Film for topical application in the treatment of skin lesions and method of obtaining and applying same

Abstract

This patent application describes a film developed from natural compounds to cover wounds, whose method of application is in the form of individual disposable packages, vials, syringes and/or others. This wound dressing provides a moist environment at the wound site allowing the occurrence of the autolytic debridement. The film incorporates bioactive agents such as acetylsalicylic acid, essential oils, plant extracts and others, which confer antibacterial, antifungal, anti-inflammatory, antioxidant and regenerative properties. The application method is also explored in order to simplify the life of patients, and to minimise pain and discomfort felt by them, during primary care treatment.

Claims

1. A film for topical application on a human consisting essentially of: a) deacetylated chitosan in an amount of 15% and 60% weight % of the film; b) chitosan-arginine in an amount of 15% and 60% weight % of the total film; c) lactic acid in an amount of 0.5% and 1% weight % of the film; d) aloe extract in an amount of 9% and 34% weight % of the film; e) acetylsalicylic acid in an amount of 0.01% and 0.5% weight % of the film; f) lavender essential oil in an amount of 0.01% and 5% weight % of the film; g) ethylene glycol in an amount of 0.05% and 0.20% weight % of the film; and h) benzoic acid in an amount of 0.05% and 0.10% weight % of the film.

2. The film of claim 1, wherein the deacetylated chitosan has a degree of deacetylation between 55% and 99.99%.

3. A method of producing the film of claim 1 consisting essentially of: a) dissolving a mixture of deacetylated chitosan in an amount of 15% and 60% weight % of the film and chitosan-arginine in an amount of 15% and 60% weight % of the film in a dilute solution of lactic acid in an amount of 0.5% and 1% weight % of the film to obtain a chitosan mixture; b) adding an aloe extract in an amount of 9% and 34% weight % of the film to the chitosan mixture and homogenise; c) dissolving acetylsalicylic acid in the homogenized mixture from step b) until the concentration of the acetylsalicylic acid is between 0.01 wt. % and 0.5 wt. % of the film; d) adding the lavender essential oil in an amount of 0.01% and 5 wt. % of the film; e) adding the ethylene glycol in an amount of 0.05% and 0.20 wt. % of the film; f) adding the benzoic acid in an amount of 0.05% and 0.10 wt. % of the film; g) homogenizing the mixture obtained from step f); h) removing air incorporated in the mixture, through sonication and/or vacuum cycles; and i) adjusting the pH of the mixture to a value between 5.0 and 7.4 to yield the film of claim 1.

Description

GENERAL DESCRIPTION

(1) This patent application is based on the development of a hydrogel-based film made from natural components to cover wounds. This film is able to provide a moist environment, allowing the natural autolytic debridement to occur. The film also incorporates bioactive agents (e.g. acetylsalicylic acid, essential oils, plant extracts and others) which confer antibacterial, antifungal, anti-inflammatory, antioxidant, and regenerative properties. The different application strategies (e.g. through individual packages, vials or syringes) are also explored in order to simplify the life of patients, to minimise pain and discomfort felt by those during primary care treatment.

(2) The preferential application method of the film of this patent application is via a formulation administered in gel form at the wound site, so as to facilitate the topical application of the wound dressing and protect the wound site against external agents.

(3) This formulation stands out from the others on the market by having a qualitative composition based on natural and/or modified products, including mixtures of bioactive agents. The gel will be composed of chitosan, plant extracts and/or mixture of plant extracts that may belong to the genus of Aloe, Matricaria, Lavandula L., among others, and/or antibacterial agents and other active substances.

(4) This technology was developed in order to present a qualitative composition compatible with topical application, which in turn assumes additional innovation as it can be applied in the form of individual packages, vials, syringes and other, thus allowing the application of the wound dressing in a simple manner, without causing pain, discomfort and embarrassment to the patient.

(5) For the purposes of this patent application, the film is understood to be the film defined in accordance with the embodiment forms of described herein, in its solid, liquid or gel form.

Description of Embodiment Forms

(6) The present patent application refers to the development of a hydrogel film based on natural components to be used as a wound dressing, obtained in accordance with the following steps:

(7) Chitosan Deacetylation Process

(8) The chitosan with a molecular weight of 1 to 375 KDa (500 mg) is dissolved in 10 mL of sodium hydroxide solution (1M) for 3-4 hours at 50 C. Later, the solution is extensively washed with Milli-Q water and the pH of the solution is adjusted to 7. The chitosan with a deacetylation degree of 55 to 99.999% is used later. A high degree of deacetylation of the chitosan allows an increase in the quantity of groups with positive charge on the surface of the chitosan, whereby improving its biological properties, including the bioadhesive, anti-microbial and hydrophilic properties.

