EA000817B1 - Anticeptic skin care composition and method for making same - Google Patents

Abstract

1. A skin care and/or cosmetic composition with antiseptic-typeantibacterial activity in the form of "an oil-in water" emulsion containing 0,025 to 1% by weight of a chelating agent, such as polyaminocarboxylic acid a salt thereof for applying on a damaged or healthy skin, characterized in that containing a basic chlorhexidine present in the oil phase of said emulsion and a chlorhexidine salt present in the aqueous phase of said emulsion, wherein the total concentration being 0,05 to 1% by weight. 2. A composition of claim 1, characterized in that further contains 0,025 to 1% by weight of primary, secondary or tertiary aliphatic alcohol and/or lower phenylalkyl alcohol, such as benzyl, phenylethyl or phenylpropyl alcohol. 3. A composition of claim 1 or 2, characterized in that contains disodium salt of etylenediaminetetraacetic acid as polyaminocarboxylic acid. 4. A composition of claim 1 to 3, characterized in that contains about 75% by weight of purified water, about 20% of grease substances and about 5% of other additional components, such as antiseptic agents, fungicidal, binding, conserving, perfumed. 5. A composition of claim 1 to 4, characterized in that contains surface-active agent comprising ethyleneglycol stearate and trolamine stearate obtained in the result of neutralization of stearic acid with trolamine. 6. A composition of claim 1 to 5, characterized in that having the following composition: % by wt 1. - Ethyleneglycol stearate 5,450 2. - Stearic acid 3,625 3. - Cetylepalmitate 0,350 4. - Solid paraffine 1,600 5. - Liquid light paraffine 6,850 6. - Perhydrosqualene 1,500 7. - Avocado oil 1,000 8. - Propyleneglycol 2,300 9. - Trolamine and sodium alginate 0,702 10. - Trolamine 0,670 11. - Potassium sorbate 0,134 12. - Disodium salt of EDTA acid 0,100 13. - Benzyl alcohol 0,200 14. - Chlorhexidine 0,023 15. - 20% solution of chlorhexidinedigluconate 0,725 16. - Purified water remaining to reach 100% 7. A composition of claim 1 to 6, characterized in that its pH is about 7. 8. A composition of claim 1 to 7, characterized in that its viscosity is 5.10<-3> to 6 Pa.s. 9. A composition of claim 1 to 8, characterized in that itshydophile/lipophile balanceisfrom 3 to 30. 10. A composition of claim 9, characterized in that represents a form of homogenous dispersion of vesicle of oil phase 2 to 20 μm in size in the aqueous phase. 11. A method for making a composition of claim 1 to 10, characterized in that preparing: a) an aqueous phase containing the following components: - purified water - trolamine and sodium alginate - trolamine - potassium sorbate - disodium salt of EDTA acid, and, if necessary - benzyl alcohol b) an oil phase containing the following components: - ethyleneglycol stearate - stearic acid cetylepalmitate - solid paraffine - liquid light paraffine - perhydrosqualene - avocado oil - propyleneglycol, and, if necessary - basic chlorhexidine with further dispersion of the oil phase into the aqueous phase with the proviso of constant agitation and maintaining appropriate temperatures and adding to thus obtained emulsion an aqueous solution of chlorhexidine salt and agitating the compound at a temperature from 20 degree C to 50 degree C. 12. A method of claim 11, characterized in that different components of the aqueous phase are added to the purified water is intensely agitated at a temperature of about 70 degree C. 13. A method of claim 11 or 12, characterized in that disodium salt of EDTA acid is added at the enduring preparation of the aqueous phase. 14. A method of claim 11 to 13, characterized in that the oil phase is prepared by mixing different its components at a temperature of about 70 degree C to obtain melted oil phase. 15. A method of claim 14, characterized in that chlorhexidine is added at the end. 16. A method of claim 11 to 15, characterized in that emulsification is carried out at a temperature of about 70 degree C.

Description

The present invention relates to a dermatological and / or cosmetological composition having antiseptic activity of the antiseptic type, as well as a method for its preparation.

Galenic forms, which are oil-in-water emulsions, are most suitable for studying the properties of external therapeutic agents with the aim of their therapeutic use for the treatment of skin lesions. The choice of excipients is based on the study of stability and healing properties that can be observed on an emulsion containing peculiar combinations of excipients.

For example, the antibacterial dermatological composition described in patent application EP-A-0 535 446 is in the form of an oil-in-water emulsion containing chlorhexidine hydrochloride in an amount of 0.5 wt.%, Also containing 0.2 wt.% Chelating an agent such as EDTA, fatty substances, and water.

