MXPA98010851A - Device for topical treatment of acne and its method of fabricac - Google Patents

Abstract

The invention features a device in the form of a patch for the topical application of an anti-acne formulation, comprising a synthetic pressure sensitive adhesive, used as a carrier or associated with a carrier, said carrier having the anti-acne-distributed formulation uniformly in the same, characterized in that said anti-acne formulation comprises effective amounts of at least two active ingredients of at least two active ingredients of at least two different groups of active ingredients and wherein said at least two different groups are selected from the group comprising keratolytic agents, anti-aging agents -irritans, antiseptic agents, antimicrobial agents, hormones, hormone agonists, hormone antagonists and other suitable agents to treat ac

Description

DEVICE FOR ACNE TOPICAL PROCESSING AND ITS MANUFACTURING METHOD ICO TECHNICAL FIELD A delivery device is provided in the form of a patch, and the method of its manufacture, for the topical treatment of acne and acneiform diseases.

BACKGROUND OF THE TECHNIQUE Acne afflicts 90% of all adolescents but also men and women in their twenties or thirties or may persist throughout adulthood. The process by which acne develops is described in "New Approaches to Acne Treatment" by W.J. Cunliffe, ed. Martin Dunitz, London, 1989. Acne vulgaris is a chronic disorder of the pilosebaceous follicles (apparatus) characterized by comedones (pimples), papules, pustules, cysts, nodules and often scars, which appear in the most visible areas of the skin, particularly on the face, chest, back and occasionally neck and upper arms. The pilosebaceous apparatus is greatly under the control of endogenous hormones (mainly androgens), which are present in unusually high concentrations in the blood during adolescence and puberty, giving an increase to an excessive production of sebum. The condition can be worsened by a simultaneous increase in the rate of keratinization of the horny layer of the skin (the stratum corneum). As corneous cells proliferate, they can form an occlusive or comedone plug, which coupled with increased sebum production, represents an ideal medium for the proliferation of resident skin species, such as the gram-positive anaerobic bacterium, Propionibacterium acnes. Eventually, the clogged follicles break and allow the discharge of their contents causing local swelling and inflammation. The exposed follicles can darken from the pigment deposit of the damaged cells in the deepest layer of the skin. Acne is a multi-stage condition and in the most severe form leads to patient hospitalization and extensive discomfort with leaving long-term skin scars. There is a need for improved acne treatments that effectively prevent the developing condition to its most severe form and that can be used by most injured without adverse effects. At this time there are numerous treatments available to treat acne but each treatment has unfortunate limitations, which would be desirable to overcome. For the most part, the treatment of acne is by topical formulations in the form of creams, gels, emulsions or lotions, which contain selected agents. These agents include hormones or hormone agonists and antagonists (EP A1 0 563 813 and US 5,439,923), antimicrobial agents (US 4,446, 145, GB 2,088,717, GB 2,090, 135, GB 1, 054, 124, US 5,409,917), salicylic acid (US 4,515,385, US 4,355,028, EP A1 0 052 705, FR-A 2,581, 542, and FR-A 2,607,498). Problems associated with topical treatment include lack of application precision and associated lack of control over the precise dose at the target site. The application of a cream, gel, emulsion or lotion results in the exposure of an area considerably in excess of the covering by the lesion, thereby exposing healthy normal skin to anti-acne formulation. For example, salicylic acid is an irritant to normal skin on prolonged exposure and particularly at high concentrations. The oral administration of anti-acne agents is currently provided for severe cases of acne. These are reviewed in "Acne, A Review of Optimum Treatment" by Sykes N.l. and Webster G.F. in Drugs 48, 59-70 (1994). Numerous side effects have been described using oral administration of anti-acne medicaments. For example, isotretinoin which is a vitamin A derivative has associated risks of teratogenicity and may be a risk for women during childbearing. The oral administration of antibiotics suitable to treat acne, can induce the appearance of adverse effects which include abdominal cramps, black tongue, cough, diarrhea, fatigue, irritation of the mouth and other undesirable symptoms. Salicylic acid in the form of a sticky hydrophilic gel dressing (US Pat. No. 5,258,421) and in combination with pantothenic acid or pantothenic acid derivative in a cleaning pad (PCT WO 93/21899) has been used to treat acne. In addition, a cephalosporin-containing patch has been described in US Patent 5,409,917, for the treatment of acne using a method for making nicotine patches. Since the patch was not optimized for the special circumstances associated with acne including optimizing the content of anti-acne agent, and placement of the patch in multiple location on exposed skin such as the face, the patch has not been adopted as a modality of delivery of anti-acne formulation. Therefore, there is a need for methods and devices to treat patients with acne that have minimal adverse effects, have maximum efficiency and can be simple and comfortable to use.

