HK40067876A - Formulations for odontological and dermatological use containing trichloroacetate salts and hydroxyacids - Google Patents

Description

Formulations containing trichloroacetate and hydroxycarboxylic acids for dental and dermatological use

Technical Field

The present invention relates to compositions for pharmaceutical, dental, cosmetic and dermatological use, in particular for gingival-collar (gingival-collagen) stripping, skin stripping, and for resurfacing (resurfacing), for treating skin hyperpigmentation, controlling sebum production, for treating acne, for reducing pore size and the appearance of scars without causing undesirable side effects such as vitiligo, leaving scars, infection, recurrence of herpes simplex infection and color contrast of the treated skin, for stimulating fibroblasts, percutaneous bioreduction, stimulating new collagen production, for improving aesthetics, for lightening the skin, beautifying the skin, firming the skin and regenerating the skin. These novel formulations containing an addition salt of trichloroacetic acid exhibit antibacterial properties and induce desquamation of the stratum corneum, stimulating skin cells to form new collagen.

Technical Field

It is known that the stratum corneum of skin is automatically repaired by desquamation, and mature skin takes more time to repair if compared to young skin. The firmness and elasticity of the skin depend on the different forces of elastin and collagen: elastin is responsible for the flexibility of the skin and collagen has the main task of maintaining the skin in a good health condition. In young skin with fresh collagen, the skin returns to its original position more rapidly after mechanical pulling than more mature skin.

The cell turnover rate of epidermal tissue can be increased by a treatment that accelerates the rate of new cell generation of epidermal tissue. Skin exfoliation (also known as chemical exfoliation) for treating mature or damaged skin has been employed by dermatologists to restore the new and youthful appearance of skin and to reduce the appearance of scars.

The outer layer of human skin can be stripped off by applying a chemical that removes dead skin and damages underlying living skin tissue.

The treatment is referred to as "chemical stripping" and may be performed using appropriate concentrations of different chemical active agents (e.g., alpha-and beta-hydroxycarboxylic acids, trichloroacetic acid, phenols, etc.) for a defined period of time in a single treatment session or up to over a period of several days of repeated treatments.

Chemical stripping can be performed to different degrees of depth defined as skin, medium, and deep stripping.

Since the skin peel only penetrates the epidermis, it produces limited or no adverse side effects. A common skin peel is performed using glycolic acid. When used properly, superficial exfoliation using glycolic acid at concentrations of 30 to 50% has shown good clinical efficacy in the treatment of superficial hyperpigmentation, mild to moderate age aging and photoaging, and fine wrinkles.

Moderate and deep exfoliation injure the entire epidermis, papillary dermis (papillary dermis) and creates trauma at the level of the middle reticular dermis (dermal dermis) and redness that typically lasts for several days.

A commonly used moderate depth chemical exfoliation is a 50% trichloroacetic acid (TCA) solution, which is used for the frequently used exfoliation treatment of fine wrinkles, actinic photodamage, hyperpigmentation, and even actinic related precancerous changes, such as actinic keratosis. Other commonly used Chemical active agents currently used for moderate Depth exfoliation are 70% glycolic acid and 35 to 50% TCA, with or without adjuvant combination products (e.g., Jessner's solution; Monheit, G.D. the Jessner's + TCA Peel: A Medium-Depth Chemical Peel.J.Dermatol.Surg.Oncol.1989, 15(9), 945) and multilayer coating with 20 to 40% salicylic acid and pyruvic acid.

Deep chemical exfoliation can lead to scar crusting (i.e., protein denaturation of keratin and collagen) resulting in "white frost" or eruption or redness of the skin on which the chemical active has been applied. In this case, the post-operative recovery period may limit the life-related activities of the patient.

Different degrees of white spots (frosting) designated as I, II and class III can be obtained using chemical strippers: in grade I, white spots appear clinically as erythema with a string-like or plaque-like light white spot; in stage II, the white spots appear as uniform, white-looking white spots with underlying erythema; in grade III, the white spot appears as a solid white enamel (enamel) white spot with little to no background erythema. With surface lift-off, the goal is to have little to no white spots (Soleymani, T.; Lanoue, J.; Rahman, Z.A Practical application to Chemical pels: A Review of Fundamentals and Step-by-Step Algorithm Protocol for treatment. J. Clin. Aester. Dermatol.2018, 11 (8): 21-28).