Also known is an oil-inlet emulsion, marketed under the name Blafine® by the laboratory of MED IX and intended for topical use in the treatment of secondary skin lesions during radiotherapy, as well as first and second degree burns or any other uninfected skin damage, which is well known and widespread in worldwide practice, the drug is described, for example, in the VIDAL dictionary, which contains trolamine in combination with conventional excipients.

The purpose of the present invention is to improve this particular emulsion, in which all dermatologists recognize remarkable healing properties that contribute to the healing of various types of skin lesions. However, Biafine®, which does not have an antiseptic or antibacterial effect, is used somewhat limited. In fact, in the treatment of wounds, in addition to using Biafine®, very strict aseptic rules must be obeyed. Observations show that this is especially necessary in the treatment of wounds in situations of mass therapy, when the possibility of making dressings at the desired intervals is excluded.

According to the present invention, these problems can be solved due to the development related to the improvement of a dermatological and / or cosmetological composition having antiseptic type antibacterial activity, intended for application to damaged or healthy skin, in the form of an oil-inlet emulsion, characterized in that it contains basic chlorhexidine present in the oil phase of said emulsion, and chlorhexidine salt present in the aqueous phase of said emulsion, total concentration x orgeksidina is 0.05 to 1 wt.%, and containing from 0.025 to 1 wt.% of a chelating agent such as polyaminocarboxylic acid or one of their salts.

The composition according to the invention may also contain one or more active principles selected, in particular, from antiseptic agents, such as quaternary ammoniums or antibacterial agents, for example penicillin.

According to a particular characteristic of the present invention, this type of composition improves its antibacterial activity upon administration of from 0.025 to 1 wt.% Primary, secondary or tertiary alcohols and / or phenylalkyl lower alcohol, i.e. the alkyl part contains from 1 to 4 carbon atoms, and, in particular, with the introduction of benzyl, phenylethyl and phenylpropyl alcohols.

According to the most effective method of using the invention, the compositions simultaneously contain basic chlorhexidine in the oil phase and a water-soluble salt of chlorhexidine in the aqueous phase, in particular, it may be hydrochloride, acetate or digluconate.

Emulsions, an object of the present invention, contain about 75 wt.% Purified water, about 20% fatty substances and about 5% of other additives, such as antiseptic, antifungal, binders, preservatives, fragrances and other agents.

It should be noted that polyaminocarboxylic acid or, more precisely, one of its salts, the disodium salt of ethylenediaminetetraacetic acid, is in practice the most effective.

The composition according to the invention is

It appears in the following composition, wt.%: Ethylene Glycol Stearate 5,450 Stearic acid 3,625 Cetyl palmitate 0.350 Paraffin wax 1,600 Light liquid paraffin 6,850 Perhydrosqualene 1, 500 Avocado oil 1,000 Propylene glycol 2,300 Trolamine and Sodium Alginate 0.702 Trolamine 0.670 Potassium sorbate 0.134 Disodium salt ethylenediaminetetraacetic acid 0,100 Benzyl alcohol 0,200 Chlorhexidine 0,023 20% chlorhexidine- digluconate 0.725 Purified water quantity sufficient up to 100% Such a composition has pH value close to neutral, and the viscosity value from

5-10 ^-3 to 6 Pa-s. It represents a hydrophilic / lipophilic balance, ranging from 3 to 30.

It was also observed that the oil phase of such an emulsion, obtained mainly when using ethylene glycol stearate and trolamine stearate, which is the result of neutralization of stearic acid with trolamine, as a surface active agent, is presented in the form of oil vesicles from 2 to 20 μm in size, dispersed homogeneously in the aqueous phase.

The present invention also extends to a method for preparing a composition as defined above. This method involves the use of the following two sequential operations.

First of all, they get:

a) an aqueous phase containing the following components: purified water, trolamine and sodium alginate, trolamyl, potassium sorbate, disodium salt of ethylenediaminetetraacetic acid and, if necessary, benzyl alcohol;

b) an oil phase containing the following components: ethylene glycol stearate, stearic acid, cetyl palmitate, paraffin wax, light liquid paraffin, perhydrosqualella - avocado oil, propylene glycol and, if necessary, chlorhexidine, and then the emulsion is carried out in a phase-dispersed oil phase mixing and appropriate temperatures and, if necessary, add to the emulsion thus obtained with continued stirring and at a temperature of 70-50 ° C an aqueous solution of chlorhexidine salt. The aqueous and / or oil phases are predominantly obtained at a temperature close to 70 ° C.

During the preparation of the aqueous phase, various components are added to the purified water, mainly sodium alginate and trolamine; it should be noted that at the end of this operation, disodium salt of ethylenediaminetetraacetic acid is added for better dissolution.

When the composition according to the invention contains basic chlorhexidine, it is added to the oil phase as the last component of this phase, which is then emulsified.

