Sexual Lubricants Containing Zinc As an Anti-Viral Agent

Europaisches Patentamt J European Patent Office Qy Publication number: 0 402 078 Office europeen des brevets A2

EUROPEAN PATENT APPLICATION

® Priority: 06.06.89 US 362058 © Applicant: Kelly, Patrick Daniel 33 Berry Oaks @ Date of publication of application: St. Louis, Missouri 63122(US) 12.12.90 Bulletin 90/50 @ Inventor: Kelly, Patrick Daniel @ Designated Contracting States: 33 Berry Oaks AT BE CH DE DK FR GB IT LI LU NL SE St. Louis, Missouri 63122(US)

Sexual lubricants containing zinc as an anti-viral agent.

© This invention relates to the use of zinc as an anti-viral agent in sexual lubricants. A selected zinc compound which has antiviral properties, and which does not irritate the skin or mucous membranes, is provided in a sexual lubricant such as a water- soluble gel. The lubricant is spread on the surface of the penis, or inside the vagina, before sexual intercourse. The zinc can serve as a preventive agent to inhibit the transmission of genital herpes through sexual contact, and may also help to reduce the spread of other sexually transmitted viral diseases such as AIDS. Such lubricants can be used in addition to a condom for maximal protection, or without a condom for a lesser yet still significant level of protection compared to unprotected intercourse. A ^preferred zinc salt which does not cause irritation ^during or after sexual intercourse comprises zinc the salt of acid derivative of 00 gluconate, a carboxylic p*, glucose. Other suitable zinc salts can be prepared ©from carboxylic acid derivatives or other oxidation £^l products of other sugars.

Xerox Copy Centre EP 0 402 078 A2

SEXUAL LUBRICANTS CONTAINING ZINC AS AN ANTI-VIRAL AGENT

This invention is in the fields of biochemistry, 1988; a list of references with complete citations is pharmacology, and anti-viral agents. contained near the end of this application, before There is a major need for methods to prevent the claims). For additional general information on the spread of viral diseases which are transmitted herpes simplex viruses, see, e.g., Mindel 1989. For through sexual contact. The most widespread sex- 5 more information on human immunodeficiency ually transmitted viral disease is genital herpes, an virus and AIDS, see, e.g., Wormser et al 1987. incurable disease usually caused by a virus re- There are several other sexually transmitted ferred to as herpes simplex virus type 2 (HSV-2). viruses that are also medically and epi- Herpes simplex virus type 1 (HSV-1) is usually demiologically important, including hepatitis, papil- associated with cold sores on the mouth and gums; w loma, and Epstein-Barr viruses. In addition to caus- however, HSV-1 has also been isolated from geni- ing their own adverse symptoms, which can be tal lesions while HSV-2 has been isolated from cold severe, all three types of virus have been linked to sores. cancer. Genital herpes, in addition to causing painful The most widely recommended protective lesions, poses a serious health threat. It can cause 75 measures to prevent the spread of herpes, AIDS, or malignant transformation in animal and human other sexually transmitted viruses involve imperme- cells, and has been linked to an increased risk of able barriers to prevent any contact of body fluids cervical and vulvar cancer in women. The virus can with the skin, or with mucous membranes exposed also infect babies during birth, causing neonatal in the mouth, vagina, urethra, etc. "Barrier protec- herpes, which is 80% fatal and can cause severe 20 tion" in the context of sexual intercourse involves health problems or deformation if the baby sur- the use of condoms; other types of barrier devices, vives. including diaphragms and cervical caps, may pro- Herpes lesions on the genitals are also be- tect the uterus, thereby possibly reducing the risk lieved to provide viral entry and exit sites which of infection, but they do not protect the rest of the increase the risk of becoming infected with other 25 vagina, or the penis. viral diseases such as AIDS during intercourse. If Even though many health care professionals someone infected with herpes has intercourse with and other people and the scientific, medical, and someone who has the human immunodeficiency mass media have repeatedly urged all sexually virus (HIV), the person with herpes is more likely active, non-monogamous people to use condoms, than a non-herpetic would be to contract AIDS as a 30 many people at risk either fail or deliberately refuse result. In addition, for people infected with both to follow that advice. In addition, condoms do not herpes and HIV (as is the case with many prosti- offer complete assurance of safety, since they can tutes), herpes lesions can provide exit points for break. Condoms can also tear out pubic hairs, the HIV virus to reach sexual partners in higher thereby creating tiny injuries to the epidermis