OBJECTIVES OF THE INVENTION The present invention addresses the need to treat acne and acneiform diseases in order to minimize the adverse effects and maximize the efficiency of the treatment. The present invention is directed to a topical delivery device, in the form of a patch, having a size and thickness suitable for the prolonged delivery of anti-acne agents at a selected site characterized as acneiform. The patch contains at least two agents suitable for treating acne, in the form of a mixture of compounds. More precisely, the invention provides a device in the form of a patch for topical application of an anti-acne formulation, comprising a synthetic pressure sensitive adhesive used as a carrier or associated with a carrier, said carrier having the anti-acne formulation. acne distributed evenly therein, characterized in that said anti-acne formulation comprises effective amounts of at least two active ingredients of at least two different groups of active ingredients and wherein said at least two different groups are selected from the group comprising keratolytic agents, anti-irritants, antiseptic agents, antimicrobial agents, hormones, hormone agonists, hormone antagonists and other suitable agents to treat acne. In another embodiment, a patch for the treatment of acne and acneiform skin diseases comprises topically acceptable carriers for topical application, such as acrylics, paper, cones, cellulosics, etc.; humectants; antioxidants; stabilizers; wherein the patch is capable of delivering an effective amount of anti-acne agents to acneiform skin to be treated (ie, comedones, pustules, papules).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a side view of a three layer patch to deliver agents for the treatment of acneiform diseases. Figure 2a is a side view of a four layer patch for delivering agents for the treatment of acneiform diseases. Figure 2b is a top view of the same patch as in Figure 2a. Figure 3 shows the stability of the patch of the invention in terms of salicylic acid and triclosan. Figure 4a shows the flow of salicylic acid through human stratum corneum as it concerns two patches according to the invention and a gel.

Figure 4b is an elongation of Figure 4a relative to the two patches of the invention.

DESCRIPTION OF THE INVENTION The term "topically acceptable carriers", as used herein, means substances that substantially lack toxicity to human tissues. The term "topical application", as used herein, means that it falls directly on the outer skin. The term "stable", as used in the specification, is defined as having a shelf life that extends for more than several weeks. The term "effective amount", as used herein, means an amount sufficient to provide an anti-acne effect. The present invention provides methods and devices for treating patients affected by acne, where the device has been optimized to minimize adverse effects and to maximize efficiency and is simple and comfortable to use. The topical treatment of acne and acneiform diseases described here uses a patch to achieve local anti-acne effects that result from the suppression of the proliferation of corneal cells and microbes involved in the pathogenicity of acne and reduction in associated inflammation. The patch has been designed in order to effectively deliver anti-acne agents to the stratum corneum (the outermost layer of the epidermis, exposed to the external environment) and subsequently penetrate into the pilosebaceous unit (in the dermis), where it originates the acneiform condition, while it has very limited penetration in the systemic circulation. This is demonstrated by the study of skin flow permeation (Example 12 below), which indicates that the amount of salicylic acid that crosses the stratum corneum is very small compared to that of the gel formulation containing 2% salicylic acid. In order to ensure that the patch is simple and comfortable to use, an adequate size and thickness of a simple patch has been identified. The patch proposed in this invention can be produced in a variety of sizes depending on the area to be treated (ie, comedones, papules, pustules). The size of the patch is classified as small being 0.5 to 2 cm2 and large patch up to 40 cm2. Typically, the size of the patch is from 0.5 to 1.3 cm2 and preferably 0.8 cm2. The patch of the invention is stable and is capable of safely and effectively delivering the anti-acne formulation. For example, the stored patch containing anti-acne agent can remain effective for up to two years, so it is believed that any chemical changes that may occur during storage, but before the predetermined expiration date, are not harmful. An example of the right patch to treat acne is described in the Figure 1 . In this embodiment, the patch may include a support film layer 1, a synthetic, simple pressure sensitive adhesive layer 2 and a release coating 3 with the anti-acne formulation contained within the pressure sensitive adhesive layer synthetic.

