NL194030C - Cream or lotion. - Google Patents

Description

1 194030

Cream or lotion

The invention relates to a polyethylene glycol-based cream or lotion that protects against chemical warfare agents, which essentially consists of at least one active ingredient which is substantially anhydrous.

Such a cream or lotion is known from Chemical Abstracts 99: 207530n (1983). This publication describes a protective cream based on polyethylene glycol containing 5-10% of the surfactant N-octylpyridine-4-aldoxime bromide. According to this document, guinea pigs treated with this cream and subsequently exposed to VX at 50 times the LD50 value for 2 h show no toxic effect

In said Chemical Abstracts publication no protection against other combat gases such as mustard gas is mentioned. In addition, the active compound in such creams is a neutral molecule that must first be converted into an anion before it can be active. Furthermore, the synthesis of such active compounds is cumbersome and it is not known whether these compounds will be harmful to the skin.

It has been found that the use of a special active ingredient solves the above-mentioned problems.

The object of the invention is therefore to provide a cream or lotion of the type mentioned in the preamble which is easy to prepare, which offers protection against different fighting gases over a reasonable period of time, which is compatible with the skin of man and at least does not cause adverse reactions for a limited time, which is not too expensive and which is easy to prepare and handle.

To this end, the invention is characterized in that the active ingredient is selected from the group consisting of the alkali metal salts of mono- and dihydroxyphenols; alkyl and mono alkoxy substituted mono- and dihydroxyphenols, wherein the alkyl groups each contain 1-4 carbon atoms; acetophenone oxime; 2,3-butanedione monoxime; and a polyethylene glycol monoether dispersed in a base medium comprising a polyethylene glycol of the general formula R10- (CH2CH2O) -NCH2CH2O2 wherein R1 and R2 each independently represent hydrogen or an alkyl group and n is an integer of at least 1, or mixtures thereof.

The above objective can be met with the cream or lotion according to the invention.

The creams or lotion compositions of the invention can be used to remove warfare agents from exposed areas. Some of these creams can also be used as creams that form a protective barrier on exposed areas, including barrier creams for use on individuals.

The types of chemical weapons considered to pose a major threat are those commonly referred to as HD, V and G. The first of these, HD, is an acronym for mustard gas, the "D" meaning it is distilled. The formula for this compound is C1CH2CH2-S-CH2CH2CI. This compound belongs to the vesicant class of chemical weapons. V and G represent the V and G series of nerve agents. The G series agents are volatile and highly toxic by inhalation, while the V agents are relatively non-volatile, persistent and highly toxic by percutaneous route 40.

Typical examples of these series are GD, namely the compound (1,2,2-trimethyl) propyl-methylphosphonofluoridate, and VX, namely the compound O-ethyl-S-2-diisopropylaminoethyl-methylphosphonothiolate.

Any cream or lotion to be used for decontamination or as a protection against chemical weapons must have certain desirable properties to be of practical significance under field conditions. First of all, it must be effective against all three of these types of chemical weapons. Second, for use as a barrier cream, it must be compatible with human skin and not cause adverse reactions for at least a limited period of time. Third, it must provide protection for a reasonable period of time. In this regard, it should be noted that 50 “disinfection” includes both pre-exposure coating to negate effects and post-exposure cleaning to remove potential lethal deposits. These three criteria exclude many of the currently known fumigation systems, which are designed as chemical weapon destruction agents, for use as barrier creams, or for fumigation of relatively sensitive materials such as fabrics. The main problem is that such disinfection systems contain very powerful reagents that will damage frequently treated surfaces. Some of these systems are very basic, and some use concentrated active chlorine or bleach solutions. Therefore, while these systems act somewhat as disinfectants for equipment exposed to chemical weapons, they are not useful in protecting or disinfecting people and do not provide any indication as to the type of systems that could be used for assembling protective systems.

For example, GB-A-2,237,739 and GB-A-2,238,475 propose a solution to the barrier cream problem 5 permitting the composition of a cream effective against all three types of agents, minimal adverse skin reactions during the periods of time which is likely to cause such a barrier cream to be worn, and also provides protection to the wearer for a reasonable period of time.

