AU2002217414A1

AU2002217414A1 - Skin-protective compositions effective against vesicants and percutaneous chemical agents

Info

Publication number: AU2002217414A1
Application number: AU2002217414A
Authority: AU
Inventors: Itzhak Barness; Eliezer Fishbine; Tamar Kadar
Original assignee: Israel Institute for Biological Research
Current assignee: Israel Institute for Biological Research
Priority date: 2001-04-25
Filing date: 2001-12-31
Publication date: 2003-04-17
Anticipated expiration: 2021-12-31

Description

-i-

HIGH EFFICACY PROTECTIVE COMPOSITIONS AGAINST

VESICANTS AND PERCUTANEOUS CHEMICAL AGENTS

Field of the Invention

The invention relates to protective compositions for protecting the skin

against damages caused by sulfur mustard gas and other chemical agents,

such as VX, pesticides, nitrogen mustard and poison ivy.

Background of the Invention

Sulfur mustard (both in gaseous and liquid form) is a potent cutaneous

vesicant which rapidly penetrates tl. Askin and causes prolonged injuries,

and is therefore representative of the percutaneous agents to the

protection against which the present invention is directed. Sulfur

CH₂ CH₂ CI

S

^\ CH₂ CH₂ CI

(I) mustard, as an example of major hazards consists of

β-chloro-diethylsulfide of the formula:

which may further contain other components, such as other active compounds.

VX as an example for nerve agent: 0-ethyl-S-(2-diisopropylaminoethyl-

methylphosphothiolate), of the formula:

O

I , 0CH2CH3

CH₃ — p

^ S CH2 CH₂N (CH (CH₃)₂) )2

There are two main ways known in the art of protecting a person's skin

against chemical warfare agents such as mustard: The first method is a

passive protection which involves covering the skin with a protective

cover, such as a protective cloth. This method has several drawbacks:

firstly, the protective clothings are heavy and uncomfortable to wear for a

long period of time, and therefore they cannot be continuously worn as a

preventive measure. Secondly, the protective covers leave areas

unprotected, such as the hands and neck, and therefore do not offer

complete protection. Furthermore, such protective measures are quite

expensive, which of course limits their usefulness.

The second method involves applying reactive materials to the skin, which

react with the sulfur mustard gas and neutralize it. The drawback

associated with this method is that it requires to apply to the skin active

materials which generally are in themselves harmful, typically require the

application of oily and uncomfortable materials to the skin, and furthermore are as yet only limited in efficacy. Additionally, such reactive

materials are also generally required in large amounts, which are difficult

to apply to the skin.

Other protections, which involve the use of creams which promote the

creation of a polymeric film on the skin are also not very effective, since

the film cracks and leaves areas below the cracks exposed. Furthermore,

such films are thick and uncomfortable to the user. Another cream exists,

which penetrates the skin, leaving an outer layer that can act as a matrix

for active protecting agents. This cream also exhibits the drawbacks

described above. In addition, this protective cream requires a thick layer

to be applied. The above composition may be toxic to the respiratory

system due to fumes emerging from smoking products, such as cigarettes,

and thus it is not effective in hot environments or where fire is present.

The art, notwithstanding the many efforts devoted to the solution of this

problem, has failed so far to provide a solution to the above problem, viz.,

a protection for the skin which overcomes the above drawbacks.

It is therefore an object of this invention to provide a protective agent

which is effective against sulfur mustard and other chemical agents, such

as VX, and which overcomes the drawbacks of prior art protections. It is another purpose of this invention to provide a protective agent which

can be applied to the skin often, which does not lead to discomfort, and

which is not harmful to the skin.

It is yet another purpose of the invention to provide a protective agent

which remains effective for a long period of time after application, in the

order of 6 - 12 hours before exposure to the harmful chemical agent.

Other purposes and advantages of this invention will appear as the

description proceeds.

Summary of the Invention

The invention is directed to a protective agent suitable to protect the

human skin against sulfur mustard gas injury, nerve agents such as VX

and injury from other harmful chemical agents, comprising a

protective-effective amount of a hydrophilic water-based cream, alone or

together with one or more additives selected from among the group

consisting essentially of polyols, mono-, oligo- or polysaccharides, salts of

organic or inorganic acids, and absorbant compounds.

The term "cream", as used herein, is intended to indicate any preparation

of sufficient viscosity to remain on the skin for a sufficient period of time

so as to be absorbed into its surface, and' should be understood to include also preparations of appearance other than creamy, such as lotions or

ointments.