In other embodiments, more than one matrix can be placed between the release liner and the support layer (see Figures 2a and 2b). According to Figures 2a and 2b and Example 4, a patch is described which includes a support film layer 1, a synthetic pressure sensitive peripheral adhesive layer 4, a paper matrix 5, and a release coating 3. The patch may have a paper matrix diameter of approximately 1.6 cm and / or a peripheral adhesive layer diameter of approximately 2.2 cm. The support film layer 1 may be made of plastic or fabric or woven or non-woven, porous or occlusive materials. Porous materials are sometimes used since some of the species resident in the skin of the bacteria in the pilosebaceous unit are anaerobic. The support film layer can be made of any suitable material such as paper; cellophane; plastic films such as polyethylene, polyester, polyurethane, polyvinyl chloride and polyamide; genres and metal sheets, which are waterproof and do not react with the anti-acne formulation distributed in the adhesive polymer matrix. The support film can be composite or transparent or opaque or flesh or aluminized or a combination thereof, with thickness ranging from about 25 to 130 μm, usually from 50 to 90 μm, and preferably about 76 μm, and can formed from any of CoTran R 9720 (3M), Saranex® (Dow Chemicals), Multilam 1009 (3M) meat tone polyester film, or any material recognized in the art as having the desired properties.

The patch has an adhesive polymer matrix 2, which is adjacent to the backing layer and is made of synthetic adhesives such as acrylics, rubber, silicone, cellulosics, paper or other suitable materials which may have pressure sensitive properties and adhere to skin directly or through a peripheral adhesive. The adhesive polymer matrix consists of at least one layer of the substances containing adhesive and / or other additives. The adhesive polymer matrix may be composed of more than one layer, but preferably consists of one layer. The thickness of this adhesive polymer matrix is in the range of about 13-760 μm, typically 13-152 μm, preferably about 13-64, and most preferably about 64 μm. A mixture of anti-acne agents including any of keratolytics, anti-irritants, antiseptics, antimicrobials, hormones, hormone agonists, hormone antagonists and other suitable agents for treating acne is contained within the adhesive polymer matrix, preferably together with solubilizers. The adhesive polymeric matrix can be made of inert materials, which are more biologically and topically acceptable and compatible with the distributed active substances described above. Preferably, topically acceptable polymers with adhesion properties can be acrylic-based polymers, such as the GELVA® series sold by Monsanto and the DU RO-TAK® series sold by National Starch; rubber-based polymers such as the DURO-TAK® series sold by National Starch; and silicone-based polymers such as BIO-PSA X7-4302 SILICON PSA sold by Dow Corning. Said adhesive polymer matrix can also be made from paper materials, preferably Whatman filter paper, which is adhered to the skin through a peripheral adhesive layer. The thickness of such an adhesive polymer matrix is usually about 178 μm. A release liner 3 is placed against the surface of the adhesive polymer matrix on the opposite surface of the support layer. The release liner can be made of materials impervious to any substance dissolved in said matrix, which is easily separated or released before use. The release liner can be made of materials such as polyvinyl chloride, polyester, polyvinylidene chloride, polystyrene, polyethylene, paper, etc. covered or not with an adhesive, but preferably with an easy-release silicon formulation. Preferably, the release liner is made of a high impact natural polystyrene film (degree code: 10106 or 15462) sold by REXAN Reléase or a siliconized polyester film sold by REXAM Reléase. The thickness of the release coating may vary from about 76 to 250 μm, or preferably be about 250 μm. In one embodiment of the invention, a combination of anti-acne agents has been selected to treat acne. These agents include a keratolytic agent, such as salicylic acid, in conjunction with an anti-irritant, an antiseptic, an antimicrobial agent and / or other anti-acne compounds, such as for example, urea, allantoin, hydroxyquinoline compounds, for delivery via a patch directly to the area to be treated. The presence of an anti-irritant counteracts the local irritation associated with the application of keratolytics to the skin. The antiseptic limits the growth of organisms which cause acne. Additionally, the antimicrobial may enhance the overall anti-acne properties of the compositions in moderate or severe stages of the disease. The use of a solubilizer ensures that the active agents in the patch are in a suitable form for a diffusion of the patch to the skin. The antimicrobials normally used for topical application can be penicillins, cephalosporins, other beta-lactam compounds, aminogiicosides, tetracyclines, erythromycin, antifungal agents, etc. , and a combination of them. Preferably, the antimicrobial agents used for topical application in acneiform skin are erythromycin, tetracycline, clindamycin, cephalosporin. The antiseptics normally used for topical application in acneiform skin are triclosan (Irgasan DP 300), fenosi isopropanol, resorcinol, chlorhexidine, povidone and iodine. The keratolytic agents normally used for topical application in acneiform skin are salicylic acid, benzoyl peroxide, sulfur, retinoic acid and any of a number of fruit acids and alpha hydroxy acids.

