Formulations for dental and dermatological use containing trichloroacetic acid salts and hydroxy acids - Patent Application 20070122993

Abstract

Pharmaceutical, dental, cosmetic and dermatological compositions comprising an addition salt of trichloroacetic acid, one or more hydroxy acids and optionally glutamic acid or bioisosteres of glutamic acid and phytic acid are useful for peeling of the gum collar, exfoliating the skin, resurfacing, treating skin hyperpigmentation, controlling sebum production, acne, reducing pore size and reducing the appearance of scars and uneven skin tone without causing undesirable side effects, for fibroblast stimulation, transdermal biorevitalization, stimulation of new collagen production, for aesthetic improvement, skin whitening, skin brightening, skin tightening and skin rejuvenation.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compositions for medical, dental, cosmetic, and dermatological uses, specifically compositions useful for peeling the gingival collar, peeling the skin, and for resurfacing, treating skin hyperpigmentation, controlling sebum production, treating acne, reducing pore size and the appearance of scars without causing undesirable side effects such as frosting, scarring, infections, reactivation of herpes simplex infections, and uneven skin tone in treated skin, stimulating fibroblasts, transdermal biorevitalization, stimulating the production of new collagen, aesthetic improvement, skin whitening, skin firming, and skin rejuvenation. These new formulations, containing addition salts of trichloroacetic acid, exhibit antiseptic properties and induce peeling of the stratum corneum and stimulation of skin cells to form new collagen.

[0002] background It is known that through desquamation, the stratum corneum of the skin renews itself, and that compared to young skin, mature skin may take longer to renew. Firmness and elasticity in the skin depend on the various forces of elastin and collagen: elastin is responsible for skin flexibility, while collagen's main job is to maintain the skin's shape. In young skin with fresh collagen, the skin returns to its original position more quickly after mechanical stress than older skin.

[0003] Cellular turnover in epidermal tissue can be increased by treatments that accelerate the rate at which new cells are formed in the epidermal tissue. Skin peeling, also known as chemoexfoliation, is used by dermatologists to treat aged or damaged skin, restoring the skin's freshness and youthful appearance and reducing the appearance of scars.

[0004] The outer layer of human skin can be peeled off with chemical agents that can remove dead skin cells and damage the underlying living skin tissue.

[0005] This treatment is known as "chemical peeling" and can be performed using a variety of chemical agents, such as alpha- and beta-hydroxy acids, trichloroacetic acid, phenol, etc., in appropriate concentrations and for a well-defined period of time, either in a single treatment session or over a period of repeated treatments over at most several days.

[0006] Chemical peels can be performed in varying degrees of depth, defined as superficial peels, medium peels, and deep peels.

[0007] Because superficial peels penetrate only the epidermis, they produce limited or no unwanted side effects. A commonly used superficial peel is performed using glycolic acid. When used appropriately, superficial peels using glycolic acid at concentrations of 30 to 50% have shown good clinical efficacy in treating superficial hyperpigmentation, mild to moderate chrono- and photoaging, and fine wrinkles.

[0008] Mid-thickness and deep peels damage the entire epidermis, the papillary dermis, causing damage down to the level of the mid-reticular dermis, and usually resulting in redness that lasts for several days.

[0009] A commonly used intermediate-depth chemical peel is 50% trichloroacetic acid (TCA) solution, which is frequently used for the peel treatment of fine lines, actinic photodamage, hyperpigmentation, and even actinic radiation-related precancerous changes such as actinic keratoses. Other common chemical agents currently used for intermediate peels are 70% glycolic acid and 35–50% TCA, with or without adjuvant combination products (e.g., Jessner's solution; Monheit, GD The Jessner's + TCA Peel: A Medium-Depth Chemical Peel. J. Dermatol. Surg. Oncol. 1989, 15(9), 945–950), and 20–40% salicylic acid and pyruvic acid applied in multiple layers.

[0010] Deep chemical peels can cause keratin coagulation (i.e., protein denaturation of keratin and collagen) that results in a "white frost" appearing on the skin where the chemicals were applied, or a skin rash or redness. In this case, the recovery period after the treatment can limit the patient's relational life.