Different types of exfoliation treatments or protocols have been described that aim at removing a predictable, uniform thickness of damaged skin, which then allows normal wound healing and skin regeneration to occur, while minimizing complications and adverse side effects.

Compounds which can be used for exfoliation treatment are hydroxycarboxylic acids such as glycolic acid, citric acid, glucuronic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucic acid, pyruvic acid, galacturonic acid, beta-phenyllactic acid, beta-phenylpyruvic acid, beta-hydroxybutyric acid, glucaric acid, tartaric acid and hydroxypropanedioic acid (US3988470, US4021572, US4197316, US4234599, US4246261, US4380549 and US 4363815).

Compositions for dermatological use comprising trichloroacetic acid (TCA) are generally known (see e.g. US4874361, US5599546, US5716625, US6139850 and US 7189406). Phytic acid has also been proposed for skin treatment (US5116605, US5434144, US5536499, US5665364 and US 5811111). Formulations comprising phytic acid or trichloroacetic acid as active ingredient are also known (US7439214 and JP 62056411).

The aforementioned compounds and formulations for chemical exfoliation should also be selected in consideration of the skin type of the patient to be treated, since these therapies are known to be adjusted based on several factors such as genetic predisposition (i.e. eye colour, hair colour/type, skin pore depth, skin thickness, and the body's ability to produce melanin), tanning habits, according to the particular concerns and desires of the individual for its aesthetic improvement of the skin and the ability to tolerate post-operative recovery periods.

Therefore, there is a need for novel and preferred topical formulations that are free of the aforementioned side effects (i.e., white spots, etc.).

The formulations developed for chemical stripping, and in particular The formulation with TCA, may also be used in dentistry as a soft tissue chemical cautery (Khorosuhi M., Tavasoli M.; The Effect of a chromatographic as a systemic and/or ethical agent on The gingival margin of a tooth for The repair of The cervical cavity (cervical compartments) with a resinous material, and The shear bond strength of resin composition to electrode Dent. (2010), 35 (187-93), Lewinstein I, Rotstein I., (1992). Furthermore, TCAs are not without side effects for this intended use, including reduction of microhardness in dentin and enamel and possible necrotic effects on the marginal gums. To avoid these side effects, the concentration of TCA and its use is limited to seconds (i.e. 30 seconds). Thus, there is a need for novel and preferred formulations that are free of the above-mentioned side effects, also for dental use.

Definition of

Folliculitis is a skin condition in which hair follicles are inflamed. It is usually caused by bacterial or fungal infection.

Wrinkles are facial wrinkles that are inferior to the muscle contraction pattern in the skin.

Actinic light damage is represented by rough patches of skin caused by damage from long-term sun exposure.

Hyperpigmentation is the darkening of the skin or nail area caused by an increase in melanin.

Scar scabbing and degeneration produce 'white frost'. It is due to protein denaturation of keratin and collagen.

Hydroxyethyl cellulose is a compound identified by CAS registry number 9004-62-0.

Is cellulose derivatized with PEG 350.

Homocysteine is a compound recognized by CAS registry No. 14857-77-3.

Bioisosteres (also known as biosters) are molecules produced by the exchange of atoms or groups of atoms with substitute, substantially similar atoms or groups of atoms (Venkatesan, n.; ramatahan, m.; manyarakarasi, v.; Solairaj, p. biosterism Review-an Biological modification. world j. phase. sci.2017, 6(9), 1918-.

Jersener's solution is a therapeutic agent for the treatment of hyperkeratotic epidermal ulcers (Monheit, G.D. the Jessner's + TCA Peel: A Medium-Depth Chemical Peel.J. Dermatol.Surg. Oncol.1989, 15(9), 945-950).

Summary of The Invention

The present invention relates to topical formulations containing trichloroacetate for the treatment of skin defects and skin rejuvenation. In particular, these agents reduce epidermal thickness, stimulate cellular turnover and induce substantial modification of the dermal compartment (dermal component) by stimulating the production of fibroblasts and mature collagen. Thus, the formulation can be used to eliminate the discoloring effects of acne and superficial scars.

Depending on the intended use, these novel formulations may be in the form of liquid solutions, gel formulations or compressed gels (compact gels). The positive effects on skin firmness and elasticity using these novel topical formulations have been confirmed before and after treatment using instrumental measurements and by perceptible improvements in skin morphology after clinical treatment.