According to a preferred embodiment of the invention the additive polyol

is selected from among polyethylene glycol, propylene glycol, polyglycerol,

glycerin, sorbitol, dulcitol, tritol, sorbitol or mannitol.

According to another preferred embodiment of the invention the additive

monosaccharide is selected from among arabinose, ribose, xylose, glucose,

fructose, galactose and mannose.

According to still another preferred embodiment of the invention the

synergistic additive oligosaccharide is selected from among sucrose,

maltose, lactose, raffinose or cellobiose.

According to yet another preferred embodiment of the invention the

additive polysaccharide is selected from among starch or gum arabicum.

The protective agent may contain, according to another preferred

embodiment of the invention, an additive salt selected from among salts of

citric acid, glycolic acid, gluconic acid, tartaric acid, glucaric acid, glyceric

acid, lactic acid, ascorbic acid, thioglycolic acid, benzoic acid, acetic acid,

glycine, alanine, serine, lysine, aspartic acid, cysteine, proline, glutamic

acid, δ-hydroxyl sine, glutamine or urea. The hydrophihc water -based cream of the invention may be of different

types, the important requirements from such base cream being its

hydrophihc nature, and its ability to be spread on the skin and accepted

thereby. For this purpose, glycerin is particularly suitable, since it is

absorbed into the skin and interacts with the epidermis, to provide a

homogeneous and long-lasting protective layer which effectively protects

the skin against sulfur mustard, VX and other chemical insults, even in

the absence of additives.

Without wishing to be bound by any particular theory, it is the inventor's

belief that the action of the cream of the invention is due to its hydrophihc

behavior, which repels sulfur mustard from the skin surface. The addition

of hydrophihc additives of the kind employed in this invention, further

enhance this phenomenon and creates a "salting-out-like" effect toward

the sulfur mustard and other chemical agents. Thus, for instance, the

addition of salts to the cream displaces water molecules and caused a

repulsion of the sulfur mustard or other toxic organic agents away from

the skin.

While, as stated, glycerin is the preferred base for the protective agent

cream, other bases can be used. Cream is defined for the present invention

as a composition having viscosity significantly higher than water. For example, the viscosity of glycerin is 1490-629 centipoise between 20-30°C,

respectively, sorbitol viscosity 110 centipoise at 25°C, while water viscosity

is 1.8 centipoise at 25°C. According to a preferred embodiment of the

invention the hydrophihc water-based cream contains one or more

additives, and the water-based cream consists essentially of a material

selected from among monosaccharides such as sorbitol, potassium

gluconate, potassium tartarate, potassium citrate, calcium chloride or

potassium carbonate. As stated, and as will be further detailed

hereinafter, the cream may contain additional salts, such as MgS0₄ or

other organic salts, or inorganic salts such as aluminum salts, MgC or

CaCl2, provided that no reaction or precipitation takes place between

them, or surface active agents such as Triton X100, esters of sugars and

lecithin.

While the presence of active materials is not a necessity in the protective

agents of the invention, any suitable active agent can be added. For

instance, the protective agent of the invention may further comprise

antiseptic materials. Furthermore, the protective agent may further

comprise reactive materials, such as nucleophilic materials, e.g.,

thiosulphate, or adsorbent compounds such as bentonite, silica gel,

zeolites. Illustrative and non -limitative examples of reactive materials

include, e.g., dithiophosphate ion, ethanedithiophosphate ion,

hexanedithiophosphate ion, butyldithiophosphate ion, ethyldithiophosphate ion, pentaethylenedithiocarbamate, thiosulphate ion

and dialkylthiophosphate.

Additional reactive agents that may be added to the protective cream are

oxidizing materials. Unstable materials, such as H2O2, may be added on

the spot and may be provided separately from the protective cream. Other

oxidizing agents may be included in the protective cream. Illustrative and

non-limitative examples of oxidizing agents are: perchlorides, peroxides,

sodium percarbonate, H2O2: urea complex, H2O2: PVP

(polyvinylpyrrolidone) complex and magnesium monoperoxy phthalate.

Non-reactive agents may include, for instance, thickening agents such as

methylcellulose, xanthan, carboxy methyl cellulose (CMC), etc.

