sub.2S.sub.2, formula weight 206.32, and its reduced form, dihydrolipoic acid. It has been variously known as acetate replacing factor, protogen A, and pyruvate oxidation factor. As used herein, where the properties and advantages of "lipoic acid" (or LA) are discussed as an active ingredient in the practice of the invention, both lipoic acid and its derivatives are encompassed. "Lipoic acid derivatives" include thioctic acid esters, particularly alkyl esters such as fatty acid esters, amides, particularly those isolated from or mimicking naturally occurring lipoamides, salts, particularly alkali metal salts, anhydrides and specifically includes the reduced form, dihydrolipoic acid and its esters, amides and salts. One particularly efficacious derivative that exhibits increased cellular uptake and biological activity useful in the practice of the invention is N,N-dimethyl,N-2-amidoethyl lipoate recently described by Sen, C. K., et al. (Free Radical Biol. Med., 1998, 25: 89) and called lipoic acid plus (LA-Plus). Derivatives may also include those involving other reactive groups known to those skilled in the art. As used herein, the term "derivatives" includes metabolic precursors of lipoic acid. Where lipoic acid derivatives are employed, they must be functionally equivalent to lipoic acid.

Since lipoic acid is both fat- and water-soluble, it is an advantage of the invention that, where employed, lipoic acid can be used as an active ingredient in either lipid or aqueous-based compositions, and it readily crosses cellular membranes and disperses in extracellular and intracellular tissue components. It is another advantage of the invention that lipoic acid has been used previously for the treatment of scars (U.S. Pat. No. 5,965,618 to Perricone), including atrophic acneform scars, and for the treatment of acne (U.S. application Ser. No. 09/475,514, filed 30 Dec. 1999 and allowed on 21 Dec. 2001). Employing it with alkanolamines and other active ingredients significantly improves the effect. Lipoic acid-containing formulations typically contain from about 0.1% to about 7% by weight lipoic acid. Many embodiments contain more than 1 weight % lipoic acid, e.g., from about 1.1% to about 3 to 5% by weight lipoic acid. One efificacious embodiment contains from about 2% to about 3% lipoic acid by weight.

Another sulfur ingredient useful in alkanolamine compositions and illustrated hereafter is glutathione. The term "glutathione" encompasses the tripeptide N-(N-L-.gamma.-glutamyl-L-cysteinyl)glycine, often called L-glutathione, glutathione-SH, or .gamma.-Glu-Cys-Gly, and sold under a variety of tradenames such as Agifutol S.TM., Copren.TM., Deltathione.TM., Isethion.TM., Neuthion.TM., Tathiclon.TM., Tathion.TM. and Triptide.TM.. An advantage of this embodiment of the invention is that glutathione, the major low molecular weight thiol in living plant or animal cells, is readily available and known to be safe when applied topically. As used herein, where the properties and advantages of "glutathione" (or GSH) are discussed as an active ingredient in the practice of the invention, biologically active glutathione derivatives are encompassed. "Glutathione derivatives" include, but are not limited to, reduced glutathione (or GSSG), glutathione salts, particularly reduced glutathione potassium or sodium salts, and glutathione alkyl esters, particularly C.sub.1 to C.sub.10 alkyl esters, especially monoesters such as monomethyl and monoethyl esters which have the glycine carboxylic acid grou acylated, as these have been shown to increase cellular levels of glutathione (U.S. Pat. No. 4,710,489 to Meister), and corresponding amides and imides (such as those set out in U.S. Pat. No. 5,541,162 to Ohmori, etal. Where employed, glutathione-containing compositions of the invention contain from about 0.5% to about 15%, more narrowly from about 5% to about 10% by weight, and even more narrowly from about 8% to about 10% by weight glutathione.

