WO1997009974A1

WO1997009974A1 - Antiseptic skin care composition and method for making same

Info

Publication number: WO1997009974A1
Application number: PCT/FR1996/001393
Authority: WO
Inventors: Jean Guilbaud; Patrick Clery
Original assignee: Laboratoire Medix
Priority date: 1995-09-11
Filing date: 1996-09-11
Publication date: 1997-03-20
Also published as: AU6991596A; MX9801902A; CA2232081A1; EP0851755A1; AU697193B2; FR2738487B1; EA000817B1; JPH11512417A; FR2738487A1; EA199800198A1; CN1215330A

Abstract

A skin care and/or cosmetic composition with antiseptic-type antibacterial activity for applying on a damaged or healthy skin is described, characterised in that it is in the form of an oil-in-water emulsion containing a basic chlorhexidine in the oil phase of said emulsion and a chlorhexidine salt in the aqueous phase of the emulsion, the total chlorhexidine concentration being 0.05 % to 1 % by weight, and containing 0.025 % to 1 % by weight of a chelating agent such a polyaminocarboxylic acid or a salt thereof.

Description

ANTISEPTIC DERMATOLOGICAL COMPOSITION AND ITS MANUFACTURING METHOD

The present invention relates to a dermatological and / or cosmetic composition provided with an antibacterial activity of antiseptic type, as well as a process for its manufacture.

The galenical formulations appearing in the form of emulsions of oil-in-water type appear to be best suited to the desired property of topical curative with a view to a therapeutic application for the treatment of skin lesions. The choice of excipients is based on studies of stability and healing properties which have been observed from an emulsion containing very specific combinations of excipients.

Thus, an oil-in-water type emulsion sold under the name Biafine® by the MEDIX Laboratory is known, with a view to its topical application for the treatment of skin lesions secondary to radiotherapeutic treatments, as well as first and second degree burns and any other uninfected skin wounds.

The aim of the present invention has been to perfect this emulsion precisely, to which all dermatological specialists agree to recognize quite remarkable healing properties for the treatment of various types of skin lesions. However, Biafine '8', having no antiseptic or antibacterial action, finds its use somewhat limited. Indeed in the treatment of wounds it is necessary, in addition to the treatment with Biafine®, to be bound by very strict aseptic rules rigorous. This observation is particularly relevant in the case of wound care, in situations of mass medicine where the dressings cannot be renewed according to the desirable sequence.

In accordance with the present invention, these problems have been able to be resolved by the development of a dermatological and / or cosmetic composition endowed with an antibacterial activity of antiseptic type, intended to be applied to injured or healthy skin, characterized in what it is in the form of an oil-in-water type emulsion containing chlorhexidine base present in the oily phase of said emulsion and a chlorhexidine salt present in the aqueous phase of said emulsion, the total concentration in chlorhexidine being between 0.05% and 1% by weight, and containing 0.025 to 1% by weight of a chelating agent such as a polyaminocaroxylic acid or one of their salts.

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

According to a particular characteristic of the present invention, this type of composition finds its antibacterial activity further improved by the introduction of 0.025 to 1% by weight of a primary, secondary or tertiary aliphatic alcohol and / or of a lower phenylalkyl alcohol, that is to say an alkyl part containing from 1 to 4 carbon atoms, and in particular by the introduction of benzyl, phenylethyl and phenylpropyl alcohol. According to a particularly effective embodiment of the invention, the compositions simultaneously contain chlorhexidine base in the oily phase and a water-soluble salt of chlorhexidine in the aqueous phase, it may especially be the hydrochloride, acetate or digluconate.

The emulsions which are the subject of the present invention contain approximately 75% by weight of purified water, approximately 20% of fatty substances and approximately 5% of other additional constituents, such as antiseptic, fungistatic agents, binders, preservatives, perfumes, etc.

It should also be pointed out that the polyaminocarboxylic acid, or one of its salts, which has proved to be the most effective in practice is disodium EDTA.

The composition according to the invention can be further characterized by the following formulation:

% by weight a) Ethylene glycol stearate 5,450 b) Stearic acid 3,625 c) Cetyl palmitate 0.350 d) Solid paraffin 1,600 e) Light liquid paraffin 6,850 f) Perhydrosqualene 1,500 g) Avocado oil 1,000 h) Propylene glycol 2,300 i ) Trolamine sodium alginate 0.702 d) Trolamine 0.670 k) Potassium sorbate 0.134

1) Disodium EDTA 0, 100 m) Benzyl alcohol 0.200 n) Chlorhexidine 0.023 o) Chlorhexidine digluconate 20% 0.725 p) Purified water QS.P. 100%

Such a composition is characterized by a pH close to neutrality, a viscosity between 5.10-3 and 6 Pa.s. It also has a hydrophilic / lipophilic balance of between 3 and 30.

