COMPOSITIONS FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS AND METHODS FOR THEIR USETechnical Field of the InventionThis invention relates to compositions for the treatment of dermatological disorders and, in particular, to topical compositions for the treatment of dermatological conditions arising from changes in normal keratinization, epidermal formation or pilosebaceous function, such as acne, psoriasis. , seborrhea, hair that grows inward and pseudofolliculitis barbae, and hyperpigmented skin.
Background of the InventionAcne, skin infections, psoriasis and other disorders of the cutaneous or filosebaceous unit and the keratogenesis process are typically characterized by the presence of visible dermatological lesions, such as raised or raised closed comedones, colored open comedones, inflamed papules that look pustular, pustules, nodules and acne cysts or cutaneous infection; Ref.025068 hair that grows inwards easily visible from pseudofolliculitis barbae; or the visible scales of seborrhea, ichthyosis and psoriasis. The clinical evaluation of potential treatments for such disorders is typically based on the effectiveness of the treatment in reducing the number and severity of these visible injuries. Prior to the eruption of visible lesions on the surface of the skin, non-visible lesions, referred to herein as pre-emergent lesions, are generally present within the skin. Although pre-emergent lesions are insufficiently visible to be graded or evaluated in conventional clinical studies, their presence within the skin can be discerned or ascertained by the sense of touch and / or pain and. the tension inside the skin. Pre-emergent lesions are caused by a pre-emerging process within the epidermis and dermis, or within and surrounding the pilosebaceous follicle, which is located within the epidermis of the skin, the dermis, or both. In acne, for example, this pre-emergent process usually begins within the pilosebaceous follicle. The pilosebaceous follicle is filled with the sebum secreted into the follicle by the sebaceous gland, the bacteria, (mainly the acnes by corynebacterium, or P. acnes) and the keratin cells which fall from the inner wall of the follicle. In the pre-emergent process, the follicular wall is attacked by inflammatory agents, in particular fatty acids free of excess, produced by the breakdown of triglycerides present in sebum by lipolytic enzymes, or lipases, and chemotactic and inflammatory agents that are produced and induced from the P. acnes. Research has shown that, compared to normal patients, patients who have acne have increased levels of sebum secretion and an increased presence of P. acnes and its associated lipase activity, with a resulting increase in the level of fatty acids free and other associated inflammatory agents. These increases have shown that they will be approximately proportional to the severity of the disorder. In addition, patients with acne frequently have abnormal follicular walls. In normal skin, the follicular wall is composed entirely of keratinized cells, formed by the keratinization process. This keratinized cell wall forms an auger between the detached keratin cells, and the sebaceous and bacterial components within the follicle and the aqueous tissue surrounding the follicle. In patients with acne, imperfect keratinization apparently allows cells that contain sebum, structurally weaker, to be inserted into the follicular wall, making the wall more vulnerable to attack and rupture. Once the cell wall is broken, free fatty acids, sebaceous and inflammatory components, live and dead bacteria, cells detached from the follicular wall and other contents of the follicle are released into the aqueous tissue surrounding the follicle. where they establish an inflammatory process (Webster, G., Jnl. Am. Acad. Dermatol., 1955; 33: 247-253). The pre-emergent process described above can progress to the point where, although they are not visible on the surface, the resulting inflammations and internal injuries can be detected within the skin as a sensation or as pain, and can also be perceived by the touch on the surface of the skin like a bump. Although several studies have been published on the individual effects of agents such as benzoyl peroxide, alpha hydroxy acids and zinc agents on visible dermatological problems on the surface of the skin, such as non-inflamed comedones, inflamed papules and pustules, skin infections, hair growing inward, and keratotic scales (Handbook of Non-Prescription Drugs, American Pharmaceutical Association, 9th Ed. (1990) 798; Goodman and Gilman, Pharmacologic Basis of Therapeutics, MacMillan Publishing Co., 6th Ed. (1980), 977; Ruey, JY, Van Scott, EJ, US Patent No. 4,363,815), the inventors are unaware of any published report on the efficacy of acne drugs recognized on pre-emergent lesions. .