Compositions of the invention may be formulated to contain other anti-acne active ingredients used in conventional acne medications including, but not limited to, peroxides such as benzoyl peroxide, lauroyl peroxide, and carbamide peroxide; alcohols such as ethanol, phenoxy ethanol, propanol, phenoxy propanol, resorcinol; other compounds known to dry skin such as ethyl acetate; acids such as salicylic acid, azelaic acid, fumic acid, dehydroacetic acid, and pyruvic acid; urea and/or cetyl betaine; scymnol sulfate; cholate and/or deoxycholate; retinoids such as adalpalene, tretinoin, and tazarotene; antibiotics such as erythromycin, lincomycin, clindamycin, tetracycline and meclocycline; and the others previously mentioned, and mixtures of any of these. As summarized above, using other anti-acne active ingredients in combination with alkanolamine active ingredients improves the overall therapy in many cases. Conventional anti-acne active ingredients are added to alkanolamine compositions in effective amounts such as those found in commercial products; example ranges are set out below with their descriptions. However, many formulations containing other active ingredients in alkanolamine compositions have a short shelf life. Therefore, preferred methods of the invention which incorporate conventional acne medications are those in which the alkanolamine composition is applied topically to affected skin areas before or after topical application of a commercial acne product. In preferred embodiments, the alkanolamine composition is applied before applying the conventional acne medication. Further details about this embodiment are given below.

Some alkanolamine compositions of the invention contain at least one adjunct ingredient in addition to active ingredients. Adjunct ingredients include, but are not limited to, .alpha.-hydroxy acids, fatty acid esters of ascorbic acid, and vitamin A and vitamin A derivatives. Many embodiments employ more than one adjunct ingredient. Where employed, adjunct ingredients have additive effects if not synergistic effects due to different mechanisms of action.

As used herein, the term ".alpha.-hydroxy acid" has reference to and encompasses the general class of organic compounds containing at least one hydroxy group and at least one carboxyl group, and wherein at least one hydroxyl group is located on the .alpha.-carbon atom. Typically, the compounds are organic acids having at least one carboxylic acid group and at least one hydroxyl group on the .alpha.-carbon atom, and may contain other functional groups including additional hydroxyl and carboxylic acid moieties. Preferred .alpha.-hydroxy acids and/or .alpha.-hydroxy acid derivatives are less bulky structurally so that they penetrate the skin well, and thus have a backbone of from one to three carbon atoms such as those more fully described by Applicant in U.S. Pat. No. 5,965,618 to Perricone at column 6 lines 4 to 29. Where employed, glycolic and/or lactic acid or their derivatives are preferred; glycolic acid is especially efficacious. Glycolic acid or other .alpha.-hydroxy acids are typically present in amounts ranging from about 1% to about 10%, more narrowly from about 3% to about 7% of the total composition.

Fat-soluble fatty acid esters of ascorbic acid (vitamin. C) is employed as an adjunct ingredient in other embodiments, alone or in combination with .alpha.-hydroxy acids. The more oxidation-resistant saturated fatty acid esters of ascorbic acid are preferred, including, but not limited to, ascorbyl laurate, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, and ascorbyl behenate. Ascorbyl palmitate is used in one embodiment. As denoted herein, where fatty acid esters are described, e.g., ascorbyl stearate, compositions having predominantly that ester, e.g., predominantly stearate, are included. The esters may be prepared using hydrogenated oils or fats, or fractions thereof, and contain small amounts of another ester. Ascorbyl stearate prepared using canola, for example, commonly contain about 4% ascorbyl palmitate. It is an advantage of the invention that where fatty acid esters of ascorbic acid are employed as an adjunct ingredient, they help stabilize the alkanolamine in the composition. Ascorbyl palmitate and the like ascorbyl esters are typically present in amounts ranging from about 0.5% to about 15%, preferably from about 1% to about 7% to 10%, of the total composition. Vitamin A or vitamin A derivatives may be alternative or additional adjunct ingredients in like concentrations. Vitamin A and vitamin A derivates include, but are not limited to, retinol, retinyl palmitate, retinoic acid, retinal, and retinyl propionate.