While these proposed creams contain a reagent that is potentially extremely basic, for example, potassium phenoxide, they have been found to be compatible with the skin.

In detail, these proposed creams provide a barrier cream consisting essentially of at least one active ingredient selected from the alkali metal salts of mono- and dihydroxyphenols, and alkyl- and monoalkoxy-substituted mono- and dihydroxyphenols, wherein the alkyl groups each have 1-4 carbon atoms dispersed in a substantially anhydrous state in a base medium comprising a polyethylene-15 glycol optionally partially etherified to reduce the free hydroxyl group content. In these creams, the active ingredient is preferably potassium phenoxide.

In said British patents, creams have been proposed in which the active ingredient is selected from an alkali metal, preferably potassium, phenol salt, acetophenoxime, acetone oxime and 2,3-butanedione monoxime, together with a similar polyethylene glycol base, which is also a macrocyclic compound from compounds known as 18-crown-6 and cryptand [2,2,2], and includes a small amount of water.

While these known creams have been found to be effective in satisfying the above three main properties reasonably efficiently, they also have certain drawbacks, for example, the fact that the macrocyclics used are expensive.

These known creams essentially contain three components: the reactive substance that destroys the chemical weapon, a macrocyclic substance and the base in which they are dispersed. To prepare these creams, the reactive substance, for example potassium phenoxide, and the macrocyclic compound must first be prepared and then added to the base. These substances are both difficult to prepare and difficult to handle because they are particularly sensitive to reaction with water.

The creams or lotions according to the invention offer the advantage that their preparation can be simplified.

According to the invention such a cream or lotion can be prepared simply and easily by dispersing the active ingredient (the alkali metal salt, for example the potassium salt) directly in the same kind of polyethylene glycol ether as used to supply the main ingredient of the cream base in the above proposed cream. In a particular case, the active substance can be prepared directly in the polyethylene glycol base by reacting a suitable polyethylene glycol with an alkali metal, especially potassium.

The potassium salts used in these creams are generally prepared separately, in a relatively pure state. Although separate preparation of the salt has the advantage that the salt can then be identified and, if desired, purified, the drawback mentioned above for creams containing, for example, potassium phenate, is associated with this, requiring careful handling under dry conditions. is. In one particular case, what is called a "one-pot" technique can be used, with the salt being prepared directly in situ. This method is particularly advantageous in that it minimizes the work with sensitive compounds and simplifies the preparation of the cream or lotion.

It is somewhat surprising that these salts can be prepared by a direct reaction of the alkali metal with a monomethylpolyethylene glycol. It would be expected that alkoxides cannot be prepared directly from polyethylene glycols and alkali metals, but that the use of an intermediate, for example sodium naphthide, is required. Our studies show that an alkali metal salt is prepared, for example, where we have isolated and characterized (using elemental analysis, IR and NMR studies) the potassium salt of diethylene glycol monomethyl ether, CH3-0-CH2-CH2-0-CH2CHa0K.

When the one-pot method is used, the choice of the polyethylene glycol as a reactant as well as a cream or lotion base - which is also present - is very wide, and generally the same as those used directly as a cream or lotion base.

The polyethylene glycol used as reactant will generally have the formula R30- (CH2CH2) -mCH2CH2 OH, wherein R3 represents an alkyl group, usually with 1-4 carbon atoms, and in particular methyl or ethyl. The value m can be very wide ranging from 1 (i.e. a diethylene glycol mono ether) to 3 194030 50, whereby a polyethylene glycol having a molecular weight of 1900 is obtained. The intended possibilities include the use of a mixture of polyethylene glycol ethers, for example to obtain both a reasonable reaction speed and a reasonable consistency of the cream or lotion. On the other hand, the alkali metal salt can be prepared directly in a mixture of a polyethylene glycol monether in a diether, for example a mixture of diethylene glycol monomethyl ether in "tetraglyme", of the formula CH3-0- (CH2CH20) -3CH2CH2OCH3.