[0011] Various levels of frosting, labeled Levels I, II, and III, can be achieved using chemical peels: at Level I, the frosting appears clinically as erythema with streaky or patchy light frosting; at Level II, the frosting appears as a uniform, white coating with underlying erythema; and at Level III, the frosting appears as a 3D white enamel frosting with little background erythema. When using superficial peels, the goal is to have little to no frosting (Soleymani, T.; Lanoue, J.; Rahman, Z. A Practical Approach to Chemical Peels: A Review of Fundamentals and Step-by-step Algorithmic Protocol for Treatment. J. Clin. Aesthet. Dermatol. 2018, 11(8): 21-28).

[0012] Various types of peeling treatments or protocols have been described with the goal of removing a predictable and uniform thickness of damaged skin, thereby allowing for subsequent normal wound healing and skin rejuvenation while simultaneously minimizing complications and unwanted side effects.

[0013] Compounds useful in peeling treatments are hydroxy acids such as glycolic acid, citric acid, glucuronic acid, α-hydroxybutyric acid, α-hydroxy-isobutyric acid, lactic acid, malic acid, mandelic acid, mucic acid, pyruvic acid, galacturonic acid, β-phenyllactic acid, β-phenylpyruvic acid, β-hydroxybutyric acid, glucaric acid, tartaric acid, and tartronic acid (U.S. Patent Publication Nos. 3,988,470, 4,021,572, 4,197,316, 4,234,599, 4,246,261, 4,380,549, 4,363,815).

[0014] Dermatological compositions containing trichloroacetic acid (TCA) are generally known (see, for example, U.S. Patent Publication Nos. 4,874,361, 5,599,546, 5,716,625, 6,139,850, and 7,189,406). Phytic acid has also been proposed for skin treatment (U.S. Patent Publication Nos. 5,116,605, 5,434,144, 5,536,499, 5,665,364, and 5,811,111). Formulations containing phytic acid or trichloroacetic acid as an active ingredient are also known (U.S. Patent Publication No. 7,439,214, and Japanese Patent No. 62,056,411).

[0015] The above compounds and preparations used for chemical peeling should also be selected taking into consideration the type of skin of the patient to be treated, since it is known that these treatments must be tailored according to the specific interests and desires of each subject based on several factors such as genetics (i.e., eye color, hair color / type, depth of skin capillaries, skin thickness, body's ability to produce melanin), tanning habits, etc., with regard to aesthetic improvement of the skin and ability to withstand the recovery period after treatment.

[0016] Therefore, there is a need for new and better topical formulations that do not have the above side effects (ie, frosting, etc.).

[0017] The above-mentioned preparations developed for chemical peeling, and in particular the TCA-based preparations, can also be used in dentistry to chemically cauterize the soft tissues of the gingival margin prior to the restoration of cervical cavities with resin materials (Khoroushi M., Tavasoli M.; The effect of trichloroacetic acid as a hemostatic and etching agent on the morphological characteristics and shear bond strength of resin composite to enamel. Oper Dent. (2010), 35(2), 187-93; Lewinstein I, Rotstein I., (1992). Effect of trichloroacetic acid on the microhardness and surface morphology of human dentin and enamel. Endodontics and Dental Traumatology, 1992, 8(1), 16-20). Furthermore, for this purpose, TCA is not devoid of side effects, including a reduction in the microhardness of both dentin and enamel, and a possible necrotic effect on the marginal gingiva. To avoid these side effects, the concentration of TCA and its application are limited to a few seconds (i.e., 30 seconds). Therefore, new and better formulations for dental use that do not have the above side effects are also needed.

[0018] definition Folliculitis is a skin condition in which hair follicles become inflamed, usually caused by a bacterial or fungal infection.

[0019] Wrinkles are fine lines on the face that occur secondary to muscle contraction patterns in the skin.

[0020] Actinic photodamage is manifested by rough patches on the skin caused by damage from years of sun exposure.

[0021] Hyperpigmentation is the darkening of some areas of the skin or nails due to increased melanin.

[0022] Corneal coagulation results in a "white frost" appearance, which is due to protein denaturation of keratin and collagen.

[0023] Hydroxyethyl cellulose is a compound identified by CAS Registry Number: 9004-62-0.