Only effective amounts of alkanolamine compositions are needed to treat or prevent acne and minimize erythema when used alone, or in combination with other acne medications more fully discussed below, so generally topical application is accomplished in association with a carrier, and particularly one in which the alkanolamine active ingredient is soluble per se or is effectively solubilized (e.g., as an emulsion or microemulsion). Where employed, the carrier is inert in the sense of not bringing about a deactivation or oxidation of the active ingredient(s), and in the sense of not bringing about any adverse effect on the skin areas to which it is applied. In one preferred practice of the invention, the active ingredients are applied in admixture with a dermatologically acceptable carrier or vehicle (e.g., as a lotion, cream, ointment, soap, stick, or the like) so as to facilitate topical application and, in some cases, provide additional therapeutic effects as might be brought about, e.g., by moisturizing of the affected skin areas. While the carrier for dermatological compositions can consist of a relatively simple solvent or dispersant such as water, it is generally preferred that the carrier comprise a composition more conducive to topical application, and particularly one which will form a film or layer on the skin to which it is applied so as to localize the application and provide some resistance to washing off by immersion in water or by perspiration and/or aid in the percutaneous delivery of the active agent(s). Many preparations are known in the art, and include lotions containing oils and/or alcohols and emollients vegetable oils, hydrocarbon oils and waxes, silicone oils, animal or marine fats or oils, glyceride derivatives, fatty acids or fatty acid esters or alcohols or alcohol ethers, lecithin, lanolin and derivatives, polyhydric alcohols or esters, wax esters, sterols, phospholipids and the like, and generally also emulsifiers (nonionic, cationic or anionic), although some of the emollients inherently possess emulsifying properties. These same general ingredients can be formulated into a cream rather than a lotion, or into gels, or into solid sticks by utilization of different proportions of the ingredients and/or by inclusion of thickening agents such as gums or other forms of hydrophilic colloids. One preferred embodiment is a solution used to saturate a pad used to wipe affected areas; another is a cleanser; and others are lotions, creams, and gels. Such compositions are referred to herein as dermally or dermatologically acceptable carriers, and are formulated using conventional techniques known to those of ordinary skill in the art.

Suitable carriers include water, alcohols, oils and the like, chosen for their ability to dissolve or disperse active ingredients. Generally, even low concentrations of active ingredients in a carrier are suitable, depending upon the application regimen and the active and adjunct ingredients employed. Mild acne typically requires lower concentrations of active ingredients than to acute conditions such as that sometimes observed in adolescence. As a practical matter, however, to avoid the need for repeated application, it is desirable that the topically applied composition be formulated to contain the amounts of active ingredients set out above. Generally in the practice of methods of the invention, the composition is topically applied to the affected skin areas as needed to lesions, often as a tinted cover-up, or at predetermined intervals as a cleanser or a lotion, cream, or gel, it generally being the case that gradual improvement is noted with each successive application. Insofar as has been determined based upon clinical studies to date, no adverse side effects are encountered. It is an advantage of the invention that compositions of the invention do not require a pharmaceutical prescription.

Topical compositions of the invention can comprise additional ingredients commonly found in skin care compositions and cosmetics, such as, for example, tinting agents, tinting agents, emollients, skin conditioning agents, emulsifying agents, humectants, preservatives, antioxidants, perfumes, chelating agents, etc., provided that they are physically and chemically compatible with other components of the composition. Preservatives include, but are not limited to, C.sub.1 C.sub.3 alkyl parabens and phenoxyenthanol, typically present in an amount ranging from about 0.5% to about 2.0% by weight percent, based on the total composition. Emollients, typically present in amounts ranging from about 0.01% to 5% of the total composition include, but are not limited to, fatty esters, fatty alcohols, mineral oils, polyether siloxane copolymers, and mixtures thereof. Humectants, typically present in amounts ranging from about 0.1% to about 5% by weight of the total composition include, but are not limited to, polyhydric alcohols such as glycerol, polyalkylene glycols (e.g., butylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, and polyethylene glycol) and derivatives thereof, alkylene polyols and their derivatives, sorbitol, hydroxy sorbitol, hexylene glycol, 1,3-dibutylene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol, and mixtures thereof. Emulsifiers, typically present in amounts from about 1% to about 10% by weight of the composition, include, but are not limited to, stearic acid, cetyl alcohol, stearyl alcohol, steareth 2, steareth 20, acrylates/C.sub.10-30 alkyl acrylate crosspolymers, and mixtures thereof. Chelating agents, typically present in amounts ranging from about 0.01% to about 2% by weight, include, but are not limited to, ethylenediamine tetraacetic acid (EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, tartaric acid, and mixtures thereof. Antioxidants, typically present in an amount ranging from about 0.02% to about 0.5% by weight of the composition, include, but are not limited to, butylated hydroxy toluene (BHT); vitamin C and/or vitamin C derivatives, such as fatty acid esters of ascorbic acid, particularly asocorbyl palmitate; butylated hydroanisole (BHA); phenyl-.alpha.-naphthylamine; hydroquinone; propyl gallate; nordihydroquiaretic acid; vitamin E and/or derivatives of vitamin E, including tocotrienol and/or tocotrienol derivatives; calcium pantothenates; green tea extracts; mixed polyphenols; and mixtures of any of these. As mentioned above, particularly preferred antioxidants are those that provide additional benefits to the skin such as ascorbyl palmitate. (See additional ingredients and methods in U.S. Pat. Nos. 4,775,530, 5,376,361, 5,409,693, 5,545,398, 5,574,063, 5,643,586, 5,709,868, 5,879,690, 5,965,618, 5,968,618, 6,051,244, 6,162,419, and 6,191,121 to Perricone).

