CA2108143A1 - Use of an antiviral coating for latex viral barrier items such as condoms - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

An antiviral cream or lotion for application to mammalian skin, under a protective skin barrier such as a surgical glove or condom, comprises a very small skin-tolerable amount of an alkyl benzyl quaternary ammonium halide disinfectant, a very small, skin-tolerable amount of a nonionic or cationic surfactant, a thickner such as aquasonic gel, an emollient such as glycerine, and water.

Description

USE OF AN ANTIVIR~L COATING FOR LATEX VIRAL

FI~h~ OF THE INV~NTION

This invention relates to anti-viral composi-tions, and more particularly to anti-viral compositions for external topical application to mammalian skin.

B~CKGROUN~ OF ~HE INV~NTION A~ PRIO~ ART

Viral transmission from body to body as a result of body surface contact and body fluid intermingling is one of the principal ways in which viruses such as hepatitis, herpes~ HIV and the like are spread. Particularly at risk from such viral transmissions are health workers such as ambulance personnel, nurs~s, doctors, operations theatre attendants and the like, who must administer to and consequently ~requently engage in body contact with virally infected persons. To date, the most commonly recommended form of protection against such viral infections has been the protective skin barrier method namely the use of latex gloves by health care workars and the use of latex condoms by those exposed to sexually transmitted viruses.

There is still a degree of concern, however, about the effectiveness of such skin barrier items. The items must be extremely thin if they are to permit the use of the required degree of sensitivity during their use.
~he thinner such latex items become, the greater the risk of physical damage to them, and the greater the risk of their proving permeable, to a greater or lesser extent to the virus particles they are intended to contain. More over, however carefully such ~arrier items are manufactured and stored, there is always a risk that areas of them will have excess porosity.

.

. ' It is an object of the present invention to enhance the ef~iciency of such latex skin barrier items in preventing the transmission of harmful viruses from body to body.

SUM~ARY OF THE IN~N~ION

The present invention provides an anti-viral gel formulation for use in conjunction with viral barrier items such as latex gloves and condoms. ~he formulation contains a very small, skin acceptable amount of a strong disinfec-tant vr antiseptic substance, formulated in~o a semi-solid, gel consistency with a~ueous based, skin acceptable carrier materials, for application to mammalian skin under viral barrier items such as latex gloves and condoms. ~he disinfectant or antiseptic substance kills the harmful virus on contact, evan in the necessarily small concentra-tions re~uired to render the compositions of the pres2nt invention skin acceptable. The user is accordingly pro-vided with a double protection against viral infection from an infected body which must be contacted, namely the viral barrier item and the antiseptic or disinfectant gel beneath it.

Thus, according to the present invention, from one aspect, there is provided a latex barrier item adapted to be fitted over a body part to inhibit viral transmission there~o, said latex barrier item having an ou~er surfacs and an inner surface to contact the body part, said inner sur~ace having a layer of semi-solid, anti-viral gel or cream comprising an alkyl benzyl quaternary ammonium halide disinfectant in an amount of from about 0.005-0.1% by weight, a non-ionic or cationic surfactant in an amount of from about 0.01-0.1% by waight, and a lubricious non-toxic hypoallergenic water compatible thickener in an amount chosen to give semi-solid, creamy consistency to the composition, and water.

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2~1~8~ ~3 DESC~IP~ION OF THE PREFEBRED EM~ODIMENT~

The alXyl benzyl quaternary ammonium halide disinfectants used in the present invention are known compounds, many of which have previously been sold and used for disinfecting purposes in non-skin contacting applica~
tions. Thus, they are sold ~or purpose~ o~ making up disinfectant wash solutions for floors, walls, operating surfaces and the like, bu~ always with strong warnings to avoid skin contact with them if a~ all posæible. They are powerful poisons and skin irritants, as well as powerful disinfectants. According to th~ present invention, they will destroy harmful viruses such as hepatitis, herpes simplex types 1 and 2 and HIV when they are present in formulations in such low concentrations that they are skin acceptable. These viruses in fact are not difficult to kill when encountered in isolation in external body fluid~
or secretions. It is after they have infected the mam-malian body and begun to replicate in the body cells that they become almost impossihle to treat e~ectively. If the viruses can be caught and treated on transmission from body to body, they are vulnerable to common disinfectant~ such as those used in the compositions o~ the present invention.