(9) Modification of Chitosan with Amino Acids (Arginine)

(10) The previously deacetylated chitosan is functionalised with arginine. The L-arginine is bound to the polymeric chain of the chitosan through the amidation reaction of the primary amine groups present in the glucosamine units of the chitosan, through a chemical reaction of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS). This functionalisation of the chitosan with L-arginine improves its biological properties, particularly antimicrobial. The deacetylated chitosan (1-2%) is dissolved in acetic acid (1-3% (v/v)) at room temperature. Later, NHS and EDC are added to the solution separately, under intense magnetic stirring. Lastly, arginine is added to the mixture and the bonding reaction occurs for 24 hours. The chitosan functionalised with the amino acid is then purified through the process of dialysis for 5 days, with deionised water. The polymer is then recovered through the freeze-drying process. Other amino acids can be bonded to the polymeric chain of the chitosan to improve the intrinsic properties of the polymer (lysine, histidine, among others).

(11) Preparation of the Aloe Extract

(12) A plant of the aloe type aged 6-10 years is selected. After washing with distilled water, it is sterilised under ultraviolet radiation for approximately 30-45 minutes. Subsequently, the leaves of the plant are separated from the plant extract with a scalpel. The plant extract is homogenised using an ultra-homogeniser for 15-25 minutes. Later, centrifugation is carried out in order to purify the aloe extract. Aloe is a polysaccharide composed essentially of mannose (60.73%), galactose (16.42%) and glucose (9.16%). Aloe extract has excellent anti-inflammatory, antiseptic and analgesic properties.

(13) Incorporation of Preservative Agents, Thickening Agents and Essential Oils

(14) The preservative agents (benzoic acid, sodium benzoate, calcium gluconate, methylparaben, sorbic acid, benzyl alcohol) are added in a percentage that may vary between 0.05%-0.10%; the thickening agents (ethylene glycol, mannitol, xylitol, butyl tetraol, among others) are also incorporated into the mixture to ensure the fluidity of the gel, in a percentage that may vary between 0.05%-0.20%.

(15) The essential oils and/or mixture of essential oils like soybean oil, lavender oil and/or other flavouring agents are added with a final concentration that may range from 0-5%.

(16) The Preparation of the Film Comprises the Following Steps:

(17) Dissolving a mixture of deacetylated chitosan (at a percentage of 15% and 60%) and chitosan modified (a percentage of 15% and 60%) with amino acids in 100 mL of a dilute solution of lactic acid at a percentage of 0.5% to 1% (w/v); Adding the aloe extract to the chitosan mixture and homogenise, with a final concentration that may range from 9.24-33.90%; Dissolving acetylsalicylic acid in the previous mixture until the concentration is between 0.01-0.5%; Adding essential oils with a final concentration that may range from 0.01-5%; Adding thickening agents at a percentage of 0.05%-0.20% of the final volume; Adding preservative agents at a percentage that may vary between 0.05%-0.10% of the final volume; Homogenising the mixture; Removing the air incorporated in the mix, through sonication and/or vacuum cycles; Adjusting the pH to values between 5.0 and 7.4; The gel is ready to be applied at the injured area; The film is formed after application at the injured area.

(18) In an embodiment form, the essential oil is soybean oil, lavender oil or combination thereof.

(19) In an embodiment form, the thickening agent is ethylene glycol, mannitol, xylitol, tetraol butyl or a combination thereof.

(20) In an embodiment form, the preservative agent is benzoic acid, sodium benzoate, calcium gluconate, methylparaben, sorbic acid, benzyl alcohol or a combination thereof.

(21) In an embodiment form, the pH is adjusted using a sodium hydroxide solution or a solution of an organic acid.

(22) In an embodiment form, the film for topical application of this technology comprises the following elements: deacetylated chitosan in a final concentration between 15% and 60%; chitosan-arginine in a final concentration between 15% and 60%; lactic acid in a final concentration between 0.5% and 1%; aloe extract in a final concentration between 9% and 34%; acetylsalicylic acid in a final concentration between 0.01% and 0.5%; essential oils in a final concentration between 0.01% and 5%; thickening agents in a final concentration between 0.05% and 0.20%; preservative agents in a final percentage volume between 0.05% and 0.10%.

(23) The following tables present different formulations that can be produced.