concentrations during intercourse. Due to both fac- 35 which may serve as entry routes for viruses. tors, any method for preventing the spread of geni- There is, therefore, an urgent need for addi- tal herpes is also likely to help reduce the spread tional methods and agents which can help prevent of AIDS. the spread of sexually transmitted viruses. As used The need for methods for reducing the spread herein, "anti-viral" refers to any agent or method of herpes and AIDS are especially acute in view of 40 that can inhibit the replication or transmission of a the difficulties that have been encountered in trying virus in an exposed or infected person or animal, to develop effective vaccines against either virus. regardless of which stage or step of the viral cycle Despite intensive effort, there has been very little is inhibited (replication within a cell, release from progress toward developing successful vaccines an infected cell, transmission across a membrane against either virus, for several reasons. The capsid 45 or within a body, etc.). particles for both viruses are glycosylated; their Before the AIDS epidemic began, several stud- surfaces are coated by sugar molecules that can ies indicated that zinc ions can inhibit the replica- prevent a host's immune cells from contacting the tion of various different types of virus. Those stud- viral proteins, recognizing them as foreign, and ies include Gordon et al 1975 (herpes virus), generating antibodies which can bind to them, in 50 Bracha et al 1976 (sindbis virus), Firpo et al 1979 addition, both viruses can dwell for long periods in (foot and mouth disease virus), Zaslavsky et al nerve cells that are inaccessible to antibodies. HIV 1979 (vaccinia viruses), and Sharma et al 1985 also mutates very rapidly; the amount of variation (aphthovirus). in a single patient is likely to be enough to render The effects of zinc on rhinoviruses (a class of antibodies ineffective against the virus (see Marx viruses which cause common colds) have also EP 0 402 078 A2 been studied, but the results have been inconsis- ings, to determine how many viable virus particles tent. Korant et al 1976A and 1976B reported that remained in the nasal sinuses after zinc was ap- zinc ions can inhibit the replication of some but not plied to the mouth. If indeed zinc requires direct all rhinoviruses. Eby et al 1984 reported that in a contact with viruses to be effective, then both ap- double-blind test, zinc gluconate tablets, when 5 proaches were apparently too indirect; they are chewed up and allowed to soak in the mouth, analogous to testing an antibiotic ointment against reduced cold symptoms. Eby also obtained US a bacterial infection by applying the ointment sev- patent 4,503,070 (1985) on the use of zinc glu- eral inches away from a skin cut. conate lozenges to treat cold symptoms. That pat- At least five different research teams' have re- ent was followed by US patent 4,684,528 (Godfrey 10 ported that certain salts of zinc, used by some 1 987) on flavor-masked zinc lozenges. researchers in combination with other active agents Those positive reports provoked a series of such as tannic acid or heparin, is effective as a rhinovirus studies which led to negative results, topical agent in treating genital herpes lesions. A including Douglas et al 1987, Farr et al 1987, and team in Missouri led by Dr. Mostafa Fahim re- Geist et al 1987. Some of the factors which contri- 75 ported that guinea pigs and humans (both male buted to the confusing and inconsistent results and female) suffering from genital herpes improved include concentration and chelation, which are dis- substantially when treated by a combination of cussed with a rather disappointing lack of clarity in ultrasound and an ointment (which they gave the Godfrey et al 1988. That exchange of letters makes tradename "Herpigon") containing 30% urea, 3% it clear that the people studying the effects of zinc 20 zinc sulfate, 2% tannic acid, and 65% HEB cream; ions on rhinoviruses are divided on the question of see Fahim et al 1978, Brawner et al 1979, Fahim et whether it works, and those who claim that it works al 1980a, and Fahim et al 1980b. cannot explain why. The most extensive study In Arizona, a team led by Dr. Patrick Tennican done to date, Al-Nakib et al 1987, stated, "We reported that female mice which had been pre- conclude that zinc gluconate lozenges...have a sig- 25 viously inoculated with herpes virus, and female nificant effect on the signs and symptoms of colds humans seeking treatment for genital herpes, im- caused by rhinoviruses, although the mechanism of proved when a collagen sponge containing zinc action remains obscure." sulfate was placed inside the vagina; see Tennican One of the factors that may be contributing to et al 1979 and Tennican et al 1980. the confusion and disagreements over rhinoviruses, 30 In Israel, Dr. Asher Wabha reported that 18 but which