When selecting the blend of polyethylene glycols and ethers for use in the creams and lotions of the invention, apart from ensuring that the hydroxyl group content is sufficient to obtain an adequate concentration of alkali metal salt (it should be recognized that for the monoethers with hydroxyl content decreasing with increasing molecular weight) two factors need to be weighed. It is ideal when the final cream or lotion does not contain an excess of hydroxyl groups to fully utilize the ability of the active alkali metal salts to destroy the chemical weapons. This suggests that the base material should be dieters. Experience shows, however, that the salts are not too soluble in such systems, and therefore a mixture of diether and a little monoether is generally required to balance the properties. In those applications where maximum capacity for dissolving the active ingredient is desired and the rate of destruction is not as critical, the use of unetherified polyethylene glycols may be appropriate.

The base medium used in these creams and lotions can be selected from a wide range of 20 compounds, and does not have to be a single compound. The main requirement is that it provides adequate cream or lotion consistency. The polyethylene glycols taken into consideration here correspond to the general formula R10- (CH2CH2O) -NCH2CH2O2 where both R1 and R2 represent hydrogen. For the creams and lotions of the invention intended for use on the skin, the hydroxyl groups must be at least partially etherified. Therefore, for application to the skin, at least one of R1 and R2 will generally not represent hydrogen. Suitable etherifying groups are alkyl groups with up to 4 carbon atoms. The etherifying groups are typically methyl or ethyl groups. It is therefore understood that a suitable base medium can be obtained by etherifying a mixture of polyethylene glycols, mixing pre-etherified polyethylene glycols, or by mixing a fully etherified polyethylene glycol with an appropriate amount of a second unetherified or monoetherified polyethylene glycol, which a polyethylene glycol with chain lengths other than the etherified polyethylene glycol.

For other applications, the aforementioned general formula R1 and R2 may each represent hydrogen or an alkyl group having up to 4 carbon atoms. The particular composition of the base medium will therefore be governed by the specific application.

The value of n in the above formulas can be selected from a wide range. When n is high enough to give, for example, a molecular weight above 750 and the like, the polyethylene glycol ether itself will provide the required consistency for the cream or lotion. On the other hand, when n is small as in the compound CH30- (CH2CH20) -3CH2CH20CH3 known as "tetraglyme", the polyethylene glycoite is a liquid and unable to deliver a cream by itself. It can be thickened by adding 40 aim to add substance commonly used in pharmaceutical creams such as silicon oxides, titanium oxides, Fuller's soil, clays, bentonite etc. The filler used must be such that it does not react with the active ingredient. necessary to etherify them before use.

The creams and lotions of the invention also provide an unexpected benefit. It was noted above that the systems commonly used for equipment disinfection due to their chemical nature cannot be applied to the skin. This also means that it is questionable whether such systems can be used to disinfect surfaces of porous equipment such as fabrics and webs. If these chemical solutions are left in contact with such porous materials for a sufficient period of time to adequately penetrate them, then it is also likely that they will also damage the materials. This has been found not to be the case with some of the creams of the invention, particularly those containing phenoxide and oximate salts, which can be left in contact with porous contaminated surfaces for long periods of time without causing damage, as noted above that some creams of the invention which again contain phenoxide and certain oximate salts do not attack the skin.

194030 4

Example 1

Preparation of the potassium salt of diethylene glycol monomethyl ether Method I.