[0024] Idroramnosan® is a cellulose derivatized with PEG350.

[0025] Homocysteic acid is a compound identified by CAS Registry Number: 14857-77-3.

[0026] Bioisosterisms (also called biosters) are molecules that result from the exchange of an atom or group of atoms with a broadly similar atom or group of atoms in its place (Venkatesan, N.; Ramanathan, M.; Mangayarakarasi, V.; Solairaj, P. Bioisosterism Review- an Biological Modification. World J. Pharm. Pharm. Sci. 2017, 6(9), 1918-1949).

[0027] Jessner's solution is used as a therapeutic agent to treat hyperkeratotic epidermopathies (Monheit, GD The Jessner's + TCA Peel: A Medium-Depth Chemical Peel. J. Dermatol. Surg. Oncol. 1989, 15(9), 945-950).

[0028] Summary of the Invention The present invention relates to topical preparations containing salts of trichloroacetic acid for the treatment of skin defects and skin regeneration. Specifically, these preparations induce substantial modification of the dermal compartment by reducing epidermal thickness, stimulating cell turnover, and stimulating the production of fibroblasts and mature collagen. Therefore, the preparations are useful for removing discoloration resulting from acne and superficial scars.

[0029] These new formulations can be in the form of a liquid solution, a gel formulation, or a compact gel, depending on the intended use. The favorable effect of using these new topical formulations on skin firmness and elasticity has been confirmed using instrumental measurements before and after treatment, and by perceptible improvements in skin appearance after clinical treatment.

[0030] Compared to other chemical peeling agents, the formulations of the present invention can reduce the risk of the most common side effects of these treatments, such as frosting, scarring, infection, reactivation of herpes simplex infection, and uneven skin tone of the treated skin.

[0031] The formulations of the present invention can also be used in dentistry for the purpose of gingival collar ablation. These new formulations are safer than conventional dental TCA formulations because they do not have a necrotic effect on the gingival margin and do not affect the microhardness and structural changes in both dentin and enamel.

[0032] Detailed Description of the Invention Aqueous formulations of the present invention contain trichloroacetate at a concentration between 20% and 40% by weight, preferably in the range of 32% to 34% by weight, one or more hydroxy acids at a concentration between 0.5% and 10% by weight, and optionally glutamic acid or bioisosteres of glutamic acid, phytic acid at a concentration between 0.2% and 4.0% by weight, glycerol at a concentration of less than 15% by weight, an oxidizing agent at a concentration of less than 1% by weight, typically 0.1% to 1% by weight, and a pharmaceutically acceptable hydrophilic gelling agent at a concentration of up to 7% by weight, typically 0.1% to 2% by weight.

[0033] Selected trichloroacetate salts include the sodium salt (1:1) (CAS Registry Number: 650-51-1), the ammonium salt (1:1) (CAS Registry Number: 7646-88-0), the potassium salt (1:1) (CAS Registry Number: 16586-14-4), the magnesium salt (2:1) (CAS Registry Number: 16094-02-3), the calcium salt (2:1) (CAS Registry Number: 21348-16-3), the zinc salt (2:1) (CAS Registry Number: 16083-12-8), and the silver salt (1:1) (CAS Registry Number: 25000-97-9). In a preferred embodiment, the trichloroacetate salt is the ammonium salt (1:1) or the silver salt (1:1), more preferably the ammonium salt (1:1).

[0034] The selected hydroxy acids include one or more of the following compounds: tartaric acid, citric acid, glycolic acid, glucuronic acid, α-hydroxybutyric acid, α-hydroxy-isobutyric acid, and lactic acid. In a preferred embodiment, the hydroxy acids are tartaric acid, citric acid, and glycolic acid, more preferably tartaric acid and / or citric acid.

[0035] Bioisosteres of glutamic acid utilized in the formulation include homocysteic acid.

[0036] The oxidizing agent includes hydrogen peroxide and benzoyl peroxide; preferably, hydrogen peroxide is used.