Brief Description of the InventionThe present invention provides a method for treating dermatological disorders arising from changes in normal keratinization, epidermal formation or pilosebaceous function, such as acne, psoriasis, seborrhea, hair growing inward and pseudofolliculitis barbae, and hyperpigmented skin. , by topical administration of a composition comprising a dermatologically absorbable topical antimicrobial, antibiotic, antibacterial or antifungal agent; an dermatologically absorbable alpha or beta hydroxy acid; and a dermatologically absorbable zinc compound in a dermatologically acceptable carrier or vehicle. The compositions of the present invention are preferably applied to an affected area of a patient's skin on a daily basis, in the form of clear gels, opaque gels, lotions, suspensions, ointments, creams, powders and the like. The antimicrobial, antibiotic, antibacterial or antifungal, topical, dermatologically absorbable agent is preferably selected from the group consisting of azoleic acid, benzoyl peroxide, erythromycin, bacitracin, zinc bacitracin, polymyxin, neomycin, chloramphenicol, tetracycline, minocycline, clindamycin, doxycycline , undecylenic acid and salts thereof, propionic acid and salts thereof, caprylic acid and salts thereof, ciprofloxacin, cephalosporins, benzoic acid, cyclopirox olamine, clotrimazole, econazole nitrate, metronidazole, miconazole nitrate, cetaconazole, oxiconazole, tolnaftate and combinations thereof; and more preferably it is benzoyl peroxide. The antimicrobial, antibiotic, antibacterial or antifungal agent may be present in an amount of between about 0.1% to about 30%, but may also be used in an amount of between 0.25% to 20%, preferably between about 0.5% to about 10% . All the percentages referred to here are by weight. The alpha or beta hydroxy acid agent is selected from the group consisting of free acids, salts, amides, amphoteric and polymeric forms of the following compounds: citric acid, glycolic acid, glucuronic acid, galacturonic acid, glucuronolactone, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, lactic acid, malic acid, mucic acid, pyruvic acid, methyl pyruvate, ethyl pyruvate, beta-phenyl-lactic acid, beta-phenylpyruvic acid, saccharic acid, tartaric acid, tartronic acid and beta-hydroxybutyric acid . In a preferred embodiment, the alpha or beta hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, mandelic acid, citric acid, tartaric acid, malic acid, salicylic acid, and acetylsalicylic acid, and is more preferably glycolic acid or lactic acid. The alpha or beta hydroxy acid is present in an amount of between about 0.10% to about 70%, with a preferred concentration for brief application on the skin of between about 5% to about 70%, with a preferred concentration for daily use left on the skin after application, from about 0.15% to about 15%. The zinc compound is selected from the group consisting of water-soluble, water-soluble, and water-insoluble salts, compounds, and zinc complexes, such as zinc acetate, zinc bacitracin, zinc bromide, zinc cysteate, caprylate zinc, zinc chloride, zinc citrate, zinc fluoride, zinc formate, zinc glycinate, zinc iodate, zinc lactate, zinc nitrate, zinc nitrite, zinc oleate, zinc oxalate, zinc oxide, zinc permanganate, zinc peroxide, zinc phenosulfonate, zinc phosphate, zinc propionate, zinc pyrophosphate, zinc ricinoleate, zinc salicylate, zinc selenate, zinc silicate, zinc selenide, zinc sulfate, zinc stearate zinc, zinc sulphide, zinc tannate, zinc tartrate, zinc valerate, zinc peptides, and zinc protein complexes. In a preferred embodiment of the present invention, the zinc compound is zinc lactate or zinc acetate, and is present in an amount of between about 0.001% to about 30%, more preferably between about 0.1% to about 10% . Other therapeutic agents can be added in a useful form to the compositions of the present invention. Such agents include retinoids, such as trans-retinoic acid, 13-cis-retinoic acid and derivatives thereof; anti-androgens, such as spironolactone; metronidazole; and anti-inflammatory agents, such as hydrocortisone, betamethasone, clobel, fluocinonide, triamcinolone, desonide, and halcinonide. These therapeutic agents may be present in an amount of between about 0.001% to about 10.0%, preferably between about 0.01% to 5.0%. The active ingredients of the present invention are combined in a dermatologically acceptable carrier or vehicle composed of non-comedogenic and hypoallergenic agents, such as water, alkyl benzoate with C? 2-? S, glycerin, cetyl stearyl alcohol, polyacrylamide, isoparaffin with C13-14, laureth-7, stearate of PEG-1000, steareth S-2, steareth S-20, sodium hydroxide, diisisone, and EDTA disodium. The Special Petrolatum Fraction, the most viscous form of Petrolatum U.S.P., which has a larger proportion of longer chain molecules, is especially useful. Other carriers or vehicles that can be used in a useful manner in the present invention are well known in the art.
Detailed description of the inventionExample 1Two formulations of the composition of the invention, Formulas I and II, composed of the reagents shown in Table 1, were prepared using the following protocol.