5 Metallic potassium (2.5 g, 6.4 x 10'2 gram atoms, accurately weighed) was placed in a nitrogen purged, 2-liter, round-necked three-necked flask containing 150 ml of hexane (dried with sodium) and was of a magnetic stir bar provided, brought. The flask was also equipped with a condenser, a nitrogen inlet tube and a pressure-leveling dropping funnel, each separated from the flask by a large-passage valve, which allows isolation of the flask and the reaction product from the rest of the equipment. . The equipment was protected from moisture and carbon dioxide and equipped with an outlet bubbler to monitor nitrogen flow (250 ml / min). A solution containing a 10% excess (8.46 g, 7.04 x 10'2 mole) of diethylene glycol monomethyl ether (2-glycol MME, dried over activated molecular sieve material) in 20 ml of cyclohexane (dried with sodium) was in the dropping funnel (in a dry laboratory argon atmosphere) before the equipment was assembled. The potassium hexane mixture was refluxed with stirring to disperse the potassium. The 2-glycol MME cyclohexane solution was then added dropwise over about 50 minutes. The reaction was continued under reflux for 6-7 hours, after which heat was dissipated while maintaining nitrogen flow to avoid entry of air. The cooled flask containing the product was isolated from the rest of the equipment through the taps and transferred to a dry laboratory for work-up. The precipitate which separated on cooling was collected and washed with hexane (dried with sodium) followed by ether (dried with sodium) to give the potassium salt of 2-glycol MME as colorless crystals. The yield was 6.98 g, 69%, mp 89-91 ° C.

Anal, calculated for CgH ^ OgK. C: 37.95; H: 7.01; K; 24.71.

Found: C: 37.70, 37.67; H: 7.03, 6.99; K: 24.45, 24.56%.

Method II

Method I was modified by using tetraethylene glycol dimethyl ether (after chromatography through both basic and acidic alumina, and drying over molecular sieve materials), 50 ml, instead of the hexane. The reaction was carried out using 0.387 g (9.9 x 10 3 gram atom) of potassium and 1.82 g 30 (1.5 x 10 2 mole) 2-glycol MME (50% excess) at 65 ° C. 70 ° C. The 2-glycol MME was added dropwise in tetraglym (20 cm3) over 15 minutes and heating was continued for 3 hours Potassium 2-glycol MME was not isolated but adjusted to a concentration of 0 with tetraglym. 1M and tested for reactivity to HD, GD and VX For the results, see Table IV.

Carbon-13 NMR and protom NMR spectra of K-2-glycol MME were recorded on a Varian 35 XL-200 FT NMR spectrometer with a solution containing 0.03 g of salt in 0.5 ml of dimethylsulfoxide-dg (DMS0-d6) , was used unless otherwise specified. Infrared spectra were recorded on a Perkin-Elmer infrared spectrophotometer Model 283.

Example 2 40

Potassium salt of polyethylene glycol monomethyl ether, molecular weight 350 (PEGMME 350)

The preparation was carried out in a drying laboratory in an argon atmosphere. Potassium (0.0979 g, 2.5x1O3 gram atoms) and PEGMME 350 (dried over molecular sieves) 12 ml were placed in a 25 ml round bottom flask equipped with a magnetic stirrer and heated at 65-70 for 4 hours ° C 45 heated. The product (potassium PEGMME 350) was not isolated but was brought to a known concentration (0.5 or 0.1 M) with PEGMME 350 and tested for reactivity to VX. For comparison, the salt isolated by Method I described above was also brought to 0.1M in PEGMME 350 and tested against VX. For the results, see Table V.

50 Example 3

Potassium salt from a barrier cream base

The preparation was carried out in a drying laboratory in an argon atmosphere. 60 ml of a base cream (50% PEGMME 550 and 50% PEGMME 1900, W: W%) melt, dried at 10 * 3 Torr for 3 hours, and potassium 55 (1.12 g, 0.029 gram atoms) were added in a 200 ml round bottom flask equipped with a magnetic stirrer, charged and heated to 65-70 ° C for 4 hours and 40 minutes. The resulting solution, after cooling, produced a homogeneous cream with excellent structure and smearing properties.

Example 4 5 Investigation of disinfectants against CW agents

The solutions of the CW agent were prepared by weighing 0.4 milliequivalents (ie 31.8 mg HD; 106.8 mg VX; 72.8 mg GD) of a given agent into 1 ml volumetric flasks and volume with the same solvent as in which the candidate fumigant salt was dissolved (see Tables I, IV, V). For the study, a 25 microliter portion of the solution of the agent was transferred through a 10 microliter syringe into a 3 ml Reacti-VialR (Pierce Chemical Co) equipped with a teflon lined silicone buffer buffer and a triangular magnetic stirrer. The candidate disinfectant solution (400 microliters) was added to the reactive via a microliter syringe and the resulting solution was stirred at 19-22 ° C. The salt: agent ratio was adjusted by changing the concentration of the salt solution.