To ~afeguard against risks of skin irritation, the strong disinfectant i8 preferably used in the composi-tion of ~h~ present inven~ion in amounts from OG00~5-0,5% bx weight, most preferably ~rom ~7~ by weight.
Specifi~ examples of such strong disinfec~ants for use in the present invention include alkyl dimethyl benzyl ammon-ium chloride and alkyl dimethylethylbenzyl ammonium chlor-ide, in which the alkyl portions are Cl2-Cl~ in length, and mixtures thereof, and myristylbenzalkonium chloride. Such a suitable mixture is available commercially under the trade name MA~UAT MQ2525M - 50%, from Mason Chemical Company, Chicago, Illinois, and under the trade name BTC
2125M from Stepan Company, North Field, Illinois.

2 ~ 3 Compositions according to the present invention also include a small amount of a non-ionic or cationic surfactant to act as a wetting agent for the disinfectant~
~his improves the spreading of khe disinfectant over th~
skin area to which it is applied. The surfactant is suitably present in amounts similar to those of~he~ ~i n-fectant, i.e. 0.0~-0.1~ by weight, preferably 0.01-0.0 by weight. Examples of speci~ic useful sur~actants of these classes include ~he polyoxye~hylene - based types such as those of the octoxynol series , which are polyethylene glycol p-isooctylphenyl ethers such as octoxynol-9 (Triton X ~ 100), those o~ the nonoxynol series, which are polyoxy-ethylene nonylphenyl ethers, of various numbers of ethylene oxide units, e.g. nonoxydol 9 and nonoxydol 10. These hava the advantage for use in the present invention in that they also have spermatocidal properties. Another type of suit-able polyoxyethylene based non ionic surfactants are the polyoxyethyl alcohols such as thosa sold under the trade name "Siponic." Other choices of surfactant may ba made ~y consulting the s~andard reference work: "Non-Ionic Surfactants," edited by M.J.Schick, Dekker, New York, 19~7.
The overriding criteria of choice are compatibility with skin and with the chosen strong disinfectant, at the chosen amounts.

The other ingredients of the composition of the present invention are a non-toxic hypoallergenic water compatible thickener, and water, in proportions suitable to provide a product of a gel, semi-solid consistency resembl-ing that of hand cream. A wide range of such thickeners is available on the markst, and commonly used in the cosmetic and pharmaceutical formulations industries. They are welt known to those skilled in the art. Various cellulose derivatives can be used for this purpose, ~or example methyl cellulose and the various -30~ carboxymethyl~, ~e~ one compounds such as Carbomers 910, 934, 934P, g40, 941 and 1342; and Carbopols 940, 941 and 930 (from , :;
.

21~81~3 ~i Goodyear~. Preferred are those which also confer a degree of lubricity on the ~inal composition. Especially pre-ferred is aquasonic gel, a gel composition commonly used for body contact with ultra sound diagnostic test appar-atus. It suitably comprises from 1 - 80~, preferably from 20 - 80% and most preferably from ~ 4~ by weight of the composition. The amount is chosen on the basis of the desired consistency of the final product, and on the basis of the precise choice of thickener - some have greater thickening power than others.

Various additional ingredients can be added to the compo~ition of the present invention to improve the nature and encourage the use thereof. Thus, it can contain one or more emollients such as glycerine, lanolin, aloe vera, paraffin oils, glycerol monostearate, myrj compounds, Tween, PEG compounds, sodium lauryl sulphate, etc., and mixtures of two or more of them, to improve the lubricity and general oiliness of the composition. It can also if desired contain various perfumes and colorants. Any ingredients which are used must be skin compatible, inert towards the active ingredient, and of a natura and used in an amount which does not destabilize or upset the general creamy consistency of the formulation.

