Barrier cream comprising hexamethylenetetramine or...

Details Barrier cream comprising hexamethylenetetramine or... Barrier cream comprising hexamethylenetetramine or...

1998-12-07

2001-05-01

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Cosmetic, antiperspirant, dentifrice

C424S400000, C424S405000, C424S406000, C424S078050, C544S185000, C514S723000, C514S759000, C514S946000, C514S947000

Reexamination Certificate

active

06224885

ABSTRACT:

The present invention relates to skin protection agents, in particular to topical compositions which can prevent the passage of toxic chemicals through the skin, such as barrier creams.
There are many occasions where people are exposed to chemicals or agents which have some degree of toxicity and which may penetrate the skin. 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 and Lewisite.
Sulphur mustard (SM) 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 atmosphere containing chemical agent vapour, without gloves for short periods.
Traditional barrier creams have placed 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 oil in water or water in oil (Barry B. W (1983) Drugs Pharmaceutical Sci 18 296-350). Water in oil emulsions are unsuitable as barrier creams because the oily deposit they leave on the surface of the skin results in loss of tactility. On their own 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-A-0401840, Japanese Patent Appln no. 57-26610).
Formulation of a reactive chemical which reacts with specific target chemical groups in the cream converts a passive barrier cream into an active cream which sequesters and inactivates a specific group of toxic chemicals before they can reach the living layers of the skin.
The use of reactive molecules which would inactivate SM before it could react with cell constituents has been investigated. 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.
It is known that increased levels of GSH and GSH synthetic enzymes (Evans et al., Cancer Res. 47 2525-2530, Ahmed S. et al., J. Biol. Chem. 262 15048-15053, and Ahmed S. et al., J. Cellular Physiol. 131, 240-246) confer resistance to nitrogen mustard on cell cultures. In previous studies attempting to protect cell cultures against SM, Gross C. L. and Smith N. J. (Proc. 1993 Med. Def. Bioscience Rev. (US Army Medical Research and Development Command) 1 141-147) found that human lymphocytes pretreated with 10 mM L-oxothiazolidine-4-carboxylate for 48 hours and subsequently exposed to 10 &mgr;M SM were 20% more viable than SM only treated cells 48 hours after exposure. Other attempts to protect human lymphocyte cultures (Gross et al., Cell Biology and Toxicology (1993) 9 259-268) by raising intracellular levels of GSH using N-acetyl cysteine (10 mM) and subsequently challenging with 10 &mgr;M SM increased viability by only 15 to 19% of control cultures at 48 hours.
The stratum corneum is the dead layer of skin which acts as a barrier to chemical penetration through the skin (Tregear R. T. (1966) Theoretical Exp. Biol. 5, 21-22). The stratum corneum is composed of the dead “protein ghosts” of the living cells of the epidermal layer of the skin, surrounded by a unique mixture of lipids which the cells of the epidermis produce (Wertz P. W. et al., (1989) “Stratum corneum: Biological and Biochemical considerations” in Transdermal Drug Delivery, Ed Hadgraft J & Guy R A. 1-22).
HMT has been used prophylactically to protect rabbits and man against exposure to lethal phosgene doses (Diller W. F. J.Occ. Med (1978) 20 189-193).
The present application relates to a topical composition for use particularly against SM. In particular the invention relates to an active barrier cream for SM.
The present invention provides a composition which comprises a composition for topical application which comprises hexamethylene triamine or analogues or derivatives thereof.
HMT has the following structure (I)
It is believed that because the structure of HMT contains four nucleophilic nitrogen groups, with a similar electronic structure to N-7 in guanine, it neutralises the bifunctional SM more effectively than conventional monofunctional thiol ligands.
Suitable analogues of HMT are compounds which have organic moieties conjugated to the HMT cage structure for example of formula (II)
where R
1
is an organic group and X is a anion.
The HMT moiety will hereinafter be represented as #.
Examples of suitable groups for R
1
include optionally substititued straight or branched hydrocarbon chains such as alkyl chains, having from 1 to 50 carbon atoms, for example from 6 to 32 carbon atoms. In particular, the hydrocarbon chains are optionally substituted by one or more substituents selected from aryl, such as phenyl, optionally substituted by halogen, and/or halogen atoms, such as fluorine, chlorine or bromine and particularly fluorine. A particular group R
1
is a fluorobenzyl or a group (CH
2
)
n
CH
3
where n is from 8 to 20, suitably about 17.
Further examples of such compounds include compounds of the following formulae:
(#)—CH
2
(CH
2
)
22
CH
3
(#)—CH
2
(CH
2
)
14
CH
3
where # represents a hexamethyltetraminyl group.
Suitable anions X are chosen such that the compound of formula (II) are pharmaceutically acceptable salts, in particular those which are suitable for topical application, for example halide ions such as iodides or bromides.
Suitable derivatives of HMT are 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 corneum (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.
Analogues of formula (II) are suitably prepared by reacting HMT with a compound of formula (III)
Y—R
1
  (III)
or a salt thereof; where R
1
is as defined in relation to formula (II) and Y is a leaving group, and thereafter if necessary converting a salt produced to a different salt.
Suitable leaving groups for Y include halogen such as fluorine, chlorine or bromine, particularly bromine, as well as mesylate and tosylate. The reaction is suitably effected in an organic solvent, for example chloroform, alcohols such as methanol or ethanol, acetonitrile at elevated temperatures conveniently at the reflux temperature of the solvent.
Salts of formula (II) may be any salt as convenient depending upon the particular nature of the reagents involved. Th

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