For these ratios, the salt concentrations, the solvents used and the reaction times, see Tables IV and V. At the end of the chosen reaction times, the systems were quenched with a twentyfive excess (relative to the nucleophilic salt) glacial acetic acid.

The degree of fumigation achieved was obtained from the degradation of the agent as determined by gas chromatographic analysis using an external standard. The standard 20 was prepared in the same solvent as used in the fumigation experiment at the same concentration initially present in the reaction mixture. Injections (1 microliter) of the standard were made before and after that of the fumigation experiments and by comparison to the peak areas, the amount of degradation of the agent was calculated.

For all gas chromatography analyzes, a Perkin-Elmer gas chromatograph (GC) Model Sigma 1B, 25 equipped with a thermal conductivity detector (TCD) and the computer, complete with recorder, were used for data processing. The TCD and the injection port were kept at 250 and 240 °, respectively. The size of the injection sample was 1 microliter. The instrument was equipped with a 3m x 2mm internal diameter column and 15cm pre-column, both made of silanized glass and both filled with 10% UCW-98 on Gas Chrom QH, 80/100 mesh. All other gas chromatography parameters are shown in Table I.

Example 5

Cream preparations The selected active ingredient salt was weighed (under suitable precautions, i.e., in a drying box and in an inert atmosphere) into an appropriately sized jar fitted with a polytetrafluoroethylene lined lid. The weighed salt in the jar, the base cream and a large syringe were then equilibrated in an oven at 55 ° C primarily to liquefy the cream. The required amount of cream was then placed in the jar and then stirred to disperse the salt 40 evenly in the liquefied cream. This may require stirring for several hours (for example with a magnetic stirrer using a small stick in the jar) at a temperature in the range of 50-60 ° C. The creams were then allowed to cool, stirred to a smooth texture with a spatula and transferred to suitable containers in a drying box.

The following creams were prepared in this manner using the following four base creams 45 (note that the numbers after PEG indicate an approximate value for the average molecular weight: for example, PEG 350 is a polyethylene glycol with a molecular weight of about 350; the percentages are weight-related.

Basic cream: 1. 50% PEG 350 Monomethyl ether 50 50% PEG 1900 monomethyl ether 2. 50% PEG 550 monomethyl ether 50% PEG 1900 monomethyl ether 3. 60% PEG 600 40% PEG 1900 monomethyl ether 55 4. 40% PEG 550 monomethyl ether 60% PEG 1900 monomethyl ether 194030 6

Using these bases, creams were prepared containing potassium phenoxide, potassium 2,3-butanedione monoximate, potassium acetophenone oximate, and potassium acetoximate in a concentration of 1.25 molar. In any case, bases 1 and 2 were found to dissolve at least about 75% of the salt while the remainder was finely divided. When using base 3, the salt was found to dissolve completely. Base 4 was only used with potassium acetophenone oximate, which was found to be soluble in this base.

Example 6

Cream Evaluation 10 Test Species - Albino male guinea pigs (approximately 500 g), from the virus-free Hartley strain, were obtained and acclimatized for 1 week before use.