In another aspect, therefore, the mvention is directed to a method for

protecting the human skin against percutaneous chemical agents such as

sulfur mustard, comprising applying to the skin a protective-effective

amount of a hydrophihc water-based cream, alone or together with one or

more additives selected from among the group consisting essentially of

polyols, mono-, oligo- or polysaccharides, and salts of organic or inorganic

acids. Brief Description of the Drawings

- Fig. 1 is a graphical description of the results obtained in Example 2.

Detailed Description of Preferred Embodiments

The above and other characteristics and advantages of the invention will

be better understood through the following illustrative and non-limitative

examples of preferred embodiments thereof.

General Procedures

Protective creams were tested for efficacy against sulfur mustard lesions

and VX poisoning. The protective potential was tested either against 0.2

and 1 microliter droplets of sulfur mustard applied topically on the back of

pigs' skin, or sulfur mustard vapor or VX (0.2 and 1 microliters). The

extent of cutaneous lesion following liquid sulfur mustard was evaluated

quantitatively using a morphometric and densitometric method with the

aid of an image analyzer.

The area of the damaged skin was measured at 24 hours post exposure

and the protective value of each cream was calculated as a percent of

control of sulfur mustard lesion (0% protection representing identity to the

sulfur mustard lesion). The same test was carried out under sweating

conditions in pigs, and gave almost identical results. When tested against

VX poisoning in pigs, the leathality and clinical signs were monitored and the percent inhibition of acetylcholinesterase (AChE) activity was

measured in blood samples. All the pigs pretreated with the protective

creams survived a 1-5 hours challenge with lethal concentrations (twice

the LD50) of VX and did not exhibit any clinical signs, up to three hours

exposure challenges. In comparison, in the absence of the protective

cream, all animals had severe clinical symptoms and the majority died

within 24-48 hours after exposure to VX. AChE activity was significantly

higher in all animals pretreated with the cream, compared to unprotected

animals. However, some decline in blood AChE activity, induced by

dermal application of VX (1.3 g/Kg, lμl) in pigs was measured in the

treated animals (see Example 2 and Fig.l). The protective creams

provided a significant protection, even when applied 12 hours (single

application) prior to a one hour challenge with Iμl droplets of VX (2 LD50),

or sulfur mustard, when LD50 = 0.65 mg/Kg in pigs, for VX.

Five formulations were tested for irritation in controlled laboratory

studies, and were found to be non-irritating by the Draize procedure in

guinea pigs and rabbits. Three preparations were tested also in Phase I

clinical study, with young male healthy volunteers. The creams were

applied on about 20% of the skin surface. The preparations were found to

be non-irritating and safe for human use. Preparation A

A cream composition containing potassium citrate was prepared using the

following components:

Citric acid monohydrate, 99% (ex Aldrich) 10.5 gr

KOH, 86% (ex Fluka) 8.4 gr

Distilled water 5.0 gr

Glycerin 87% (ex Merck) 20.0 gr

Comparable results were obtained when Glycerin 100% was used.

Preparation B

A cream composition containing potassium acetate was prepared using the

following components:

Potassium acetate (ex Hopkin & Williams) 30.0 gr

Glycerin 87% (ex Merck) 20.0 gr

Preparation C

A cream composition containing sorbitol was prepared using the following

components:

Sorbitol (ex BDH) 30.0 gr

Distilled water 9.0gr Glycerin 87% (ex Merck) 15.0 gr

Preparation D

A cream composition containing potassium β-alanine was prepared using

the following components:

β-alanine, 98% (ex Aldrich) 8.9gr

KOH, 86% (ex Fluka) 5.6 gr

Distilled water 5.0gr

Glycerin 87% (ex Merck) 10.0 gr

Preparation E

A cream composition containing magnesium sulfate was prepared using

the following components:

Magnesium sulfate 10.0 gr

Glycerin 87% (ex Merck) 30.0 gr

Preparation F

A cream composition containing potassium borate was prepared using the

following components:

Sodium borate (Na₂B θ7-10H₂O) 20.0 gr

Glycerin 87% (ex Merck) 30.0 gr Preparation G

A cream composition containing glycerin was prepared containing only

glycerin 87%.