Buffering agents are employed in many compositions. Preferably, the amount of buffering agent is one that results in compositions having a pH ranging from about 4.5 to about 8.5, more preferably from about 5.5 to about 8.5, most preferably from about 6.5 to about 8.0. Typical buffering agents are chemically and physically stable agents commonly found in cosmetics, and can include compounds that are also adjunct ingredients such as citric acid, malic acid, and glycolic acid buffers.

As summarized above, alkanolamine compositions of the invention may be applied before or after application of a conventional acne medication available over-the-counter or by prescription. These methods are particularly efficacious in therapies for moderate to severe acne and advantageously combine the anti-inflammatory and anti-acne properties of alkanolamine compositions of the invention, and take advantage of the comedolytic, keratolytic, and drying properties of other anti-acne ingredients previously described, while minimizing the redness and inflammation often caused by when these products are applied to skin, especially sensitive skin. Many conventional acne medications contain 0.5% to 2% salicylic acid or 3% to 10% benzoyl peroxide, marketed as Aveeno.RTM., Benvoxyl.RTM., Biore.RTM., Clean and Clear.RTM., Clinac.TM., Clearasil.RTM., ClearLogix.RTM., Fostex.RTM., Oxy Balance.RTM., PanOxy.RTM., SalAc.RTM., Stridex.RTM.; Triz.RTM., and ZapZit.RTM. products sold as gels, creams, lotions, astringents, bars, and cleansers. A 20% azelaic acid cream is sold under the name Finevin.TM..

Alkanolamine compositions of the invention are especially useful when used before or after topical application of a composition containing at least one retinoid. Useful retenoids include commercially available adapalene, tazarotene and/or tretinoin. Adapalene, for example, is sold as a gel or solution marketed as Differin.RTM.. Tretinoin can be obtained as a cream, gel or encapsulated microsphere marketed as Avita.RTM., Renova.RTM., Retin-A.RTM., or Retin-A.RTM. Micro.RTM.. Tazarotene is marketed as a Tazorac.RTM. gel. Effective formulations typically contain from about 0.025% to about 0.1% by weight retinoid or retinoid mixture. It is an advantage of the invention that use of alkanolamine compositions with retinoid compositions methods for treating acne that can employ less retinoid than would be required if a retinoid is used alone, further minimizing skin irritation observed in some patients. It is unfortunate that many acne patients in their zeal to rid themselves of blemishes and pimples tend to overuse the medications. Using compositions of the invention can reduce this amount and the duration of drug use in patients presenting acne conditions warranting the beneficial normalizing desquaminating properties that retinoids can provide, and alleviate side effects. Compositions of the invention also minimize or eliminate skin irritation, particularly in areas surrounding acne lesions, while at the same time treating acne lesions.