Test Procedure - An 80 cm2 surface on the back of each animal was shaved and treated with a hair remover to obtain a depilated test surface. The following morning, the animals were weighed and placed on a restraint tray that allowed head movement and food on the front of the tray but did not allow sufficient hull movement to compromise the test surface on the back. A 3 x 4 cm area was marked on the depilated skin of the back and a measured volume of 0.8 ml volume cream was spread evenly over the marked area. This gave a layer with a thickness of 0.5-0.6 mm. One hour after application of the cream, drops of a chemical weapon were applied to the surface of the cream in separate places until the desired total dose was administered. The animals with restricted freedom of movement were placed in a smokecap facing the air stream to exclude as much as possible that they inhaled the vapor of the agent. After 6 hours they were freed, transferred to small individual wire cages in which they were kept overnight. During the period of freedom of movement they were given fresh lettuce and carrots and the caged animals were given food and water. All animals were examined regularly for clinical signs during the restriction period. When they died, the time of death was recorded. 24 hours after application of the agent, the cream was carefully washed away from the backs of the surviving animals and the area where the cream was applied was examined for damage to the skin. Surviving animals were examined for other physiological abnormalities and killed with carbon dioxide. When abnormal tissues were found in necropsy, biological samples were collected.

In each test animal group, there were at least 2 treated with the drug in the absence of cream (drug controls). At least 4 were treated with agent after applying base cream with no active ingredient therein (cream control). At least 10 were treated with agent after applying active cream.

In the case of nerve agents, group statistics include mean time to death, percent survival, body weight, agent dose and tissue study data.

In the case of mustard (HD), a modified Draize rating system was used, similar to the one described elsewhere, but expressed as percentage protection afforded by the 40 base on the active core in proportion to the skin damage seen in untreated controls was caused.

Doses of the applied agent 1. Mustard (HD): 0.4, 0.8; 1.2; and 1.6 microliters per 12 cm2 area.

2. GD in droplet sizes of 4 microlitres and fractions thereof 45 a. Barrier cream; 16 LD ^ b. base cream: 8 LD ^ 3. VX in droplet sizes of 4 microlitres and fractions thereof a. barrier cream: 68 LD, »b. base cream: 34 LD ^ 50 Active ingredients 1. Potassium phenoxide (KOPh) 2. Potassium 2,3-butanedione monoximate (KDAMO) 3. Potassium acetophenone oximate (KOMP)

Cream Compositions 55 These were prepared as described in Example 5. For ease of tabulating the results and for discussing them, the following terms were used: MG 1 - base cream 1.

4 7 194030 MG2 - base cream 2.

MG3 - basic cream 3.

MG4 base cream 4.

PMG1 (1.25 m KOPh) - 1.25 molar KOPh, in base cream # 1 5 PMG2 (1.25 m KOPh) - 1.25 molar KOPh, in base cream # 2 PMG3 (1.25 m KOPh) - 1, 25 molar KOPh, in base cream # 3 PMG2 (1.25 m KOPh) - 1.0 molar KOPh, in base cream # 2 PMG2 (1.25 m KOPh) - 1.5 molar KOPh, in base cream # 2 PMG2 (1, 25 m KOPh) - 2.0 molar KOPh, in base cream # 2 10 OMG2 (1.25 m KDAMO) - 1.25 molar KDAMO, in base cream # 2 OMG2 (1.25 m KOMP) - 1.25 molar KOMP, in base cream # 2 OMG4 (1.25 m KOMP) - 1.25 molar KOMP, in base cream # 4

A subjective assessment was made of the cosmetic properties (appearance, color, smear and integrity) of the creams and their irritation to the skin and eyes.

15 Results

The base creams MG2 and MG4 gave significant levels of protection against HD when tested at the same dosage level as used in the active creams (Table VI). On the other hand, they gave only erratic protection against GD and no protection against VX when tested at half the normal dose used for the active creams.

All active creams provided high levels of protection against all three agents, demonstrating excellent properties and reproducibility, except in the case of PMG2 (1.25 m KOPh), in the case of VX and OMG4 (1.25 m KOMP ) in the case of GD.

The cosmetic properties of the MG2-based systems were found to be slightly better assessed than those of the MG1 and MG3 systems, which were slightly softer and slightly harder, respectively (Table VIII). It is possible that these small differences could be corrected by small adjustments of the proportions of the PEG components.

The base creams MG2 and MG4 and the active creams PMG2 (1.25 m KOPh) and OMG2 (1.25 KDAMO) were found not to be irritating to the guinea pig's skin (applied for 24 hours under ventilated or confined condition) and rabbit eyes. Active cream OMG4 (1.25 m KOMP), on the other hand, was found to be slightly irritating to the skin and very irritating to the eyes. The other creams were not tested for skin or eye irritation.