The formulations according to the present inven tion can be prepared using standard cosmetic or pharma-ceutical gel formulating procedures and equipment. There is no particular, critical order of addition of components, mixing temperatures or the like, provided that a homogene-ous, reasona~ly stable end product is achieved.

SP~CIFI~_D~SCRIP~ION OF THE MOST PREFERR~D EMBODIMENT

The specific, most preferred formulation accord-ing to the present invention has the following composition (parts by weight):

2~ ~8~3 Water 53.7~
A~uasonic ~el 42.50 Glycexin 2.27 Aloe Vera Oil l.lg Triton X-100 0.10 (octoxynol-9) MQ 2525-50~ 0.05 Pragrance ~vanilla extract) 0~15 ~ he invention is further described and illus-trated in the following speci~ic, non limiting examples.

An emulsion formulation according to the inven-tion of semi-~olid, cream-liXe consistency, was made up from the following components (percent by weight).

EDTA Tetrasodium salt 0.05 actoxynol-9 (Triton X-100) 0.02 BTC-2125 0.05 Glycerin 0.05 Methyl Cellulose (~000 cps) 1.0 Siponic C-20 5.0 Water 93.83 The prepara~ion was made by simple mixing of ingredients in a container, at room temperature. It was then tested for its anti-viral effectiveness in vitro against Her~s Hominis types 1 and 2.

Clinical isolates where obtained of Herpes ~Qmini~ type 1 and 2, specifically:

: Type 1 isolates 103, 104, 105, 117 ~ype 2 isolates 109, 106,142 : Virus suspensions were clarified by low speed centrifugation and kep~ frozen at -70 C. Infectivity was titrated and e~pressed in TCID 50/0.1 ml.

~g~3 Equal volumes of virus were added to the tes~
formulation in the concentration given in the following table of results. Thus, the most concentrated emulsion wa~
10% after the virus was added.

The inoculated mixtures were incubated at 22C
for 10 minutes. 10 fold dilutions were then quickly made With chilled medium. Residual infectivity was then deter-mined by using 4 tubes of cell culture per tube dilution.
The results are expressed as TCID 50/0.1 ml. Controls were used consisting of medium without the test formulation.

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After incubation the residual test formulation activity had been reduced to an undetectable level in all the test formulatlons/virus mixtures at concentrations of 10, 5, 2 7 5, 1, 0.5, 0.05% of test formulation, The con-trols consisting of medium contained 3.0 and 4.0 log ten TCI~ 50/0.1 ml. The reductions in the titers of virus after contacting with 10, 5, 2.5, 1, 0.5, 0.05% tes~
formulation were in excess of 2 log 10 TCID~o~

In order to con~irm the experimants, the test formulation/virus mixtures were incubated at 37C ~or 10 minutes and the same inactivity resulted with both types o~
herpes virus.

EXAMPLE 2 - ~OXICITY STU~Y

A cream was fo~mulated having the same ingredi-ents in the same relative proportions as described above in Example 1.

rats were shaved to expose posterior epidermis. The cream was then applied topically to each rat in the exposed area and observed 48 hours. The results are given below:

AT # # APPLICATIONSTO~ICITY

6 4*
: 7 4 : : 8 4 :~ 9 4 ~ ' .

- 10 ~ 8 ~ ~ 3 - Indi~ates no visual sign o~ toxicity present in 48 hr.
period.

* Cream applied at 4 hour intervals for a total of 4 applications.

EX~MPLE ~

A cream formulation according to the specific, most preferred formulation given above was tested for its ef~ectiveness against human hepatitis B in the morphologi-cal alteration test and destruction test.