It has thus been observed that the oily phase of such an emulsion, advantageously obtained by using as surfactant ethylene glycol stearate and trolamine stearate resulting from the neutralization of stearic acid by trolamine, occurs in the form of oily globules of 2 to 20 μm, homogeneously dispersed in the aqueous phase.

The present invention also extends to the process for manufacturing a composition as defined above. This process involves the implementation of the following successive operations:

First of all, we prepare: i) an aqueous phase comprising the following constituents: Purified water - Trolamine sodium alginate

- Trolamille Potassium sorbate

- EDTA disoded, and possibly

- Benzyl alcohol, ii) an oily phase comprising the following constituents:

- Ethylene glycol stearate

- Stearic acid

- Cetyl palmitate

- Solid paraffin

- Light liquid paraffin

- Perhydrosqualèlle - avocado oil

- Propylela glycol, and possibly

- Chlorhexidine,

and an emulsion is produced by dispersing the oily phase in the aqueous phase under appropriate stirring and temperature conditions and, if necessary, adding to the emulsion thus obtained, while maintaining stirring and at temperature between 70 and 50 ^β C, an aqueous solution of chlorhexidine salt. The aqueous and / or oily phases are advantageously prepared at a temperature in the region of 70 ° C.

During the preparation of the aqueous phase, the various constituents are added to the purified water, mainly sodium alginate and trolamine; it should be noted that it is advantageous to add the disodium EDTA at the end of this operation to promote its solubilization.

When the composition according to the invention contains chlorhexidine base, the latter is added to the oily phase as the last constituent of this phase which will subsequently be subjected to emulsification.

On the other hand, when the composition according to the invention is intended to contain a water-soluble salt of chlorhexidine, the latter will not be added directly to the aqueous phase because it would risk in particular reacting with disodium EDTA, which would lead to precipitation followed by heterogeneity of the emulsion resulting in a loss of stability over time. The aqueous solution of chlorhexidine salt is however added after formation of the emulsion while maintaining its stirring and at a temperature advantageously between 20 and 50 C.

Starting from Biafine®, the aim of the present invention was to develop a composition constituting a true antiseptic covering. We therefore thought of adding chlorhexidine to this very specific emulsion. The addition of chlorhexidine to this type of emulsion, however, encountered a number of prejudices. First of all, the bactericidal effect capable of being obtained with chlorhexidine requires an application at a minimum concentration which could quickly reach thresholds at which irritation phenomena are observed, in particular in the case of compositions in the form of emulsion ensuring good persistence in the skin. In addition, in the presence of certain anionic constituents of Biafine®, for example surfactants, thickening agents, preservatives or others, the introduction of chlorhexidine risked encountering various incompatibilities, in particular resulting from reactions leading to risks of demixing of the emulsion. A loss of stability of this type of emulsion generally results in obtaining a consistency which is in the excessively liquid state.

For certain particular applications, it was in particular advisable to consider obtaining an emulsion having a homogeneity at the level of the antiseptic covering. This type of composition in the form of an emulsion therefore involves two phases of different persistence in the skin. On the one hand, the aqueous phase is subject more to evaporation phenomena and penetrates the basal layers fairly quickly. of the skin, while the oily phase remains more on the surface and ensures a persistence of the product on the skin. In certain particular cases, it may therefore be advantageous to provide for the introduction of chlorhexidine both into the oily phase under the form of the free base, and in the aqueous phase in the form of a solution of a water-soluble salt.

The development of a formula with good activity required a very long systematic study, since in some cases we observe significant losses of activity of chlorhexidine and this in particular due to phenomena of inactivation of this antiseptic by organic products rejected by wounds, in particular exudates or secretions.

Finally, we knew that the minimum inhibitory concentration of chlorhexidine increased very significantly in the presence of certain alginates such as sodium alginate. It is clear that, in this type of emulsion, the presence of alginate is essential and it is therefore important to develop a formulation retaining an antiseptic activity of chlorhexidine.

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

These studies were conducted not on the basis of the germs used in the AFNOR standards deemed too undemanding for the moment, but on germs, some of which are mutants which have become resistant to many antibiotics and which have been taken from patients in surgical and treatment services for burn victims. The list of these germs is given below. We will note in particular P. cepacia, which is a very resistant and which when present in burn victims, generally leads, in the event of sepsis, to certain death.

However, the reference bacteria CIP and ATCC were also tested.