Compared to other chemical peels, the formulations of the invention reduce the risk of the most common side effects of these treatments, such as white spots, scarring, infection, recurrence of herpes simplex infection and color contrast of the treated skin.

The formulations of the present invention may also be used in dentistry for gum collar stripping. These novel formulations are safer than conventional dentistry TCA formulations because they do not have any necrotic effect on the peripheral gums and do not affect the microhardness and structural changes of dentin and enamel.

Detailed Description

The aqueous formulation of the invention comprises trichloroacetate at a concentration of between 20 and 40% w/w, preferably 32-34% w/w, one or more hydroxycarboxylic acids at a concentration of between 0.5 and 10% w/w, and optionally glutamic acid or glutamic acid bioisosteres at a concentration of between 0.2 and 4.0% w/w, phytic acid, glycerol at a concentration of less than 15% w/w, an oxidising agent at a concentration of less than 1% w/w, typically 0.1 to 1%; and a hydrophilic pharmaceutically acceptable gelling agent at a concentration up to 7% w/w, typically 0.1 to 2%.

The trichloroacetic acid salts selected include sodium salt (1: 1) (CAS registry number 650-51-1), ammonium salt (1: 1) (CAS registry number 7646-88-0), potassium salt (1: 1) (CAS registry number 16586-14-4), magnesium salt (2: 1) (CAS registry number 16094-02-3), calcium salt (2: 1) (CAS registry number 21348-16-3), zinc salt (2: 1) (CAS registry number 16083-12-8), and silver salt (1: 1) (CAS registry number 25000-97-9). In a preferred embodiment, the trichloroacetate salt is an ammonium salt (1: 1) and a silver salt (1: 1), preferably an ammonium salt (1: 1).

The selected hydroxycarboxylic acids include one or more of the following compounds: tartaric acid, citric acid, glycolic acid, glucuronic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid and lactic acid. In a preferred embodiment, the hydroxycarboxylic acids are tartaric acid, citric acid and glycolic acid, more preferably tartaric acid and/or citric acid.

The glutamate bioisosteres used in the formulations include homocysteine.

The oxidant comprises hydrogen peroxide and benzoyl peroxide; preferably, hydrogen peroxide is used.

Examples of hydrophilic pharmaceutically acceptable gelling agents include hydroxyethyl cellulose,Xanthan gum, sclerotium rolfsii gum (sclerostinum gum), hydroxypropyl starch phosphate, Sepigel^TM305 and Sepimax^TMzen, preferably hydroxyethylcellulose andthe gelling agent may be absent to produce liquid and non-viscous formulations, or present in concentrations typically up to 0.8 wt% to give a gel formulation and up to 7 wt% to give a compressed gel formulation.

Example 1

25Kg of an aqueous solution having the following composition was added to 49.8% w/w of an aqueous solution of ammonium trichloroacetate (66.3Kg) at 20-25 ℃ with stirring: 1Kg of tartaric acid, 4Kg of citric acid and 20Kg of deionized water. Then stirring at 20-25 ℃ 50% w/w phytic acid aqueous solution (400g), 30% hydrogen peroxide (3.3Kg), deionized water (4.4Kg) and,(600g) The resulting solution was added (in 30') in portions in sequence. The resulting mixture was then maintained under stirring at room temperature to obtain a homogeneous solution, which was then filtered on a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Example 2

Homocysteine (2.0Kg), a 50% w/w aqueous solution of tartaric acid (2.0Kg), citric acid (4.0Kg), and deionized water (25.6Kg) were added to a 50.2% w/w aqueous solution of ammonium trichloroacetate (65.8Kg) at 20-25 deg.C in sequence with stirring. Hydroxyethyl cellulose (600g) was then added portionwise (in 30') to the resulting solution. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered on a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Deionized water	59.4Kg	59.4％
Tartaric acid	1.0Kg	1.0％
			Homocysteine	2.0Kg	2.0％
Citric acid	4.0Kg	4.0％
			Trichloroacetic acid ammonium salt	33.0Kg	33.0％
Hydroxyethyl cellulose	0.6Kg	0.6％