A human hepatitis B virus (HBV) formulation was prepared having 5.0% bovine calf serum ~40 ~1) with 760 ~1 HBV (Gilbralter Biological Laboratories, Inc., HBV Pool 11, GBL reference no. 018-2~2A-153). Into 25 x 150 mm gla~s tubes was injected 2 ml of the cream formulation and 0.2 ml of the H~V formulation. ~he mixtures were vortexed vigor-ou~ly for one minute. ~he reaction was stopped ~y adding 18 ml o~ Trypticase Soy Broth containing 20% serum, vortex-ing well and placing into ice bath. Virus controls were prepared in the same way by pipetting 0.~ ml HBV into 2.0 ml phosphate buffered saline (PBS). The reaction mixtures were concentrated by ultracentrifugation with appropriate sucrose gradients, the supernatant gently poured off, and the pellets were re-suspended with a 0.5 ml PBS, with similar pellets being combined. ~he HBV particles were purified by late-zonal ultracentri~u~ation in a 60-5%
linear gradient (sucrosa~J and fractionated. Dane particle fractions having a re~ractive index between 1.396 and 1.404 were saved and pcoled.

Positive staining was used to quantitate the number of virions destroyed by the test formulation. This was done with potassium permanganate (2%) and blotting, followed by deionized water and blotting, followed by ' 2~081 ~3 uranyl acetate (1.5%) and ~lotting. Ten fields from 20 randomly selected squares were observed with a Philips transmission electron microscop , and counted at 50,000 magnification~ No virions were detected. By comparison with the controls, it wa~ evident that greater than 40,000 virions had been destroyed in one minute.

Negative staining was used to detect morphologi-cally altered virions. For this, 5% uranyl acetate in water, at pH 3.~, was used, with blotting. ~hirty or more fields from six rando~ly selected squares were observed with a Philips transmission electron microscope, and thoroughly enumerated for each of the four alteration phases AP0, ~Pl, AP2 and AP3. No morphologically intact virions wera observed, only highly morphologically altered, AP~ and AP3 forms, which are non-infectious. In contrast, the control samples evidenced the great majority of virions to be morphologically intact and in the in~ectious (AP0 or APl) pha~es.

The mechanism of action of the composition of the invention is probably membrane disruption.

The cream according to the specifia, most pre-pared formulation according to the invention, was tested ~ for m vitro inactivation of HIV.

: The human T-cell leukemia virus type 1 immortal-ized cell line MT~2 was maintained in growth medium ; : (Dulbecco's Modified Eagle's Medium with 15~ heat-ina¢ti-vated ~etal calf serum, 2 mm glutamine, 100 iu of penicillin per ml and 100 ~g of s~reptomycin per ml).

HIV-1 (IIIB) the prototype laboratory strain, was obtained from the culture supernatant of H9 infected cells - 12 - 2~ 43 and was concentrated to 1,000 x by banding in sucrose.
Filtered viral stocks were aliquoted and stored at -45 C
until used. The virus stock was determined by an end point titration method using MT-~ cells in a 96-well microtiter plate configuration. ~he virus stock contained a TCID 50 virus titer of 5.50 log 10 TCID 50/ml calculated by the Reed-Muench method.

In order to per~orm cytotoxicity studies, MT-2 ~7`~ cells in exprudential growth phase were exposed to various ~ dilutions of~compound~. Af~er 4 days, the cell viability wa~ assessed by the Tryptan-Glu exclusion method and compared to controls without drug.

Virus stocks were thawed and diluted with phos-phate buffered saline to obtain the required amounts of virus necessary for inactivation assay experiments.
Untreated virus served as the TCID 50 control ~or this experiment. After a one minute exposure of HIV-l with the compound, sequential ten-fold dilutions of the treated or untr0ated virus control were prepared in PB5 and each dilution was used to infect MT-2 cells as previously described. Virus expression was monitored by the presence of synoytium ~ormation. HIV-induced syncytiu~ formation was assessed after 6 days of culture using a syncytium-formation assay.