On the contrary, when the composition according to the invention contains a water-soluble chlorhexidine salt, it is not added directly to the aqueous phase, since its interaction with the disodium salt of ethylenediaminetetraacetic acid causes precipitation, which leads to heterogeneity of the emulsion and, over time, to loss of stability. An aqueous solution of chlorhexidine salt, on the contrary, is added after the formation of the emulsion with continuous stirring and at a temperature of 20-50 ° C.

Taking the Biafine® emulsion as a starting material, the present invention aims to develop a composition comprising a true antiseptic coating. It was supposed to add chlorhexidine to this very peculiar emulsion. However, the addition of chlorhexidine to this type of emulsion encountered certain difficulties. First of all, the bactericidal effect that can be obtained with chlorhexidine requires its use in a minimum concentration, which can very quickly reach thresholds at which irritation phenomena are observed, especially in the case of compositions in the form of an emulsion that create a residual effect at the skin level. In addition, in the presence of certain anionic components of the Biafine ^® emulsion, for example surfactants, thickeners, preservatives, and others, the introduction of chlorhexidine runs the risk of various incompatibilities resulting from reactions leading to possible separation of the emulsion. The loss of stability of this type of emulsion occurs mainly due to obtaining too liquid consistency.

For some particular applications, it is necessary, in particular, to consider obtaining an emulsion having homogeneity at the level of antiseptic coating. This type of composition is an emulsion form that contains two phases of different residual effects at the skin level. The aqueous phase, on the one hand, is more exposed to evaporation and penetrates quickly enough into the basal layers of the skin, while the oil phase stays longer on the surface and creates a residual effect on the skin. In some special cases, one can keep in mind the introduction of chlorhexidine simultaneously into the oil phase as a free-acting base, and into the aqueous phase as a solution of a water-soluble salt.

The development of a composition with good activity required a very long systematic study, because in some cases there was a significant loss of chlorhexidine activity, in particular, as a result of inactivation of the antiseptic effect by organic substances contained in exudates or other body secrets.

Finally, it became known that the minimum inhibitory concentration of chlorhexidine significantly increases in the presence of certain alginates, such as sodium alginate. It is clear that the presence of sodium alginate is significant in this type of emulsion, and therefore it is important to develop a formula that preserves the antiseptic activity of chlorhexidine.

In the framework of this study, a very large number of compositions were analyzed from a bacteriological point of view on 52 types of bacteria.

These studies were not based on pathogens used in the rules.

AFNOR, which are considered not too demanding at the moment, but on pathogens, some of which are mutants that have become resistant to a number of antibiotics, and which were selected for patients in surgical and burn centers. A list of these pathogens is given below. Among them, P. cepacia, which is a very persistent bacterium and which, if present in severely burnt ones, is especially distinguished, in case of sepsis, usually leads to death.

Bacteria from the C1P and ATCC databases were also investigated.

Some bacteria phenotypically showed initial resistance to antibiotics, while others showed variable resistance. These bacteria were distributed as follows:

Staphylococcus

S. aureus

S. epidermidis

Streptocoques In

Enterococcus

E. faecalis

E faecium

Pseudomonas

P.aeruginosa

I P.stutzeri

P.cepacia

Xanthomonas maltophilia

I Alcaligenes xylosoxidans

I acinetobacter

I A. baumanii

A.Lwoffii

Enterobacteries.

Escherichia coli

Klebsiella pneumoniae

K.oxytoca

Enterobacter cloacae

I E. aerogenes

I serratia marcescens

I Citrobacter freundii

With diversus

Proteus mirabilis

P. vulgaris

Morganella morganii

I Providencia stuartii

Shigella sonnei

Salmonella typhi

I S.enteridis

As the table below shows, some optimized compositions of the present invention cause the destruction of bacteria of this type.

Table

Example No. one 2 3 4 5 6 7 8 nine 10 eleven 12 thirteen Ethylene Glycol Stearate X X X X X X X X X X X X X Stearic acid X X X X X X X X X X X X X Cetyl palmitate X X X X X X X X X X X X X Hard paraffin X X X X X X X X X X X X X Light liquid paraffin X X X X X X X X X X X X X Perhydrosqualene X X X X X X X X X X X X X Avocado oil X X X X X X X X X X X X X Propylene glycol X X X X X X X X X X X X X Purified water X X X X X X X X X X X X X Trolamine and Sodium Alginate X 1,404 X X X X X X X X Sodium Alginate 0.7 Trolamine X X X X X X X X X X X X X Chlorhexidine digluconate wt.% Relative chlorhexidine in their respective% ratio 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.2 Chlorhexidine% relative base chlorhexidine in their respective percentage 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.2 EDTA disodium salt 0.4 0.2 0.4 0.4 0.2 0.2 0.2 0.1 0.2 0.1 Benzyl alcohol 0.2 0.2 0.2 0.2 0.2 pn 7.22 7.15 6.78 7.18 6.91 6.83 7.14 6.91 7.06 7.06 7.00 7.14 7.13 The number of resistant pathogens at 60 32 thirty 6 6 3 2 one one 0 0 0 0 26