did not receive adequate attention in the patients, four of whom had genital herpes, showed exchange of letters in Godfrey et al 1988, is that improvement after being treated with zinc sulfate in some strains of virus may be resistant to inhibition water; see Wahba et al 1980. by zinc, in a manner analogous to the way some In Texas, George Eby and Dr. William Halcomb bacteria are resistant to antibiotics. For example, 35 reported that aqueous solutions of zinc gluconate the inventor has used zinc lozenges roughly twenty accelerated recovery in four human females suffer- times to fight colds, since learning about Eby's ing from herpes; see Eby et al 1 985. patent 4,503,070. In most cases, he found that zinc And in Switzerland, Bohumir Lukas et al dis- was highly effective and either prevented the cold closed that a mixture of zinc sulfate and heparin entirely, or greatly reduced its severity. However, in 40 reduced herpes infections in tissue culture tests one or two specific instances, it seemed to have and in guinea pigs; see US patent 4,465,666, as- little or no effect. signed to Ciba-Geigy. Another factor tha't may have contributed to the There have also been reports that zinc solu- confusion over zinc and rhinoviruses involves the tions help people suffering from non-genital herpes, apparent need for direct contact between the zinc 45 including cold sore lesions in the mouth (see ions and the virus. On a couple of occasions when Wahba et al 1980 and Brody et al 1981) and the inventor chewed zinc gluconate tablets to fight keratitis lesions in the eyes (see DeRoeth et al colds, he ended up with a severe runny nose and 1963). soreness in the lower throat, but with no adverse The work by Lukas et al is a good example of symptoms inside the mouth. Those results suggest 50 the apparent attitude of most medical researchers that the anti-viral action of zinc depends upon toward the use of zinc to combat herpes infections. direct contact of the zinc ions with the viral par- In column 3 of patent 4,465,666, Lukas et al re- ticles. However, several .of the rhinovirus studies ported that zinc sulfate, when mixed with a gel tried to evaluate zinc by applying it in the mouth carrier and applied to guinea pigs three days after and then determining whether it could prevent a 55 the guinea pigs were infected with herpes viruses, cold that was induced by injecting viral particles reduced the number of guinea pigs suffering from into the nose via nasal sprays. In addition, some of observable symptoms. As described by Lukas, the assays for effectiveness involved nasal wash- about 50% of the animals treated with the gel alone EP 0 402 078 A2 were free of herpes symptoms, but if zinc was vigorously rubbed in for prolonged periods of time, added to the gel, then about 70% of the animals yet which is also effective as an anti-viral agent. were free of symptoms. However, Lukas et al criti- This invention relates to the use of zinc as an cized that result and pointed out the additional anti-viral agent in sexual lubricants. A selected zinc improvement that could be obtained by adding 5 compound which has anti-vira! properties, but both zinc and heparin to the gel. When both com- which does not irritate the skin or mucous mem- pounds were used, more than 90% of the animals branes, is provided in a sexual lubricant such as a were free of symptoms. water-soluble gel. The lubricant is spread on the That result indicates that heparin, when used surface of the penis, or inside the vagina, before jointly with zinc, provides a more effective treat- io intercourse. The zinc can serve as a preventive ment than zinc alone for animals that were pre- agent to inhibit the transmission of genital herpes viously infected with herpes. However, heparin is a through sexual contact, and may also help to re- powerful anti-coagulant; it prevents the blood from duce the spread of other sexually transmitted viral clotting normally. Therefore, even though it might diseases such as AIDS, hepatitis, and papilloma be used safely under the supervision of a physician 75 viruses. Such lubricants can be used in addition to for several days (the typical duration of a herpes a condom for maximal protection, or without a flare-up that is properly treated), it would be highly condom for a lesser yet still significant level of inadvisable to administer heparin to anyone on a protection compared to unprotected intercourse. A frequent basis (such as every night for weeks or preferred zinc salt which does not cause irritation months), or to sell it for use as an over-the-counter 20 during or after sexual intercourse comprises zinc non-prescription drug. It is clear, therefore, that the gluconate, the salt of a carboxylic acid derivative of inventors of patent 4,465,666 did not anticipate the glucose. Other suitable zinc salts can be prepared potential of zinc, without heparin, in a form that can from carboxylic acid