Example 1

(24) TABLE-US-00001 Deacetylated chitosan 4.0 G 40.82% Chitosan-arginine 2.0 G 20.41% Lactic acid pH 5.5 0.5%-1% Aloe 2.0 G 20.41% Acetylsalicylic acid 0.8-1.00 g 8.16%-10.20% Essential oils 0.01-0.5 g 0.10%-5.10% Thickening agents 0.05-0.2 g 0.51%-2.04% Preservative agents 0.05-0.1 g 0.51%-1.02%

Example 2

(25) TABLE-US-00002 Deacetylated chitosan 4.0 g 57.14% Chitosan-arginine 2.0 g 28.58% Lactic acid pH 5.5 0.5%-1% Aloe 1.0 g 14.29% Acetylsalicylic acid 0.8-1.00 g 11.43%-14.29% Essential oils 0.01-0.5 g 0.71%-7.14% Thickening agents 0.05-0.2 g 0.71%-2.86% Preservative agents 0.05-0.1 g 0.71%-1.43%

Example 3

(26) TABLE-US-00003 Deacetylated chitosan 4.0 g 33.90% Chitosan-arginine 2.0 g 16.95% Lactic acid pH 5.5 0.5%-1% Aloe 4.0 g 33.90% Acetylsalicylic acid 0.8-1.00 g 6.78%-8.47% Essential oils 0.01-0.5 g 0.08%-4.24% Thickening agents 0.05-0.2 g 0.42%-1.69% Preservative agents 0.05-0.1 g 0.42%-0.85%

Example 4

(27) TABLE-US-00004 Deacetylated chitosan 4.0 g 33.90% Chitosan-arginine 4.0 g 33.90% Lactic acid pH 5.5 0.5%-1% Aloe 2.0 g 16.95% Acetylsalicylic acid 0.8-1.00 g 6.78%-8.47% Essential oils 0.01-0.5 g 0.08%-4.24% Thickening agents 0.05-0.2 g 0.42%-1.69% Preservative agents 0.05-0.1 g 0.42%-0.85%

Example 5

(28) TABLE-US-00005 Deacetylated chitosan 4.0 g 37.04% Chitosan-arginine 4.0 g 37.04% Lactic acid pH 5.5 0.5%-1% Aloe 2.0 g 9.26% Acetylsalicylic acid 0.8-1.00 g 7.41%-9.26% Essential oils 0.01-0.5 g 0.09%-4.63% Thickening agents 0.05-0.2 g 0.46%-1.85% Preservative agents 0.05-0.1 g 0.46%-0.93%

Example 6

(29) TABLE-US-00006 Deacetylated chitosan 4.0 g 28.99% Chitosan-arginine 4.0 g 28.99% Lactic acid pH 5.5 0.5%-1% Aloe 4.0 g 28.99% Acetylsalicylic acid 0.8-1.00 g 5.78%-7.25% Essential oils 0.01-0.5 g 0.07%-3.62% Thickening agents 0.05-0.2 g 0.36%-1.45% Preservative agents 0.05-0.1 g 0.36%-0.72%

Example 7

(30) TABLE-US-00007 Deacetylated chitosan 2.0 g 20.41% Chitosan-arginine 4.0 g 40.82% Lactic acid pH 5.5 0.5%-1% Aloe 2.00 g 20.41% Acetylsalicylic acid 0.8-1.00 g 8.16%-10.20% Essential oils 0.01-0.5 g 0.10%-5.10% Thickening agents 0.05-0.2 g 0.51%-2.04% Preservative agents 0.05-0.1 g 0.51%-1.02%

Example 8

(31) TABLE-US-00008 Deacetylated chitosan 2.00 g 22.73% Chitosan-arginine 4.00 g 45.45% Lactic acid pH 5.5 0.5%-1% Aloe 2.00 g 11.36% Acetylsalicylic acid 0.8-1.00 g 9.09%-11.36% Essential oils 0.01-0.5 g 0.11%-5.68% Thickening agents 0.05-0.2 g 0.57%-2.27% Preservative agents 0.05-0.1 g 0.57%-1.14%

Example 9

(32) TABLE-US-00009 Deacetylated chitosan 2.00 g 16.95% chitosan-arginine 4.00 g 33.90% Lactic acid pH 5.5 0.5%-1% Aloe 2.00 g 33.90% Acetylsalicylic acid 0.8-1.00 g 6.78%-8.47% Essential oils 0.01-0.5 g 0.08%-4.24% Thickening agents 0.05-0.2 g 0.42%-1.69% Preservative agents 0.05-0.1 g 0.42%-0.85%
Polymer Characterisation Data

(33) TABLE-US-00010 Degree of Degree of deacetylation modification Commercial chitosan 83.35 0.23 Deacetylated chitosan 95.08 0.48 Chitosan-Arginine 97.26 0.02 17.09 0.25

Examples of Application

(34) The technology described in this application is intended for the treatment or improvement of dermatologic symptoms, due to different types of lesions, which include acute wounds (caused by cuts or burns), chronic wounds (pressure or diabetic ulcers), genetic disorders and surgical interventions.

REFERENCES

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