The compound according to the invention yielded a reduction in HIV infectivity of greater than 2.5 log lo TCID 50/ml, when compared with untreated controls after one minute of exposure at room temperature (~3 - 27~C).

E~AMPL~ 5 The effectiveness of the cream according to the specific, most preferred formulation of the invention was asses~ed in association with commercially available surgi-~ .

cal latex glove~.

An operators hands were cov~red with cream according to the formulation described above, applying approximately 2~ cc's to each hand, and then latex surgical glove~ wers appli~d over the hands. In one case, the latex glov~s contained a residue of starch lubricant powder, in conventional form. In another case, the glove contained no powder. The gloves were le~t in place on the users hands ~or 16 hsurs.

Then the gloves were removed, and centrifuged to draw the liquid/semi-solid contents (residual cream, users pexspiration, powder sediment etc.3 into ona fisure of the glsve. Aliquots of this liquid residue were extracted, and subjected to the 1~ it~o inactivation of HIV by the serial dilution technique against the HIV prototype laboratory strain with virus titers using M~-2 cells and ten-fold serial dilutions as described with Example 4.

The residues from the latex gloves without powder and ~rom the latex gloves with powder sediment both showed a log virus titer reduction of greater than 3.0, as did the cream which had been subjected to the latex glove test, thereb~ demonstrating that the composition according to the invention maintains its HIV inactivation properties when mixed with latex gloves for at least 16 hours.

Claims (14)

I CLAIM:

1. A latex barrier item adapted to be fitted over a body part to inhibit viral transmission thereto, said latex barrier item having an outer surface and an inner surface to contact the body part, said inner surface having a layer of semi-solid anti-viral gel or cream comprising an alkyl benzyl quaternary ammonium halide disinfectant in an amount of from about 0.005-0.1% by weight;

a non-ionic or cationic surfactant in an amount of from about 0.01-0.1% by weight;

a non-toxic hypoallergenic water compatible thickener in an amount of from about 1-80% by weight:
and water.

2. The latex barrier item of claim 1 which is a latex surgical glove or a latex condom.

3. The latex barrier item of claim 2 wherein the disinfectant is present in an amount of from about 0.005-0.05% by weight.

4. The latex barrier item of claim 3 wherein the disinfectant is present in an amount of from about 0.005 -0.01% by weight.

5. The latex barrier item of claim 3 wherein the disinfectant is selected from the group consisting of alkyl dimethyl benzyl ammonium chloride in which the alkyl groups are from C12 - C18;

alkyl dimethyl ethylbenzyl ammonium chloride in which the alkyl groups are from C12 - C18;

and mixtures thereof.

6. The latex barrier item of claim 4 wherein the surfactant is present in an amount of from about 0.01 -0.05%.

7. The latex barrier item of claim 6 wherein the surfactant a non-ionic surfactant of the polyoxyethylene-based type.

8. The latex barrier item of claim 7 wherein the surfactant is oxtoxynol-9.

9. The latex barrier item of claim 3 wherein the thickener is aquasonic gel.

10. The latex barrier item of claim 9 wherein the aquasonic gel is present in an amount of from about 30-40%
by weight.

11. The latex barrier item of claim 3 wherein the antiviral gel or cream additionally includes an emollient.

12. The latex barrier item of claim 11 wherein the emollient is glycerine.

13. A semi-solid anti-viral gel or cream composition, for topical application to mammalian skin under a viral barrier item, said composition comprising an alkyl benzyl quaternary ammonium halide disinfectant in an amount of from about 0.005-0.1% by weight;

a non-ionic or cationic surfactant in an amount of from about 0.01-0.1% by weight;

a non-toxic hypoallergenic water compatible thickener in an amount of from about 1-80% by weight:

and water.

14. The composition of claim 13 wherein the disinfec-tant is selected from the group consisting of alkyl dimethyl benzyl ammonium chloride in which the alkyl groups are from C12-C18;

alkyl dimethyl ethylbenzyl ammonium chloride in the alkyl groups are from C12-C18;
and mixtures thereof.