Disodium EDTA and zinc lactate are dissolved in hot water at 60 ° C (30% of the batch weight) and the glycerin is added. Then polyacrylamide-Isoparaffin is added with Ci3-? 4-Laureth-7, and mixed until it becomes uniform, to provide part A. Separately, the glycolic acid is dissolved in a part of an equal amount of water and sodium hydroxide is added slowly. It is added to part A and kept at 60 ° C. Separately, steareth S-2, and S-20, glyceryl monostearate SE and cetyl stearyl alcohol are heated until the mixture becomes fluid and uniform. This is added to part A with mixing until it becomes uniform. Dimethicone is added; the cooling starts at 40 ° C. Separately, the benzoyl peroxide is dispersed in the alkyl benzoate with C12-15 and added to the cooled part A. Finally, a CS (sufficient quantity) of water is added up to 100% and homogenized if necessary.
TABLE I% IN WEIGHT FORMULA I FORMULA II benzoyl peroxide 10.0 6.0 benzoate ester with C12-15 7.0 7.0 glycerin 6.0 6.0 cetyl stearyl alcohol (C5-50 4.0 4.0LIPO) polyacrylamide, isoparaffin and 3.0 3.0 laureth-7 glycolic acid 4.0 2.0 sodium hydroxide 0.5 0.5 steareth S-2 (LIPO) 2.0 2.0 glyceryl monostearate, SE 2.0 2.0 steareth S-20 (LIPO) 1.5 1.5 dimethicone 200 (100 cps ) 1.0 1.0(Dow Corning) zinc lactate 0.6 0.6EDTA disodium 0.5 0.5 strontium chloride 2.5 2.5 water up to 100% up to 100%A third formulation of the composition of the invention, specifically a gel that can be used as a cleanser or that is left on the skin for treatment, hereinafter referred to as Formula III, composed of the reagents shown in Table II, is prepare as follows. The petrolatum, sodium and choline isethionate, potassium metaphosphate, titanium dioxide and zinc lactate, are mixed and homogenized until uniform, to form the mixture I. The carbomer is dispersed in a portion of the glycerin, heated to a 75 ° C and it is added to the mixture I, homogenizing if necessary until it becomes creamy, to form the mixture II. The glycolic acid dissolves in the remaining glycerin at 50 ° C. To this is added sodium hydroxide, previously dissolved in 5 parts of water. The resulting mixture is added to mixture II and then added at 45 ° C to provide mixture III. The benzoyl peroxide is dispersed in C12-15 alkyl benzoate and added to mixture III. The resulting product is milled when necessary.
TABLE II% IN WEIGHT glycerin, anhydrous 50. 0 petrolatum 15, .0 benzoyl peroxide 10, .0 zinc lactate 2, .0 sodium isethionate and 4,4-alpha olefin sulfonate, 2. potassium 0, .5 alkyl benzoate with C12-15 5, .0 glycolic acid 0, .25 sodium hydroxide 0, .05 carbomer 0, .7 water up to L00%Example 2Formula III of Example 1 was tested on two patients who have persistent dermatological lesions; The lesions of both are more commonly present on the face and on the neck. Both patients have suffered continuously from inflamed papules, hair that grows inward, not inflamed, hair that grows inward, inflamed, and pre-emergent lesions. Prior to treatment with formula III of the present invention, each patient has used a wide range of treatments, including topical benzoyl peroxide, topical erythromycin, topical erythromycin plus zinc, topical clindamycin, alpha hydroxy acid lotions, and topical erythromycin plus peroxide of benzoyl. Each of these medications was used individually on a daily basis for at least two months. Each medication initially caused a reduction in the number and severity of the dermatological lesions but this effect subsequently decreased. None of these medications was successful in substantially and consistently reducing injuries, particularly pre-emergent lesions. Prior to treatment with formula III of the present invention, patients had a range of dermatological problems as shown in Table III.
Table III Patient I Patient 2 Emerging lesions 3 to 6 4 to 8 Moderate soft-moderate rednessPapules 1 to 2 2 to 4 Hairs that grow 1 to 3 2 to 5 inwards Each patient applied formula III topically twice a day to the affected area. The range of dermatological lesions present after treatment for one month and two months are shown in Tables IV and V, respectively.
TABLE IV Patient 1 Patient 2Emerging lesions 1 to 2 0 to 3 Mild reddening-none none Papules 0 to 1 0 to 2 Hairs that grow 0 to 2 1 to 2 inwardsTABLE V Patient 1 Patient 2Emerging lesions 0 to 1 0 to 2 Redness none none Papules 0 0 Hairs that grow 0 to 1 0 inwardsThese results demonstrate that the compositions of the present invention are effective in reducing the number and severity of both visible lesions, such as papules, and pre-emerging lesions. Although the present invention has been described in terms of specific embodiments, changes and modifications may be made without departing from the scope of the invention, which is proposed to be limited only by the scope of the appended claims.
It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, property is claimed as contained in the following