derivatives or other oxidation be used frequently to provide an anti-viral protec- products of other sugars. tive agent for people who are not yet infected by 25 In one preferred embodiment of this invention, herpes. a selected zinc compound which has anti-viral All of the reports cited above which involve properties is added to a sexual lubricant. The lubri- herpes involve the use of zinc compounds to treat cant is then spread on the surface of the penis, or herpes lesions, or to prevent the occurrence of inside and around the vagina, before sexual inter- active outbreaks, in animals or people who are 30 course. It can be used in addition to a condom or already infected with herpes virus. To the best of other barrier device for maximal protection, or with- the Applicant's knowledge, no one has ever pub- out a condom for a lesser yet still significant level licly suggested the use of zinc as a preventive of increased protection compared to unprotected agent to inhibit the transmission of herpes to some- intercourse. one who is not already infected. 35 As used herein, the term "sexual lubricant" In a patent application filed under the Patent refers to any gel, emulsion, lotion, ointment, or Cooperation Treaty, number WO 8702246, William other fluidized substance which is spread on the Sergio of Florida suggested that the risk of infec- sexual organs of the male or female before or tion with AIDS might be reduced by topical admin- during intercourse. istration of compounds which generate anions hav- 40 One water-soluble gel which is widely used as ing charges greater than one. Sergio's reference to a sexual lubricant is sold over-the- counter by anions appears to be mistaken, since an anion is a Johnson and Johnson (New Brunswick, NJ) under negatively charged ion, while zinc is released from the tradename "K-Y Lubricating Jelly." It contains a zinc salt as a cation (positively charged). Sergio purified water, glycerine as a lubricant, hydrox- states that his preferred salts are zinc 45 yethylcellulose as the thickening agent, glucono- phosphonoformate and/or zinc tungstate. However, delta-lactate to prevent crystallization, chlorhexidine it is likely that the use of either of those com- gluconate as a preservative, and sodium hydroxide pounds as a sexual lubricant would cause severe to reduce the acidity. A generic version which irritation to the mucous membranes and perhaps to appears to have the same ingredients is sold by the epidermis as well, and might also cause var- so Walgreens. A modified form of KY Lubricating Jelly ious other adverse effects. His suggestion concern- sold by Johnson and Johnson contains propylene ing zinc tungstate appears to be based on the glycol residuals, which are a by-product of pro- tungsten-containing compound HPA-23, which, as pylene oxide, a sterilizing agent. Sergio concedes elsewhere, has "serious side ef- Various other water-soluble gels can also be fects" (Sergio 1988). 55 used. For example, several other derivatives of There remains, therefore, a need for a sexual cellulose, such as methylcellulose or ethylcellulose, lubricant which is non-toxic and non-irritating to can be added to water to form a gel which is highly sensitive mucous membranes even when viscous (slow-flowing) and hydrophilic (water-solu- EP 0 402 078 A2 ble). Other derivatives of cellulose, such as Second, any zinc salt used as described herein carboxymethyl-cellulose or microcrystalline cellu- must be non-irritating to the genital skin and to the lose, may also be suitable, as can be determined mucous membranes inside the vagina. This can be through routine experimentation as described be- determined using a sequence of tests involving • low. 5 volunteers, who preferably should have some un- For most people, hydrophobic substances (i.e., derstanding of the process, such as medical stu- substances which are not soluble in water) are not dents, hospital interns, nurses, graduate students in preferred as sexual lubricants, since they cannot biology or chemistry, and their spouses. A pre- be washed off easily, and because some of them ferred sequence of tests is as follows. (such as petrolatum) can damage some types of 10 In the first test, a selected zinc salt is first condoms. However, it was stated in Shilts 1987 that tested on the relatively hairless portion of the fore- a certain vegetable shortening (sold under the arm, using a mortar and pestle to grind the zinc trademark Crisco, by Proctor and Gamble, Cin- salt into a fine powder, then using distilled and cinnati, Ohio) is used as a sexual lubricant by deionized water to dissolve or suspend the salt in some male homosexuals who engage in frequent 75 solution and spread it evenly across a patch of anal intercourse, presumably because it does not skin. If the zinc salt does not cause irritation after rub off easily and remains in place longer, offering being left in place for an hour or