Alkanolamine compositions may also be used in combination with topical antibiotics such as tetracycline, clindamycin, and erythromycin sometimes used for acne cases, particularly for patients with inflammatory papules and pustules. Clindamycin, for example, is sold in a gel, lotion, solution, marketed as BenzaClin.TM., Cleocin T.RTM., Clindagel.TM., and Clindets.RTM. (which also contains 5% benzoyl peroxide). Erythromycin is sold in a gel marketed as Emgel.RTM.. Doxycycline is a tetracycline marketed as a Vibramycin.RTM. monohydrate suspension; another tetracycline, minocycline, is also marketed as a Minocin.RTM. suspension. Topical antibiotics typically contain from about 0.05% to 0.5% to about 2% active ingredient; formulations containing 1% antibiotic are common. As with retinoid therapy, an advantage of using alkanolamine compositions with antibiotics in cases where the latter are indicated is that a lower antibiotic dose or a shorter antibiotic regimen may be employed. As has been mentioned, it is now recognized that prevalent use of antibiotics in general is undesirable, and long-term use of antibiotics can cause enhanced susceptibility to infection, nausea, gastrointestinal upset, phototoxicity, and interactions with other medications. Use of alkanolamines advantageously augments the treatment and minimizes the amount of antibiotic necessary to cause improvement in patients presenting with an extreme inflammatory phase of acne, and helps to minimize or eliminate side effects.

In therapies that combine topical application of compositions of the invention and topical application of conventional acne medications, alkanolamine compositions are preferably applied first, followed by application of a commercial product. This prevents erythema caused by the product. Saturated pads were used for this purpose in examples that follow; alkanolamine compositions were wiped on affected skin areas, which were then treated with a gel or cream containing a retinoid, a peroxide, or an antibiotic. However, as set out above, any other topical administration may be used. In alternate embodiments, alkanolamine compositions are administered after treatment with a conventional medication or during treatment. Best results are obtained if the two compositions are applied immediately before or immediately after one another, but the invention encompasses embodiments involving a lag period between dosings.

It is an advantage of the invention that topical application of an alkanolamine composition of the invention containing about 2% to about 3% by weight DMAE, for example, typically results in a decrease in redness within an hour of topical application. Beneficial effects are immediate, and formulations of the invention are well-tolerated by the skin. It is another advantage of the invention already discussed that alkanolamines are anti-inflammatories, and decrease erythema in both lesions and perilesional areas. Since compositions of the invention are both anti-inflammatory and anti-acne, their use in combination with conventional acne medications, particularly those requiring a prescription, reduce the need for frequent application of these products and high concentrations of irritating ingredients in these products. Use of combination treatments provides superior acne therapies.

It is a further advantage of the invention that topical administration of alkanolamine compositions provide other beneficial alkanolamine effects: alkanolamines advantageously treat and prevent skin damage and aging (U.S. Pat. No. 5,554,647 to Perricone), increase subcutaneous muscle tone (ibid), prevent and treat acne scars (U.S. Pat. No. 5,965,618 to Perricone) and disfigurement, and cause visible contraction of skin pores (U.S. patent application Ser. No. 09/900,680, filed 6 Jul. 2001), resulting in clearer, smoother appearing complexion, firmer skin tone, and a healthier look. The results are cumulative. With continued applications, skin tone increases and pores become smaller and tighter over time, enhancing the appearance of skin areas not affected by acne and decreasing the number of clogged pores that cause acne whiteheads.
 

Claim 1 of 5 Claims

1. A topical acne composition consisting of a) from about 0.1% to about 10% by weight of an alkanolamine of the formula ##STR00002##  (see Original Patent) wherein X, Y and Z are selected from the group consisting of hydrogen, C1 C3 alkyl groups, C2 C4 alkanol group, wherein at least one of X, Y, or Z is a C2 C4 alkanol group bearing at least one hydroxyl group and optionally at least one carboxyl group; b) from about 0.01% to about 6% by weight tyrosine; c) from about 0.01% to about 10% by weight of a sulfur-containing ingredient selected from the group consisting of lipoic acid, glutathione, and mixtures thereof; d) a dermatologically acceptable carrier; and optionally, an adjunct ingredient selected from the group consisting an .alpha.-hydroxy acid, a fatty acid ester of ascorbic acid, and mixtures of any of these, wherein the topical composition is applied to skin and acts upon the skin to treat acne.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.