CLAIM

Claims (16)

CLAIM 1. A dermatological and / or cosmetic composition possessing an antibacterial activity of an antiseptic type, in the form of an oil-in-water emulsion, containing from 0.025 to 1% by weight of a chelating agent, such as a polyamino carboxylic acid or its salt, intended for application to an injured or healthy skin, characterized in that it contains the main chlorhexidine present in the oil phase of the named emulsion, and the salt of chlorhexidine present in the aqueous phase of the named emulsion, and the total concentration of chlorhexidine m 0.05 to 1 wt.%. 2. The composition according to claim 1, characterized in that it additionally contains from 0.025 to 1% by weight of primary, secondary or tertiary aliphatic alcohol and / or lower phenylalkyl alcohol, such as benzyl, phenylethyl and phenylpropyl alcohol. 3. The composition according to claim 1 or 2, characterized in that it contains a disodium salt of ethylene diamine tetraacetic acid as a salt of polyamino carboxylic acid. 4. Composition according to one of claims 1 to 3, characterized in that it contains approximately 75% by weight of purified water, approximately 20% of fatty substances and approximately 5% of other additional components, such as antiseptic agents, antifungals, binders, preservatives, fragrant. 5. Composition according to one of paragraphs. 1-4, characterized in that it contains surface active agents, including ethylene glycol stearate and trolamine stearate, obtained by neutralizing the stearic acid with trolamine. 6. Composition according to one of paragraphs. 1-6, characterized in that it has the following composition, wt.%: Ethylene glycol stearate 5,450 Stearic acid 3,625 Cetyl palmitate 0,350 Paraffin wax 1,600 Liquid light paraffin 6,850 Perhydrosqualene 1,500 Avocado oil 1,000 Propylene glycol 2,300 Alginate trolamine and sodium 0,702 Trolamine 0.670 Potassium Sorbate 0.134 Disodium salt of ethylenediaminetetraacetic acid 0,100 Benzyl alcohol 0,200 Chlorhexidine 0.023 20% chlorhexidindigluconate 0.725 solution Purified water - an amount sufficient to 100% 7. Composition according to one of paragraphs. 1 -6, characterized in that the value of its pH is approximately 7. 8. Composition according to one of paragraphs. 1-7, characterized in that its viscosity ranges from 5 · 10 ^-3 to 6 PA-s. 9. Composition according to one of claims 1 to 8, characterized in that its hydrophilic / lipophilic balance is from 3 to 30. 10. The composition according to claim 9, characterized in that it is a form of a homogeneous dispersion of oil phase vesicles with a size of 220 μm in the aqueous phase. 11. The method of obtaining the composition according to one of claims 1 to 10, characterized in that they receive: a) an aqueous phase containing the following components: purified water, trolamine and sodium alginate, trolamine, potassium sorbate, ethylenediaminetetraacetic acid disodium salt and, if necessary, benzyl alcohol; b) an oil phase containing the following components: ethylene glycol stearate, stearic acid, cetyl palmitate, solid paraffin, light liquid paraffin, perhydrosqualene, avocado oil, propylene glycol and, if necessary, chlorhexidine basic with subsequent dispersion of the oil phase into the volume of the zyrophalanate in a hydrogen supply system, in case of necessity, chlorhexidine basic, followed by dispersing the oil phase into the volume of an inoculum, in propane glycol, and then in chlorine-hexidine basic water, followed by dispersing the oil phase into an inundated dichloridase in a hydrogen supply system, in a basic process, in an aqueous phase containing a chlorofluxidine oil. and maintain the appropriate temperatures, and add to the emulsion thus obtained with stirring at a temperature of from 20 to 50 ° C an aqueous solution of chlorhexidine salt. 12. The method according to claim 11, characterized in that the various components of the aqueous phase are added to purified water with vigorous stirring at a temperature of about 70 ° C. 13. The method according to one of paragraphs.11 and 12, characterized in that the disodium salt of ethylenediaminetetraacetic acid is added during the preparation of the aqueous phase in the last turn. 14. The method according to one of paragraphs.11-13, characterized in that the oil phase is obtained by mixing between its various components at a temperature of about 70 ° C, which results in a molten oil phase. 15. The method of claim 14, wherein chlorhexidine is added last. 16. The method according to one of paragraphs.11-15, characterized in that the emulsification is carried out at a temperature of about 70 ° C.