Example 3

Homocysteine (2.0Kg), a 50% w/w aqueous solution of tartaric acid (2.0Kg), citric acid (4.0Kg), trichloroacetic acid (11.0Kg), and deionized water (14.6Kg) were added to a 50.2% w/w aqueous solution of ammonium trichloroacetate (65.8Kg) at 20-25 deg.C in sequence with stirring. Hydroxyethyl cellulose (600g) was then added portionwise (in 30') to the resulting solution at room temperature with stirring. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered over a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-1.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Deionized water	48.4Kg	48.4％
Tartaric acid	1.0Kg	1.0％
			Homocysteine	2.0Kg	2.0％
Citric acid	4.0Kg	4.0％
			Trichloroacetic acid ammonium salt	33.0Kg	33.0％
Trichloroacetic acid	11.0Kg	11.0％
			Hydroxyethyl cellulose	0.6Kg	0.6％

Comparative example 4

Sodium trichloroacetate (97%; 34.0Kg) and homocysteine (2.5Kg) were added to pure water (62.9Kg) sequentially at 20-25 deg.C with stirring. Hydroxyethyl cellulose (600g) was then added (in 30') portions. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered over a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Deionized water	62.9Kg	62.9％
Homocysteine	2.5Kg	2.5％
			Trichloroacetic acid sodium salt	34.0Kg	34.0％
Hydroxyethyl cellulose	0.6Kg	0.6％

Example 5

Homocysteine (2.0Kg), a 50% w/w aqueous solution of tartaric acid (2.0Kg), citric acid (4.0Kg), 30% hydrogen peroxide (3.3Kg), glycerol (10Kg), and deionized water (12.9Kg) were added to a 50.2% w/w aqueous solution of ammonium trichloroacetate (65.8Kg) at 20-25 deg.C in sequence with stirring. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered over a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Deionized water	47.9Kg	49.0％
Tartaric acid	1.0Kg	1.0％
			Homocysteine	2.0Kg	2.0％
Citric acid	4.0Kg	4.0％
			Trichloroacetic acid ammonium salt	33.0Kg	33.0％
Glycerol	10.0Kg	10.0％
			Hydrogen peroxide	1.0Kg	1.0％

Example 6

Homocysteine (2.0Kg), citric acid (0.6Kg), tartaric acid (0.2Kg), a 50% w/w aqueous solution of phytic acid (400g), glycerol (10.0Kg) and deionized water (19.8Kg) were added to a 49.7% w/w aqueous solution of ammonium trichloroacetate (66.4Kg) at 20-25 ℃ in sequence with stirring. Hydroxyethyl cellulose (600g) was then added portionwise (in 30') to the resulting solution. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered over a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Trichloroacetic acid ammonium salt	33.0Kg	33.0％
Homocysteine	2.0Kg	2.0％
			Citric acid	0.6Kg	0.6％
Tartaric acid	0.2Kg	0.2％
			Phytic acid	0.2Kg	0.2％
Glycerol	10.0Kg	10.0％
			Deionized water	53.4Kg	53.4％
Hydroxyethyl cellulose	0.6Kg	0.6％

Example 7

Homocysteine (2.0Kg), citric acid (0.6Kg), tartaric acid (0.2Kg), a 50% w/w aqueous solution of phytic acid (400g), glycerol (10.0Kg), 30% hydrogen peroxide (3.3Kg) and deionized water (12.1Kg) were added to 49.7% w/w aqueous ammonium trichloroacetate solution (66.4Kg) sequentially at 20-25 deg.C with stirring. Then Sepigel is added^TM305(5.0Kg) was added portionwise (in 30') to the resulting solution. The resulting solution was then maintained at room temperature under stirring for 60' and then filtered over a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Example 8

Homocysteine (2.0Kg), citric acid (0.6Kg), tartaric acid (0.2Kg), a 50% w/w aqueous solution of phytic acid (400g), glycerol (10.0Kg) and deionized water (15.4Kg) were added to a 49.7% w/w aqueous solution of ammonium trichloroacetate (66.4Kg) at 20-25 ℃ in sequence with stirring. Then Sepigel is added^TM305(5.0Kg) was added portionwise (in 30') to the resulting solution. The resulting solution was then stirred at room temperatureStirred and maintained at 60' and then filtered on a suitable 10 micron filter. The pH of the resulting solution is comprised in the range of 1.8-2.2.