Preparation H

Magnesium sulfate -7H₂0 1.5gr

Glycerin 87% 4.5gr

Silica gel 2 gr

Manoxol OT (dioctyl ester of sodium sulfusuccinic acid) 30 mg

Alternative surface active agents

Manoxol OT

Triton x 100

Lecithine

Sodium Lauryl Sulfate

Alternative Adsorb ants

Bentonite

Fumed silica gel

Silica gel

Nanosize- MgO, ZnO, Al₂0₃, Ti0₂

Zeolites

Activated charcoal Example 1

The efficacy of various protective compositions of the invention were

tested according to the general procedure described above. The results are

summarized in Table I below:

Table I

Time of exposure to liquid sulfur mustard

** Time of application of protective agent prior to exposure

Ratio cream component:water:glycerin a NaOH b R-oxothiazolidine-4-carboxylate Example 2

The efficacy of preparation E against VX challenge (twice the LD50, LDso=

0.65 mg/Kg in pigs) was tested in pigs according to the procedure

described above. The results of one of the experiments, where the cream of

preparation E was dermally applied once, 6 hours before a one hour

challenge with 1.3 mg/Kg VX (lμl) are shown in Fig.l.

While embodiments of the invention have been described by way of

illustration, it will be understood that the invention can be carried out by

persons skilled in the art with many modifications, variations and

adaptations, without departing from its spirit or exceeding the scope of the

claims.

Claims

1. A protective agent suitable to protect the human skin against lesions

caused by vesicants or other percutaneous chemical agents, particularly

against sulfur mustard gas injury and VX intoxication, comprising a

protective-effective amount of a hydrophihc water-based cream, alone or

together with one or more additives selected from among the group

consisting essentially of polyols, mono-, oligo- or polysaccharides, and salts

of organic or inorganic acids.

2. A protective agent according to claim 1, wherein the additive polyol is

selected from among polyethylene glycol, propylene glycol, polyglygcerol,

glycerin, sorbitol, dulcitol, tritol, sorbitol or mannitol.

3. A protective agent according to claim 1, wherein the additive

monosaccharide is selected from among arabinose, ribose, xylose, glucose,

fructose, galactose, mannose.

4. A protective agent according to claim 1, wherein the additive

oligosaccharide is selected from among sucrose, maltose, lactose, raffinose

or cellobiose.

5. A protective agent according to claim 1, wherein the additive

polysaccharide is selected from among starch or gum arabicum.

6. A protective agent according to claim 1, wherein the additive salt is

selected from among salts of citric acid, glycolic acid, gluconic acid, tartaric

acid, glucaric acid, glyceric acid, lactic acid, ascorbic acid, thioglycolic acid,

benzoic acid, acetic acid, glycine, alanine, serine, lysine, aspartic acid,

cysteine, proline, glutstoic acid, 8-hydroxylysine or glutamine.

7. A protective agent according to claim 1, wherein the additive salt is

selected from among aluminum salts, MgC or CaGb.

8. A protective agent according to any one of claims 1 to 7, wherein the

hydrophylic water -based cream consists essentially of glycerin.

9. A protective agent according to any one of claims 1 to 7, wherein the

hydrophylic water-based cream contains one or more additives, and

wherein the water-based cream consists essentially of a material selected

from among monosaccharides, potassium gluconate, potassium tartarate,

potassium citrate, calcium chloride or aluminum sulfate.

10. A protective agent according to any one of claims 1 to 9, further

comprising antiseptic materials.

11. A protective agent according to any one of claims 1 to 10, further comprising reactive materials.

12. A protective agent according to claim 11, wherein the reactive material

is a nucleophylic material.

13. A protective agent according to claim 11, wherein the reactive material

is selected from among dithiophosphate ion, ethane dithiophosphate ion,

hexane, dithiophosphate ion, butyl dithiophosphate ion,

ethyldithiophosphate ion, pentaethylenedithiocarbamate, thiosulphate ion

and alkyl dithiophosphate.

14. A protective agent according to claim 11, wherein the reactive material

is an oxidizing agent.

15. A protective agent according to claim 14, wherein the oxidizing agent

is selected from among H2O2, perchlorides, peroxides, sodium

percarbonate, H2O2: urea complex, H2O2: PVP complex and magnesium

monoperoxy phthalate.

16. A method for protecting the human skin against injury caused by

vesicants or other percutaneous chemical agents, comprising applying to

the skin a protective-effective amount of a hydrophylic water-based cream,

alone or together with one or more additives selected from among the group consisting essentially of polyols, mono-, oligo- or polysaccharides,

and salts of organic or inorganic acids.

17. A method according to claim 16, wherein the vesicant is sulfur

mustard gas.

18. A method according to claim 16, wherein the organophosphate is VX.