The anti-irritants normally used for topical application on acneiform skin are a-bisabolol, farnesol, chamomile extract and glycyrrhetinic acid. The solubilizers used in the anti-acne formulation of the present invention include any of glycerol, propylene glycol, polyalcohols, sorbitol and sorbitol derivatives, preferably sorbitan monooleate. The compositions of the present invention may also comprise other topically acceptable agents, such as solvents, antioxidants, humectants, etc. According to a preferred embodiment, the invention provides a device as described above, which comprises, in relation to the total weight of the carrier and the formulation: - one or more keratolytic agents, each in an amount of 0.1 to 10.0% p / p, preferably from 0.1 to 2.0% w / w and more preferably from 0.6% w / w; - one or more anti-irritant agents, each in an amount of 0.01 to 5.0% w / w, preferably 0.01 to 3.0% w / w and more preferably 1.0% w / w; - one or more antiseptic agents, each in an amount from 0.05 to 2.0% w / w, preferably from 0.1 to 1.0% w / w and more preferably from 0. 3% p / p; and - one or more solubilizers, each in an amount of 0.1 to 5% w / w, preferably 1 to 3.0% w / w and more preferably 2% w / w. This invention is further illustrated by the examples. The Examples should not be construed as limiting the scope of the invention, said scope is defined by the appended claims. The examples are conducted using salicylic acid, as a keratolytic agent, in an amount of 0.1 to 2% w / w together with an anti-irritant, such as a-bisabolol at 0.01 to 3% w / w, an antiseptic such as triclosan ( Irgasan DP 300) in 0.1 to 1% w / w and a solubilizer, such as sorbitan monooieate in 0.1 to 5% w / w, having all of them distributed in a variety of adhesive polymer matrices. Controlled delivery is achieved over a period of at least 4 hours, preferably over a period of at least 24 and most preferably over a period of at least 8 hours.

Example No. 1 Preparation of polymer matrix and delivery device in the form of a patch. A composition of the adhesive polymeric matrix used in the preparation of a patch for the topical treatment of acne and acneiform skin diseases contains salicylic acid as a keratolytic agent, as described in Table 1.

TABLE 1. Composition of the simple adhesive delivery system 1 . a-bisabolol is 6-methyl-2- (4-methyl-3-cyclohexen-1-yl) -5-hepten-2-ol 2. Irgasan DP 300 is 2,4,4'-trichloro-2'-hydroxy diphenyl ether A method for producing the patch having the above composition is as follows: Salicylic acid (0.6 g), I rgasan DP 300 (0.3 g), a-bisabolol (1.0 g), sorbitan monooleate (2.0 g) are added to 293.88 g of Gelva® 737 multi-polymer resin solution (total solids content of about 32.7%), and the mixture was stirred at room temperature until all the ingredients dissolved. The mixture was allowed to stand for several minutes in order to remove air bubbles. The adhesive mixture was formulated in a patch system as follows: Using an appropriate coating device (Multi Clearance Applicator of square tool steel, sold by BYK Gardner) with approximately 130-250 μm pouring aperture, a layer of adhesive mixture was coated on a siliconized polyester film and dried on an oven at 76-78 ° C for 15-18 minutes. A breathable polyurethane film (Bertek Medfilm 390) was then laminated onto the adhesive film. The system was then delaminated and further laminated onto an easily released silicon polystyrene film (REXAM Releas). The final thickness of the dried polymer matrix was then approximately 76-130 μm. The multi-layer laminate was then cut to form a circular shaped patch with nominal size of 1 cm2 (actual size of 0.8 cm2) and thickness of approximately 178-457 μm.

