GB2314020A - Topical compositions containing perfluoro compounds - Google Patents

Abstract

Topical barrier compositions which hinder or prevent passage of e.g. chemical warfare agents , pesticides, solvents etc. into the skin contain a perfluorinated polymeric compound. Suitable compounds are available as Fomblin (RTM). Compositions are preferably emulsions and further contain an oil.

Description

A Topical Composition The present invention relates to a topical composition which can act as a skin protectant to hinder or prevent passage of chemicals and agents such as chemical warfare agents, pesticides and solvents, to the skin. In particular the invention provides a topical composition which comprises a layer of inert fluorocarbons into which chemicals cannot readily partition and thereby gain access to the skin surface. Such compositions are useful as barrier creams for use in industrial, agricultural or military applications.

There are many occasions where people are exposed to chemicals or agents which have some degree of toxicity and which may penetrate the slain. It is often desirable or necessary to prevent contact of these chemicals to the skin as far as possible.

For instance, many volatile pesticides can provide a potential hazard to operators applying them.

Examples of such pesticides include volatile insecticides, particularly organophorphorus insecticides such as isofenphos, or diethyl toluimide. In other industrial applications, workers exposed to industrial solvents such as acetone, chloroform, methanol, hexane, benzene and toluene, may require protection.

In chemical warfare situations, highly toxic volatile chemicals, which may penetrate the skin can be used. These include Sarin, Soman and Tabun as well as sulphur mustard.

Sulphur mustard is a vesicating chemical used as a war gas. It is a potent alkylating agent which is thought to be toxic to living tissue by virtue of its ability to alkylate vital cellular constituents (Fox M. and Scott M., Mut. Res (1980)75, 131-168). SM has been shown to alkylate DNA, RNA and proteins (Paprimeister B. et al., (1991) Medical Defence against Mustard Gas (CRC Press) 91-122), though a causal link between alkylation of either of these cellular constituents and vesication has yet to be established.

Although considerable protection from toxic chemical vapours can be afforded by protective clothing in the form of respirators, charcoal cloth garments and gloves these measures may not be completely effective in all circumstances. The use of a barrier cream might augment the charcoal cloths used in protective clothing and permit tasks requiring manual dexterity to be carried out in an atrnosphere containing for example, chemical agent vapour, without gloves for short periods.

Barrier creams place a passive barrier between the skin and the environment which prevent access of chemicals generally to the surface of the skin. Cream bases consist of an emulsion, either mineral oil in water or water in mineral oil ( tarry B.W (1983) Drugs Pharmaceutical Sci 18 296-350). On their own, conventional mineral oil in water type creams have required layers of greater than 0.56 mm to be established and maintained on the skin in order to be effective.

More recently creams based on silicone derivatives have allowed effective barriers against general chemical penetration of the skin to be produced using very thin layers of cream (EP-A0401840, Japanese Patent Appln no. 57-26610).

The applicants have found a class of compound which are very effective as, or as a basis for, a barrier cream.

The present invention provides a topical compositions comprising a perfluorinated polymeric compound.

Such compounds have a low surface energy and thereby prevent partitioning of the volatile chemical into the topical composition and skin.

Suitably the perfluorinated polymeric compound is of formula (I): CF3O[CF(CF3)CF2O]j[CF2O]rnCF3 (I) where n and m are independently selected from 4 to 150, suitably from 6 to 140.

Suitably the compound of formula a) is in the form of an oil. Examples of such compounds are set out in the following Table:

Compound No. n m 1 140 13 2 40 11 3 25 6 4 18 8 5 6 6 6 25 9 7 14 6 6 16 6 These compounds are available commercially from Aldrich Chemical Company, Gillingham, Dorset and are sold under the trade name 'Fomblin'lTM. Other compounds of formula (T) may be prepared using conventional methods.

The compositions ofthe invention may comprise up to 100% w/w perfluorinated compound.

Suitably, the compositions comprise from 30-100%w/w perfluorinated compound. Where 100% prefluorinated compound is used, this must comprise an oil.