Certain bacteria presented with antibiotics a phenotype of wild resistance and others a phenotype of variable resistance. They are distributed as follows:

8 Staphylococcus

4 S. aureus

4 S. epidermidis

2 Streptococcus B 7 Enterococcus 5 E. faecalis

2 E faecium

5 Pseudomonas

3 P. aeruginosa

1 P. stutzeri 1 P. cepacia

2 Xanthomonas maltophilia

1 Alcaligenes xylosoxidans

2 Acinetobacter

1 A. baumanii 1 A. Lwoffii

25 Enterobacteriaceae 5 Escherichia coli

2 Klebsiella pneumoniae 1 K. oxvtoca 2 Enterobacter cloacae 1 E. aerogenes

1 Serratia marcescens 1 Citrobacter freundii 1 C diversus

1 Proteus mirabilis

3 P. vulgaris

2 Morganella morganii

1 Providencia stuartii 1 Shigella sonnei

2 Salmonella typhi 1 S. enteridis.

As will appear on examining the table below, some of the optimized compositions of the present invention have enabled the destruction of this type of bacteria.

Claims

1. Dermatological and / or cosmetic composition provided with an antibacterial activity of antiseptic type, intended to be applied to injured or healthy skin, characterized in that it is in the form of an emulsion of the oil type in the water containing chlorhexidine base present in the oily phase of said emulsion and a chlorhexidine salt present in the aqueous phase of said emulsion, the total concentration of chlorhexidine being between 0.05% and 1% by weight, and containing 0.025 to 1% by weight of a chelating agent such as a polyaminocarboxylic acid or one of their salts.

2. Composition according to claim 1, characterized in that it additionally contains 0.025% to 1% by weight of a primary, secondary or tertiary aliphatic alcohol and / or of a lower phenylalkyl alcohol, such as alcohols benzyl, phenylethyl and phenylpropyl.

3. Composition according to one of claims 1 and 2, characterized in that as the polyaminocarboxylic acid salt it contains disodium EDTA.

4. Composition according to one of claims 1 to 3, characterized in that it simultaneously contains chlorexidine base in an oily phase and a water-soluble salt of chlorhexidine in the aqueous phase.

5. Composition according to one of claims 1 to 4, characterized in that it contains approximately 75% by weight of purified water, approximately 20% of fatty substances and approximately 5% of other additional constituents, such as agents. antiseptics, fungistats, binders, preservatives, perfumes.

6. Composition according to one of claims 1 to 5, characterized in that it contains surfactants comprising ethylene glycol stearate and trolamine stearate resulting from the neutralization of stearic acid by trolamine.

7. Composition according to one of claims 1 to 6, characterized by the following formula:

D EDTA disodium 0.100 m) Benzyl alcohol 0.200 n) Chlorhexidine 0.023 o) Chlorhexidine digluconate 20% 0.725 P) Purified water QS.P. 100%

8. Composition according to one of claims 1 to 7, characterized in that it has a pH close to 7.

9. Composition according to one of claims 1 to 8, characterized in that it has a viscosity between 5.10 ^-3 and 6 Pa.s.

10. Composition according to one of claims 1 to 9, characterized in that it has a hydrophilic / lipophilic balance of between 3 and 30.

11. Method according to claim 10, characterized in that it has in the form of a homogeneous dispersion of oily phase globules of 2 to 20 μm in the aqueous phase.

12. Method for manufacturing a composition according to one of claims 1 to 11, characterized in that one prepares:

i) an aqueous phase comprising the following constituents: Purified water

Trolamine sodium alginate Trolamine

Disodium potassium EDTA sorbate, and possibly Benzyl alcohol

ii) an oily phase comprising the following constituents:

Ethylene glycol stearate

Stearic acid Cetyl palmitate

Solid paraffin

Light liquid paraffin

Perhydrosqualene

Propylene glycol avocado oil, and possibly

Chlorhexidine base

and in that an emulsion is produced by dispersing the oily phase in the aqueous phase under suitable stirring and temperature conditions and the emulsion thus obtained is added, while stirring being maintained at a temperature between 20 and 50 ° C, an aqueous solution of chlorhexidine salt.

13. The method of claim 12, characterized in that the various constituents of the aqueous phase are added to the purified water with vigorous stirring, at a temperature of about 70 ° C.

14. Method according to one of claims 12 and 13, characterized in that the disoded EDTA is added last during the preparation of the aqueous phase.

15. Method according to one of claims 12 to 14, characterized in that the oily phase is prepared by mixing together its various constituents at a temperature of about 70 ° C leading to a molten oily phase.

16. The method of claim 15, characterized in that chlorhexidine is added last.

17. Method according to one of claims 12 to 16, characterized in that the emulsification is carried out at a temperature of the order of 70 ° C.