Example No. 2 Preparation of adhesive polymer matrix The procedure of Example 1 is repeated to prepare the adhesive polymer matrix. The adhesive used in this example is the acrylic-based polymer GELVA® 788. The patch, produced in this way, finally has a circular shape of 1 cm 2 and thickness of approximately 203-610 μm.

Example No. 3 Preparation of adhesive polymer matrix containing a mixture of adhesives The composition of the adhesive polymer matrix described in this Example, in the specified amounts, is presented in Table 2: Table 2. Composition of the delivery system of mixed adhesives A homogeneous mixture is obtained by mixing 18.95 g of Duro-Tak® acrylic solution 87-2287 (total solids content of approximately 50.7%) and 238.92 g of Duro-Tak® 87- 2353 acrylic solution (total solids content of approximately 36.2). %). To this mixture of adhesives, salicylic acid (0.6 g), a-bisabolol (1.0 g), Irgasan DP 300 (0.3 g), sorbitan monooleate (2.0 g) are added and the mixture is stirred at room temperature until all the ingredients dissolve. The mixture is then kept separate for several minutes to have completely removed the air bubbles.

The adhesive mixture is formulated in a patch system as follows: Using a suitable coating device with an applicator opening of approximately 130 μm, a layer of adhesive mixture was coated on a siliconized polyester film. The coating was allowed to dry in an oven at 80CC for 17 minutes and then laminated using an occlusive polyethylene film. The process ends by cutting the multi-layer laminate to a circular patch, size of 1 cm2, and thickness of approximately 190-500 μm, which is finally bagged into a flexible, bagging film composed of paper, low density polyethylene, aluminum and Surlyn ®.

Example No. 4 Preparation of a delivery device in the form of a patch containing a simple adhesive layer and a polymeric matrix with and without adhesive properties In this Example, substances such as antimicrobials, antiseptics, keratolytics, anti-irritants and solubilizers are distributed in a polymer matrix, in which the polymers may or may not have adhesive properties. The procedure to prepare this patch is presented as follows: To 10 g of AR ethanol, salicylic acid (1.0 g), a-bisabolol (0.1 g), Irgasan DP 300 (0.3 g) and sorbitan monooleate (0.2 g) are added and the mixture is stirred until all the ingredients are dissolved. Pieces of Whatman filter paper are impregnated with 3 ml of the above ethanolic solution and allowed to drain at room temperature. The pieces of impregnated paper are then dried in an oven at 40 ° C for 5 minutes and finally cut into a desirable shape and size (i.e., circular shape of 1.58 cm in diameter or area of 5 cm2). Polyester-sterilized films are coated with a simple acrylic-based adhesive, such as Duro-Tak® 87-2287 or Duro-Tak® 87-2353. The bilayer system is dried in an oven at 78-80 ° C for 15 minutes and then, it is laminated with a polyethylene film such as CoTranMR 9720. The complete system is cut into a desirable shape and size (ie, circular shape). 2.22 cm in diameter or area of 7 cm2). The polyester film is removed and, on the exposed laminate, the impregnated paper is placed in a co-centric order. Finally, the multilayer system is covered in a polystyrene film, which can be marked on the back side (see Figures 2a and 2b).

Example No. 5 Preparation of a delivery device in the form of a patch as in Example No 4 containing an additional adhesive layer The procedure of Example 4 is repeated to prepare a patch, in which the exposed laminate is coated on a polystyrene film completely or partially coated with a simple adhesive.