[0037] Examples of pharmaceutically acceptable hydrophilic gelling agents include hydroxyethylcellulose, Idroramnosan®, xanthan gum, sclerotium gum, hydroxypropyl starch phosphate, Sepigel® 305, and Sepimax® zen, preferably hydroxyethylcellulose and Idroramnosan®. The gelling agent may be absent for liquid and non-viscous formulations and may be present in concentrations typically up to 0.8% by weight to give gel formulations, and up to 7% by weight to give compact gel formulations.

[0038] [Example 1] To 66.3 kg of 49.8 wt% ammonium trichloroacetate solution, 25 kg of an aqueous solution having the following composition: 1 kg of tartaric acid, 4 kg of citric acid, and 20 kg of demineralized water was added with stirring at 20-25°C. Next, 400 g of 50 wt% phytic acid solution, 3.3 kg of 30% hydrogen peroxide, 4.4 kg of demineralized water, and 600 g of Idroramnosan® were added in small portions to the resulting solution with stirring at 20-25°C (within 30 minutes). The resulting mixture was then maintained under stirring at room temperature until a homogeneous solution was obtained, which was then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8-2.2. [Table 1]

[0039] [Example 2] To a 50.2 wt% aqueous solution of ammonium trichloroacetate (65.8 kg), homocysteic acid (2.0 kg), 50 wt% aqueous tartaric acid (2.0 kg), citric acid (4.0 kg), and demineralized water (25.6 kg) were added sequentially with stirring at 20°C to 25°C. Hydroxyethylcellulose (600 g) was added in small portions (within 30 minutes). The resulting solution was then stirred at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8 to 2.2. [Table 2]

[0040] [Example 3] To a 50.2 wt% aqueous solution of ammonium trichloroacetate (65.8 kg), homocysteic acid (2.0 kg), 50 wt% aqueous tartaric acid (2.0 kg), citric acid (4.0 kg), trichloroacetic acid (11.0 kg), and demineralized water (14.6 kg) were added sequentially with stirring at 20-25°C. Hydroxyethylcellulose (600 g) was then added in small portions (within 30 minutes) to the resulting solution at room temperature with stirring. The resulting solution was then maintained under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 0.8-1.2. [Table 3]

[0041] Comparative Example 4 Sodium trichloroacetate (97%; 34.0 kg) and homocysteic acid (2.5 kg) were added sequentially to purified water (62.9 kg) with stirring at 20-25°C. Hydroxyethylcellulose (600 g) was then added in small portions (within 30 minutes). The resulting solution was then kept under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH value of the resulting solution was in the range of 1.8-2.2. [Table 4]

[0042] [Example 5] To 65.8 kg of 50.2 wt% ammonium trichloroacetate solution, homocysteic acid (2.0 kg), 50 wt% tartaric acid (2.0 kg), citric acid (4.0 kg), 30% hydrogen peroxide (3.3 kg), glycerol (10 kg), and demineralized water (12.9 kg) were sequentially added with stirring at 20-25°C. The resulting solution was then maintained under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8-2.2. [Table 5]

[0043] [Example 6] To 66.4 kg of 49.7 wt% ammonium trichloroacetate solution, homocysteic acid (2.0 kg), citric acid (0.6 kg), tartaric acid (0.2 kg), 400 g of 50 wt% phytic acid solution, 10.0 kg of glycerol, and 19.8 kg of demineralized water were sequentially added with stirring at 20°C to 25°C. Hydroxyethyl cellulose (600 g) was then added in small portions to the resulting solution (within 30 minutes). The resulting solution was then maintained under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8 to 2.2. [Table 6]

[0044] [Example 7] To 66.4 kg of 49.7 wt% aqueous ammonium trichloroacetate solution, homocysteic acid (2.0 kg), citric acid (0.6 kg), tartaric acid (0.2 kg), 400 g of 50 wt% aqueous phytic acid solution, 10.0 kg of glycerol, 3.3 kg of 30% hydrogen peroxide, and 12.1 kg of demineralized water were sequentially added with stirring at 20-25°C. Sepigel™ 305 (5.0 kg) was then added in small portions (within 30 minutes) to the resulting solution. The resulting solution was then maintained under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8-2.2. [Table 7]