Final composition of the formulation

Components	Measurement of	Composition (weight%)
			Trichloroacetic acid ammonium salt	33.0Kg	33.0％
Homocysteine	2.0Kg	2.0％
			Citric acid	0.6Kg	0.6％
Tartaric acid	0.2Kg	0.2％
			Phytic acid	0.2Kg	0.2％
Glycerol	10.0Kg	10.0％
			Deionized water	49.0Kg	49.0％
SepigelTM305	5.0Kg	5.0％

Cosmetic testing

Skin firmness and elasticity: to evaluate the effect of the test formulations, the reference was an untreated skin area of the same individual. The subject is treated with the test formulation in a single treatment course: the formulation was applied to the skin three to five times (about 0.2ml each time). This course was repeated once a week for a total of three weeks. The individuals tested were women between the ages of 40 and 80. Utilization before and at the end of treatment via visual inspection "Skin analysis System and 3D Camera for Antera skin analysisMIRAVEX S/N: 12371150 (serial number), version 2.1.8-it-Pro (http:// miravex. com/antea-3 d /) evaluation of treated skin was performed at 100cm relative to untreated skin²The effect of the formulation on skin area treatment (table 1).

By the above analysis, in particular taking and quantitatively evaluating the wrinkles (depth, width and overall size; table 1) of the tested patients before and after treatment with formulation 7, we observed a perceptible improvement in the treated skin surface, with a reduction of the average depth, average width and overall size of the wrinkles by-34%, -15% and-40%, respectively (table 2). Similar results were obtained using formulations 1-3, 5, 6 and 8.

Table 1. andra 3D camera results on the tested patients before and at the end of the treatment.

Table 1 (continuation) andra 3D camera results on the examined patients before and at the end of treatment

Table 2.an andrera 3D camera: average results on the tested patients before and at the end of the treatment

Claims (17)

1. An aqueous formulation for dental and topical use comprising trichloroacetate at a concentration between 20 and 40% w/w, one or more hydroxycarboxylic acids at a concentration between 0.5% and 10% w/w, and optionally glutamic acid or glutamic acid bioisosteres at a concentration between 0.2 and 4.0% w/w, phytic acid, glycerol at a concentration of less than 15% w/w, an oxidizing agent at a concentration of less than 1% w/w and a hydrophilic pharmaceutically acceptable gelling agent at a concentration up to 7% w/w.

2. The formulation according to claim 1, wherein said trichloroacetate is present at a concentration of 32-34% w/w.

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

4. The formulation according to claim 1, wherein said hydroxycarboxylic acid is selected from the group consisting of tartaric acid, citric acid, glycolic acid, glucuronic acid, α -hydroxybutyric acid, α -hydroxyisobutyric acid and lactic acid.

5. The formulation according to claim 1, wherein said glutamate bioisostere is homocysteine.

6. The formulation according to claim 1, wherein said oxidizing agent is hydrogen peroxide.

7. The formulation according to claim 1, wherein said hydrophilic pharmaceutically acceptable gelling agent is selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, and mixtures thereof,Xanthan gum, sclerotium rolfsii gum, hydroxypropyl starch phosphate, Sepigel^TM305 and Sepimax^TMzen。

8. The formulation according to claim 1, wherein said gelling agent is absent.

9. A formulation according to claim 1 wherein the gelling agent is present at a concentration of up to 0.8%.

10. A formulation according to claim 1 in the form of a compressed gel wherein the gelling agent is present at a concentration of up to 7%.

11. The formulation according to claims 1 to 10 for use in the treatment of skin defects.

12. The formulation for use according to claim 11, wherein the skin imperfections are wrinkles, actinic light damage, hyperpigmentation and scars.

13. A formulation according to claims 1 to 10 for use as an antibacterial agent for the treatment of acne and folliculitis.

14. The formulation of claims 1 to 10 for use in gum collar stripping in dentistry.

15. Use of the formulation of claims 1 to 10 in a cosmetic method for obtaining skin rejuvenation by inducing substantial modification of the dermal compartment and production of fibroblasts and mature collagen by stimulating cellular turnover of the skin.

16. Use of the formulation of claims 1 to 10 for cosmetic skin change.

17. A formulation according to claims 1 to 10 for use according to claims 11 to 14 for stimulating fibroblast proliferation.