Example No. 6 Stability of the produced patch The patch proposed in the present invention will remain stable for two years. Methods such as compound test for salicylic acid and physical tests (such as 90 ° dynamic adhesive peeling test for stainless steel plate matrix patch as in "Test Methods for Pressure Sensitive Adhesive Tape" developed by The Technical Committee of the Pressure Sensitive Tape Council, 1st Edition) are used to determine its stability over this time. Additionally, the stability of the proposed patch was examined under environmental conditions. The results expressed as% of amount of salicylic acid and triclosan detected in the patch over time, are presented in Figure 3.

Example No. 7 Patch deletion analysis The produced patch is designed to release its content in 4, 6, , and up to 24 hours after the application. To determine the rate and degree of release for salicylic acid from the part, a patch suppression analysis was performed.

Example No. 8 Primary dermal irritation study A primary dermal irritation study was conducted, in compliance with FDA requirements per 21 CFR 58, using patches containing salicylic acid, as described in the preferred embodiments, in order to identify the potential irritation or corrosive effects resulting from exposure of the rabbit skin to the test material. The skin of six healthy New Zealand rabbits was skinned as close to the skin as possible at the test site twenty-four hours before the application of the test material. The test material was applied to both intact and abraded skin, and each test area was covered with a 2.54 cm gauze patch held in place with non-irritating tape. The skin was exposed to the test material for a period of twenty-four hours and the animals were examined for signs of erythema, edema and any other toxic effects or lesions in thirty to sixty minutes after removal of the patch, and then to seventy two hours The study showed that the patches produced a very light erythema with some scaly skin in some test sites but no edema. In addition, no other toxic effects were observed during the study. The Primary Irritation Record was estimated as 0.54 which indicates that the test material is not considered to be a primary skin irritant as defined in 16 CFR 1500.3 (c) (4).

Example No. 9 Delayed contact hypersensitivity test - modified Buehler sensitization test A delayed contact hypersensitivity test was performed, in compliance with the FDA Requirements per 9 CFR 2.31, using patches containing salicylic acid, as described in preferred embodiments, in order to determine the ability of the test substance to induce a systemic hypersensitivity response. The experimental procedure consisted of two phases: 1. Induction phase A group of 20 guinea pigs was exposed to the patch of test material and a group of 10 guinea pigs was exposed to Dinitrochlorobenzene (DNCB), a known sensitizer. The day before dosing, the animals were left free of hair as close to the skin as possible, using electric shearers. The material patch of test material was applied to the shorn area of each of the 20 guinea pigs and held in place with a non-irritating tape. The patches were left in place for 6 hours and then removed. The test sites were recorded for erythema 24 and 48 hours after the application. This procedure was repeated on the same site once a week for the next two weeks for a total of three 6-hour exposures. After the last application of the patch, the animals remained untreated for approximately two weeks.

To the positive control group of 10 guinea pigs, a 0.75% solution of DNCB in 50% ethanol was applied and recorded as previously described. In the following tables, the individual records for the test material patch and the positive control are presented.

TABLE 3. Individual animal records for the test material. Erythema There was no erythema noted for the patch of test material during the three induction phases.

TABLE 4. Individual animal records for positive control. Erythema During this test, the animals showed no weakness and confluent erythema of weakness. 2. Challenge phase After a two-week break, the test group and the positive control group were challenged at natural sites. The test material was applied to the test group and DNCB to the positive control group. The procedure used was as described above, except that the skin evaluations were done at 24, 48 and 72 hours after the application. The results are presented in the following tables.

TABLE 5. Records of individual animals for the test material. Erythema During the challenge phase, no erythema was noted in the group of test or test material without affecting at any point.

TABLE 6. Records of individual animals for positive control. Erythema During this test, the animals showed no weakness and confluent erythema of weakness.

Example No. 10 Repetitive attack patch test for contact sensitization and photosensitization.