TABLE I

Gas chromatographic parameters for analysis of CW resources 35 -—------—

Medium Solvent- Carrier Gas Lower Hold Program- Higher Hold Retention Time del (He) furnace- from lower maspeed furnace- from higher of medium flow rate temp. (min) (° C / min) temperature temp. (min) (min) temperature (° C) temperature (° C) 40 (ml / min) HDa 100 0 5 150 0

Tetraglyme 20 8.0 HDb 150 0 40 230 5 45 GD Tetraglyme 20 95 15 40 230 5 8.6 VX Tetraglyme 30 200 5 35 235 5 5.1 VX 2-Glycol 30 200 5 35 235 5 4.9

MME

VXa 200 5 35 235 5 50 PEG MME 30 5.3 350 VX0 235 5 35 250 45 a: first step in temperature program 55 b: second step in temperature program ft 194030 8 TABLE I!

Proton NMR Spectrum of K-2-glycol MMEa Compound CH3 - OC-CH2 - CH2 - O - CH2 - OK

5 -—-

Proton label A

Chemical shift (ppm) b 3.28 3.48 3.33 3.96

Peak type singlet singlet singlet singlet

Integration 3C 4 ° 2 ° 2 ° 10 - a: K-2-glycol MME = potassium salt of diethylene glycol monomethyl ether. b: field down from trimethylsilane. c: number of hydrogen atoms

TABLE III

Chemical shift in Proton NMR of K-Salt-2-Glycol MMEa at different concentrations

Proton label0 A B C D

2Q Signal type Singlet Singlet Triplet Triplet

Concentration (g per 0.5 mL) Chemical Shift (ppm) (DMSO-de) 0.0062 3.27 3.46 3.32 3.85 25 0.0106 3.27 3.47 3.33 3.91 0.0208 3.27 3.47 3.34 3.93 0.0304 3.28 3.48 3.33 3.96 0.0459 3.28 3.48 3.33 3.96 30 a: K-2- glycol MME = potassium salt of diethylene glycol monomethyl ether. b: See Table II for label identification, c: field down from trimethylsilane.

35 TABLE IV

Decontamination efficiency of K-2-Glycol MME in Tetraglyme against HD, VX and GD

preparation CW agent salt: salt conc. % Disinfection after reaction time of method medium (M) -— 4q ratio 5 min 3 min 1 min 30 sec 10 sec I HD 2: 1 0.05 - - 100 100 99 HD 1: 1 0.025 96 91 - 75 VX 2: 1 0.05 - - - 100 100 45 VX 1: 1 0.025 87 80 67 GD 2: 1 0.05 - 100 100 100 GD 1: 1 0.025 93 91 88 67 II HD 2: 1 0.05 100 100 100 99 87 HD 1: 1 0.025 94 89 82 92 85 50 VX 2: 1 0.05 - 100 - 100 100 VX 1: 1 0.025 - - 100 100 98 GD 2: 1 0.05 - - 100 100 GD 1: 1 0.025 80 77 82 78 55 I = salt prepared in hexane / cyclohexane isolated and identified.

II = in situ in tetraglyme t 9 194030

• TABLE V

Decontamination efficiency of potassium salts of 2-Glycl MME and PEG 350 MME against VX

Experiment Salt: Salt Concentrate-% Disinfection after reaction time of 5 no. middle centering medium -

ratio (M) 10S 30S 1M 5M 10M 15M 20M

1a'b 2: 1 0.05 tetraglyme 100 100 2® 4: 1 0.1 2-Glycol ΜΜΕ “- - 7 19 36 48 54 10 3® 4: 1 0.1 PEGMME 350® - - 33 56 73 88 96 4C 4: 1 0.1 PEGMME 350 - - 33 53 72 89 97 5C 20: 1 0.5 PEGMME 350 46 100 100 100 100 - a: K salt of diethylene glycol monomethyl ether.