The compositions may also be in the form of oil in water or water in oil emulsions. Other components of such emulsions include emulsifying agents and oils conventionally used in barrier cream type formulations such as mineral or silicone oils.

In addition the compositions of the invention may further comprise active agents which react with or sequester the chemical which it is intended should be prevented from reaching the skin.

For instance, reactive molecules which would inactivate for example, SM before it could react with cell constituents may be included. A series of sulphydryl compounds designed to enter the living cell and fortify it against reactive compounds such as SM has already been disclosed in PCT GB91/01462 and GB90148994.5. Other examples of compounds which react with and sequester SM and may be incorporated into a barrier cream are described and claimed in our copending British Patent Application No. 9610405.4 filed on 17 May 1996. Such compounds include nucleophilic scavengers, in particular compounds which have nucleophilic nitrogen and/or sulphur atoms, preferably nitrogen, such as hexamethylene tetramine (HMT), otherwise known as methenamine, or analogues thereof. Examples of sulphur containing nucleophilic compounds include glutathione (GSH) and esters of cysteine, for example as shown in WO 92/04024.

Suitable analogues of HMT comprise molecules which retain the structure of the nitrogen atoms, specifically compounds wherein hydrocarbon chains such as alkyl chains having for instance up to 32 carbon atoms, are conjugated to the HMT molecule. Examples of such compounds include compounds of the following formulae: (#)-CH2(CH22CH3 (#)-CH2(CH2)l4CH3 where # represents a hexamethyltetraminyl group.

In addition, suitable HMT derivatives could be made by the conjugation of HMT with either the normal constituents of barrier creams (such as palmitic or stearic acids), the normal constituents of the stratum comeum (cholesterols or ceramides) or large long chain aliphatic molecules.

Suitably the long chain aliphatic molecules have from 16 to 32 carbon atoms. Particular aliphatic molecules which may be employed are fatty acids having from 16 to 32 carbon atoms.

These potentially reactive conjugates, inter alia, may form constituents of the topical compositions of the invention.

Small molecules in a barrier cream can diffuse through the skin and be absorbed into the blood which may result in local irritation or systemic toxicity. Therefore, in a preferred embodiment, the composition ofthe invention includes large lipophilic molecules which do not penetrate the skin leaving the reactive molecule either on the surface of the skin or retained within the superficial layers until they slough off in the normal cycle of the epidermal tissue.

Consequently in a preferred embodiment, a complex comprising a suitable reactive molecule and a large lipophilic molecule is formed and the resultant complex is included in the composition of the invention.

A specific embodiment of the invention is a barrier cream which comprises an oil in water emulsion cream base which further comprises a perfluorinated polymeric compound such as a compound of formula (I) and optionally also HMT.

Preferred ratios ofthe active compound in a barrier cream formulation are from 10:90 to 60:40 w/w, most preferably 25:75 w/w.

Penetration of radiolabelled SM across rubber latex membranes has been measured in vitro using glass diffilsion cells is reported hereinafter.

In a diffusion cell system the chemical diffuses through the membrane (the penetrant) by partitioning between its vehicle and the membrane, then between the membrane and the receptor flair When the thermodynamic activity, of the penetrant (usually synonymous with concentration) on both sides of the membrane is equal the system is in equilibrium and there will be no further change in the amount of penetrant in the receptor fluid.

In diffusion studies reported hereinafter, the ability of each composition to slow the rate of penetration through the membrane was shown by a calculation of the retardant index (Rt) using the equation RI = J,(control)/J,(treated) where J is the maximum penetration rate of sulphur mustard through control (untreated) and treated membranes.

As illustrated hereinafter, formulations referred to in this application can result in a 45 fold decrease in the rate of penetration of SM.

The following Examples illustrate the invention. In these examples reference is made to the attached Figures in which Figure 1 is a graph showing the ability of perfluorinated polymers to retard the rate of penetration of SM (expressed as retardation index). "Stoko" is an abbreviation for the commercially available barrier cream Stokodenn e consisting of an oil-in-water emulsion and was included for comparison (positive control); and Figure 2 is a graph showing the amount of SM penetrated through pretreated membranes expressed as percentage of control amount penetrated after 3 hours.