The purpose of this study was to determine the contact and skin sensitization and photosensitization in human volunteers of the salicylic acid-containing patch as described in the preferred embodiments of the present invention, in order to claim the "hypoallergenicity" of the product. Forty (40) healthy volunteers of both sexes were included, aged 20-55 years in the study. 1 . Induction phase In this part, the repeated attack patch tests were used in combination with maximization test. On the intact skin of the upper back of the forty volunteers, a 1% solution of sodium lauryl sulfate was applied. The test product was then applied and held with a non-irritating tape. The test material was left for 48 hours and the site was read 30 minutes after the removal of the patch. Then a new patch was placed in the same place. New patches were applied 3 times per week and the assessments were made 48 hours after the removal. Repeated application of the patches using this method was continued for three weeks (ten applications in total). Additional patch tests were used to determine the contact photosensitization of the patch. During the induction phase and in parallel with the repetitive patch tests, the patch tests were irradiated five times with solar stimulator or UVA (5 Joules) after the removal of five repetitive patches (serial). The phototoxic potential of the test patch was evaluated at hours, 6 and 24 hours after a simple treatment. 2. Challenge phase After the end of the three-week period, a rest period of fifteen days followed. At the end of the rest period patch tests were performed as follows: The sodium lauryl sulfate solution was first applied to the back followed by the patch of test material. In the challenge test, the patch was removed 48 hours after application and the assessments were made 24, 48 and 72 hours after the application. During the challenge phase, a second patch test was performed at another site and after its removal the site was irradiated with UVA (5 Joules). Readings were made at 72 and 96 hours after the application. The valuations for both phases were carried out by the same researcher and under the same conditions. The record was based on the standard ICDRG scale. The results were negative for both phases and in this way the patch can be considered as "hypoallergenic" and "dermatologically tested".

Example No. 11 Test for repetitive irritation in humans The purpose of this study was to provide a quick and simple indication of potential irritation by the test patch. Due to the lower sensitivity of human skin to irritants, against the animal model, the test in man is usually performed by repetitive application of the test patch. The study involved 20 volunteers, male or female (15-50 years of age), whose upper backs were free of any skin problems. The patch of test material was initially applied to the volunteer's upper back for 24 hours, kept with a non-irritating Scanpor tape and then removed. After one hour of removal, the skin site was gently cleaned with a wet and classified wool ball. The application of test material was repeated at the same site, 24 hours later. The application of test material continued for 20 days (total of 10 applications with a rest period during weekends). The results showed no signs of erythema, edema or exudation induced by the test patch and in this way the product can be considered as "non-irritating".

Example No. 12 Permeability of the anti-acne patches In order to evaluate the local effect of the anti-acne patches according to the invention, the transdermal absorption (Flow) of the salicylic acid of the adhesive matrix of the invention was determined in vitro when using human cadaver skin, according to the procedure described by Franz T., in Percutaneous absorption on the relevance of the in vitro data, J. Invest. Derm. 64, 190-195, 1975.

For in vitro flow studies, the stratum corneum of human cadaver skin was used. Using fresh, post-mortem skin samples, the stratum corneum was separated from the skin by the technique described by Kiigman, A.M. et al in Preparation of the isolated sheets of the human stratum corneum, Arch. Derm. 88, 702, 1963. It is presented in Figure 4 [Fig. 4a and Fig. 4b) a comparative study of the determination of skin flow (expressed as acrylic permeation amount of salicylic acid per unit area at any time) between the anti-acne patch of the invention (Patch 1), the same patch but having a double thickness adhesive matrix (Patch 2) and a reference gel formulation containing 2% salicylic acid (Gel).

The results showed a very limited penetration for the anti-acne patch of adhesive matrix thickness, compared to that of the reference gel formulation, thus affirming the local effect of the proposed anti-acne patch.