[0045] [Example 8] To 66.4 kg of 49.7 wt% ammonium trichloroacetate solution, homocysteic acid (2.0 kg), citric acid (0.6 kg), tartaric acid (0.2 kg), 400 g of 50 wt% phytic acid solution, 10.0 kg of glycerol, and 15.4 kg of demineralized water were added sequentially with stirring at 20-25°C. Sepigel™ 305 (5.0 kg) was then added in small portions (within 30 minutes) to the resulting solution. The resulting solution was then maintained under stirring at room temperature for 60 minutes and then filtered through a suitable 10-micron filter. The pH of the resulting solution was in the range of 1.8-2.2. [Table 8]

[0046] Cosmetic Testing Skin firmness and elasticity: To assess the effect of the tested formulations, an untreated area of ​​skin of the same subject was used as a reference. The subjects were treated with the tested formulations in a single treatment session: the formulation was applied evenly to the skin 3-5 times (approximately 0.2 mL each time). This session was repeated once a week for a total of 3 weeks. The subjects tested were women between the ages of 40 and 80. The effect of the formulations was assessed by measuring the firmness of the skin at 100 cm 2 The results were evaluated by visual inspection of treated skin against untreated skin before and at the end of treatment using the VISIA™ Skin Analysis System and the Antera 3D Skin Analysis Camera ANTERA 3D™ MIRAVEX S / N: 12371150 (serial number) Version 2.1.8-it-Pro (http: / / miravex.com / antera-3d / ) (Table 1).

[0047] By the above analysis, and specifically by obtaining and quantitatively assessing the fine lines (depth, width, and overall size; Table 1) of the tested patients before and after treatment with Formulation 7, the inventors observed a perceptible improvement in the surface appearance of the treated skin, with a reduction in the mean depth, mean width, and overall size of fine lines of -34%, -15%, and -40%, respectively (Table 2). Similar results were obtained using Formulations 1-3, 5, 6, and 8.

[0048] [Table 9]

[0049] [Table 10]

[0050] [Table 11]

Claims

1. 1. An aqueous formulation for use in chemical peeling of the skin, comprising trichloroacetic acid salt at a concentration ranging between 20% and 40% by weight, one or more hydroxy acids at a concentration ranging between 0.5% and 10% by weight, and optionally glutamic acid or bioisosteres of glutamic acid, phytic acid at a concentration ranging between 0.2% and 4.0% by weight, glycerol at a concentration less than 15% by weight, an oxidizing agent at a concentration less than 1% by weight, and a pharmaceutically acceptable hydrophilic gelling agent at a concentration up to 7% by weight.

2. 2. The formulation of claim 1, wherein the trichloroacetate salt is present in a concentration of 32 to 34% by weight.

3. 2. The formulation of claim 1, wherein the trichloroacetate salt is selected from sodium salt (1:1), ammonium salt (1:1), potassium salt (1:1), magnesium salt (2:1), calcium salt (2:1), zinc salt (2:1), and silver salt (1:1).

4. 2. The formulation of claim 1, wherein the hydroxy acid is selected from tartaric acid, citric acid, glycolic acid, glucuronic acid, alpha-hydroxybutyric acid, alpha-hydroxy-isobutyric acid, and lactic acid.

5. The formulation of claim 1, wherein the bioequivalent of glutamic acid is homocysteic acid.

6. 2. The formulation of claim 1, wherein the oxidizing agent is hydrogen peroxide.

7. 10. The formulation of claim 1, wherein the gelling agent is present in a concentration of up to 0.8%.

8. 10. The formulation of claim 1 in the form of a compact gel, wherein the gelling agent is present in a concentration of up to 7%.

9. 9. A formulation according to claims 1 to 8 for use in the treatment of skin imperfections.

10. 10. The formulation for use according to claim 9, wherein the skin imperfections are wrinkles, actinic photodamage, hyperpigmentation, and scars.

11. Use of a preparation according to any one of claims 1 to 8 in a cosmetic method of skin regeneration obtained through substantial modification of the dermal compartment and stimulation of skin cell turnover inducing the production of fibroblasts and mature collagen.

12. Use of a formulation according to any one of claims 1 to 8 for cosmetic peeling.

13. 11. A formulation according to any one of claims 1 to 8 for use according to claim 9 or 10 for stimulation of fibroblast proliferation.

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