Example 1 Diffusion Studies Assessment of topical skin protectants was carried out using Franz-type glass diffusion cells substantially as previously described (Jenner et al., J. Pharm. Pharmacol. (1995) 47 206-212), with an area available for diffusion of 2.54 cm2. In this case however, each diffusion cell consisted of a rubber latex membrane (26% ethylene vinyl acetate (EVA), RMCS Shrivenham) placed on a metal gauze support forming a barrier between an upper (donor) and lower (receptor) chamber.

Previous studies had shown that this apparatus, including the rubber latex membrane would provide a suitable model for identifying compounds with a barrier function and that penetration rates provide a quantitative method of assessing the retardant properties of the compounds.

The receptor chamber fluid was filled with 50:50 aqueous ethanol. Each composition was applied as a 200 Crl volume, giving a nominal thickness of 0.8 mm on the membrane surface.

Each composition was applied two hours before the addition of 20 ,ul [35S]SM (50pCi.ml l) as an airborne droplet to the donor chamber. The experiments were subsequently conducted under occluded conditions in that the donor chamber was sealed with a plastic lid using contact adhesive (Bostik All Purpose Clear Adhesive).

Samples (20 curl) of receptor chamber fluid were taken at regular intervals for up to 8 hours.

Each sample was replaced with an equivalent volume of 50:50 aqueous ethanol. The amount of radioactivity in each sample was measured by liquid scintillation counting in 5 ml Emulsifier Safe scintillation cocktail (Canbera Packard, Michigan USA), using a Rackbeta II 1215 scintillation counter. Amounts of radioactivity were related to amounts of SM determined from a sample of donor chamber liquid taken at the start of the study.

Results were initially plotted as total amount of 35S-radiolabelled sulphur mustard penetrated against time. During the first four hours, a straight line is observed (the maximum penetration rate, JmJ. From this, the retardant index could be calculated and the results are shown in Figure 1.

In addition, the total amount of SM penetrated through the membranes over three hours was calculated and expressed as a percentage of the untreated control. The results are shown in Figure 2.

It can be seen from these Figures that the compositions of the invention provide significant protective barrier effects and are more effective than a commercially available barrier cream.

Claims (16)

Claims

1. A topical composition comprising a perfluorinated polymeric compound.

2. A topical composition according to claim 1 wherein the perfluorinated polymeric compound is as oil.

3. A topical composition according to claim 1 or claim 2 wherein the perfluorinated polymeric compound is of formula (I): CF30-[CF(CF3)CF20]"-[CF20]m-CF3 (I) where n and m are independently selected from 4 to 150.

4. A topical composition according to claim 3 wherein n and m are independently selected from 6 to 140.

5. A topical composition where n and m are respectively 140 and 31; 40 and 11,25 and 5, 18and8,or6and6.

6. A composition according to any one of claims 1 to 5 wherein the composition contains up to 100% w/w perfluorinated compound.

7. A composition according to claim 6 which comprises from 30- 100% w/w perfluorinated compound.

8. A composition according to any one of the preceding claims which comprises an oil in water or water in oil emulsion.

9. A composition according to any one ofthe preceding claims which further comprises a mineral or silicone oil.

10. A composition according to any one ofthe preceding claims which further comprises an active agent which reacts with or sequesters the chemical which it is intended should be prevented from reaching the skin.

11. A composition according to claim 10 wherein the composition further comprises a reagent which inactivates or sequesters sulphur mustard.

12. A composition according to claim 11 wherein the said reagent comprises hexamethylene tetramine or an analogue thereof.

13. A process for protecting the skin of a human or animal against volatile chemical agents which comprises applying to the skin a composition according to any one of claims 1 to 12.

14 A process according to claim for protecting against the effects of volatile pesticides, industrial solvents or chemical warfare agents.

15. A perfluorinated polymeric compound for use in a topical composition.

16. A barrier cream comprising a composition according to any one of claims 1 to 12.