Claims (25)

1. CLAIMS 1 . A device in the form of a patch for topical application of an anti-acne formulation, comprising a synthetic pressure sensitive adhesive, used as a carrier or associated with a carrier, said carrier having the anti-acne formulation evenly distributed in the same, characterized in that said anti-acne formulation comprises effective amounts of at least two active ingredients of at least two different groups of active ingredients and wherein said at least two different groups are selected from the group comprising keratolytic agents, anti-irritant agents , antiseptic agents, antimicrobial agents, hormones, hormone agonists, hormone antagonists and other agents suitable to treat acne.
2. 2. A device according to claim 1, characterized in that said anti-acne formulation further comprises one or more solubilizers.
3. 3. A device according to claim 1 or 2, characterized in that it further comprises one or more carriers acceptable for topical application.
4. 4. A device according to any of claims 1 to 3, which comprises, in relation to the total weight of the carrier and the formulation: - one or more keratolytic agents, each in an amount of 0.1 to 10% w / w , preferably from 0.1 to 2.0% w / w and more preferably from 0.6% w / w; - one or more anti-irritant agents, each in an amount of 0.01 to 5.0% w / w, preferably 0.01 to 3.0% w / w and more preferably 1.0% w / w; - one or more antiseptic agents, each in an amount of 0.05 to 2.0% w / w, preferably 0.1 to 1.0% and more preferably 0.3% w / w; and - one or more solubilizers, each in an amount of 0.1 to 5% w / w, preferably 1 to 3.0% w / w and more preferably 2% w / w.
5. 5. A device according to any of claims 1 to 4, wherein the synthetic adhesive (2) is provided with a layer of support film (1) on a first side, and with a release coating (3) adhered on its opposite side, said opposite side will come into contact with the surface of the skin upon use.
6. 6. A device according to claim 5, wherein the support film is occlusive.
7. 7. A device according to claim 5, wherein the support film is breathable.
8. 8. A device according to any of claims 1 to 7, wherein the synthetic carrier is formed in multiple layers.
9. 9. A device according to claims 1 to 8, wherein the synthetic carrier is an adhesive polymer matrix.
10. A device according to claim 9, wherein the adhesive polymer matrix is formed of one or more adhesive polymers. eleven .
11. A device according to claim 9 or 10, wherein the adhesive polymeric matrix is made of one or more polymers selected from the group consisting of acrylic-based polymers, rubber-based polymers and polymers based on silica, topically acceptable and with properties of adhesion.
12. A device according to any of claims 1 to 11, wherein the keratolytic agent is selected from the group consisting of salicylic acid, benzoyl peroxide, sulfur, retinoic acid and any of a number of fruit acids and acids Alpha hydroxy.
13. 13. A device according to any of claims 1 to 12, wherein the anti-irritant agent is selected from the group consisting of a-bisabolol, farnesol, glycyrrhetinic acid and chamomile extract.
14. 14. A device according to any of claims 1 to 13, wherein the antiseptic agent is selected from the group consisting of triclosan, phenoxy isopropanol, resorcinol, chlorhexidine, povidone and iodine.
15. 15. A device according to any of claims 2 to 14, wherein the solubilizer is selected from the group consisting of glycerol, propylene glycol, polyalcohols, sorbitol and sorbitol derivatives, preferably sorbitan monooleate.
16. 16. A device according to any of claims 1 to 15, which further comprises an anti-microbial agent, preferably selected from the group consisting of erythromycin, tetracycline, cephalosporin and clindamycin.
17. 17. A device according to any of claims 1 to 16, providing prolonged delivery of the formulation for at least 4 hours, preferably at least 24 hours, more preferably 8 hours.
18. 18. A device according to any of claims 1 to 17, which has a size in the range of 0.5 to 2 cm2 and a thickness in the range of approximately 178 to 610 μm.
19. 19. A device according to any of claims 1 to 18, wherein the keratolytic agent is salicylic acid.
20. 20. A device according to claim 19, wherein the effective amount of salicylic acid is 0.6% w / w.
21. 21. A device according to any of claims 1 to 20, where the antiseptic is triclosan.
22. 22. A device according to any of claims 1 to 21, wherein the anti-irritant is a-bisabolol.
23. 23. A device according to any of claims 1 to 22, wherein the solubilizer is sorbitan monooleate.
24. 24. A device according to any of claims 1 to 23, wherein the anti-acne formulation is evenly distributed in a paper associated with the synthetic adhesive.
25. 25. A method for manufacturing the delivery device according to any of claims 1 to 23, comprising: (a) mixing a simple adhesive or a mixture of adhesives with an anti-acne formulation in order to form a mixture; and (b) laminating the mixture on a first side with a release coating and on a second side with a support film.