15 b: Data from Table IV.

c. K salt of polyethylene glycol monomethyl ether, molecular weight 350.

d: 2-Glycol MME = diethylene glycol monomethyl ether.

e: EGMME 350 = polyethylene glycol monomethyl ether, molecular weight 350.

20 TABLE VI

Protection1 granted to guinea pig males by active and basic creams against HD, VX and GD

Cream Medium

25 HD GD VX

Base MG2 77 ± 6 (26) 43 ± 31 (15) 2 0 <13) 2 MG4 76.91 (2) 1 0.25 (2) 0 (3)

Active PMG2 (1.25m KOPh) 91 ± 8 (6) 3 98 ± 4 <8) 66 ± 21 (10) 30 OMG 2 (1.25m KDAMO) 92 ± 4 (6) 96 ± 4 (5) 98 ± 4 ( 4) OMG2 (1.25m (KOMP) 95 ± 4 (9) 98 ± 4 (5) 96 ± 4 (7) OMG4 (1.25m KOMP) 98 ± 2 (3) 60,100 (2) 90,100 (2) 1. Protection =% survival for GD and VX and% reduction in total effects of skin damage (modified Draize) compared to unprotected controls for HD.

2. The mean tests for GD and VX on base creams were only half of those on active creams, respectively. 8 LDjo and 34 LDgo instead of 16 LDM and 68 LDM. A full test was used for HD.

3. Values in brackets for active creams indicate the number of experiments performed with at least 10 animals per experiment.

TABLE VII

40 Effect of KOPh concentration on protection1 conferred on guinea pig males by PMG barrier creams Cream% protection range against VX

Barrier Base 45 ------------—-— - PMG2 (1m) 0.50 (2) 2 0 (2) PMG2 (1.25m) 75.90 (2) 0 (2) PMG2 (1.5m) 40,100.90 (3) 0 (3) PMG2 (2m) 62.90 (2) 0 (2) 50 ___—-- 1. Protection =% survival.

2. Values in brackets for active creams indicate the number of experiments performed with 10 animals per experiment.

Claims (6)

194030 10 TABLE VIII Cosmetic Properties of and irritation from base creams and barrier creams Cream Color Appearance Hardness Smearing Integri- Irritation8 5 ring quality skin eyes MG1 color smooth soft good good * * devoid 10 MG2 color „medium very very empty good good MG3 color„ hard bad good * * empty MG4 color „medium good very 15 empty good PMG1 (1.25m KOPh) medium brown„ soft good reasonable * * PMG2 (1mKOPh) medium brown „medium good good * * PMG2 (1.25m KOPh) medium brown„ medium very very good good 20 PMG2 {1.5m KOPh) medium brown „medium very very * * good good PMG2 (2m KOPh) medium brown„ medium good good * * PMG3 (1.25 KOPh) medium brown „hard bad good * * OMG2 (1.25m orange „medium very very - - 25 KDAMO) good good OMG2 (1.25m don- „soft very reasonable * * KOMP) kerbro good OMG4 (1.25 KOMP) don-„ medium very very ++ ++++ kerbro good good 30 ---- 1. 24 h contact time 2. Intact skin, 24 h contact time - not irritating + hardly visible irritation ++ slight irritation +++ medium irritation +44+ severe irritation * not tested 40 Conclusion Polyethylene glycol based cream or lotion protecting against chemical warfare agents, consisting essentially of at least one active ingredient which is substantially anhydrous, characterized in that the active ingredient is selected from the group consisting of the alkali metal salts of mono- and dihydroxyphenols-45, wherein the alkyl groups each contain 1-4 carbon atoms; acetophenone oxime; of 2,3-butanedione monoxime; and a polyethylene glycol monoether dispersed in a base medium comprising a polyethylene glycol of the general formula R10- (CH2CH2O) -NCH2CH2O2 wherein R1 and R2 each independently represent hydrogen or an alkyl group and n is an integer of at least 1, or mixtures thereof.