more, the second prolonged lubrication. Accordingly, it may be possi- test involves spreading it upon the male genitals. ble to use hydrophobic substances for the purpose The first test on the male genitals should involve a of this invention, as a carrier for zinc ions. How- 20 passive test; the zinc compound is applied gently ever, any such hydrophobic substance should be and allowed to remain, without rubbing it in, for a tested in vivo to ensure that it does not sequester period such as an hour. If it causes no irritation in the zinc ions in microdroplets or otherwise render it that test, the third test involves mixing the zinc salt ineffective as an anti-viral agent. with a lubricant such as a gel, applying it to the Various ointment and lotion formulations are 25 male genitals, and rubbing it in for several minutes known to those skilled in the art; several are de- in a manner that simulates the rubbing motion of scribed in detail in the US. Pharmacopeia and in intercourse. If it causes no irritation in that test, it various texts on cosmetics. In addition, various can be applied gently (dissolved in either water or emulsions (viscous mixtures of hydrophobic and gel) to a female volunteer, to the mucous mem- hydrophilic substances, usually in the form of mi- 30 branes that are near the opening of the vaginal croscopic droplets of one liquid suspended in the canal which can be reached without deep penetra- other liquid) are also known to those skilled in the tion. The woman should have a douche readily art; see, e.g., Lieberman et al 1988, Becher et al available before the test begins, to rinse out the 1965, and Robinson et al 1987. Such ointments, substance if it begins to cause irritation. If the zinc lotions, and emulsions can be used to carry zinc 35 compound causes no irritation in that type of test, it for the purpose of this invention, if no significant can be applied to the deeper areas in the vagina, quantities of compounds which chelate the zinc are preferably using a finger during the first such test present. However, ointments and lotions which con- to apply it and to rub it in gently. If no irritation tain alcohols or other substances which irritate the results, it can be tested during actual intercourse. genitals, and emulsions contain emulsifying agents 40 During the first test involving intercourse, the zinc which irritate the genitals, should be avoided. compound preferably should be applied and tested If desired, compounds such as preservatives, only after a first act of coitus has been completed, coloring agents, and fragrances can be added to so that if irritation does result, the rest of the the sexual lubricants described herein, provided evening won't be ruined and the partners won't be that (1) they do not chelate the zinc ions or other- 45 left in a state of sexual frustration, which exag- wise interfere with the anti-viral activity of the se- gerates any feelings of sexual irritation. lected zinc compound, and (2) they do not irritate People vary in their skin sensitivity; for exam- or have other adverse effects on the genitals. ple, some people are easily sunburned while others Zinc salts which are suitable for use as de- are highly tolerant of direct sunlight. Therefore, as scribed herein must have two characteristics. First, so used herein, references to "non-irritating" zinc salts they must have a substantial degree of anti-viral or formulations refer to salts or formulations that do activity. Such activity can be initially tested using not cause irritation in at least some people. Such in vitro assays, as described below, and can be formulations can be used by such people regard- confirmed with respect to specific formulations less of whether they may cause irritation in other (such as a specific zinc salt in a hydrophilic gel, 55 people with more sensitive skin or membranes. hydrophobic cream, emulsion, etc.) using animal A preferred zinc compound for use as de- tests involving mice or guinea pigs, which are scribed herein comprises zinc gluconate, which highly susceptible to herpes. was purchased from a commercial supplier and EP 0 402 078 A2 10 tested using the series of tests described above. It than zinc gluconate, and which is tested and shown did not cause any significant irritation during inter- to be non-irritating during intercourse, is especially course using K-Y Lubricating Jelly as the carrier preferred, since it will release more zinc ions than substance. Zinc gluconate is a physiologically ac- zinc gluconate. ceptable salt of zinc, which is in turn an essential 5 Zinc compounds which display low but signifi- mineral. Zinc gluconate tablets (23 mg) are sold cant and adverse levels of irritation when mixed over the counter as mineral supplements at Walg- with an aqueous gel can be tested to determine reens and other drug stores. It should also be whether the irritation can be lowered to acceptable noted that zinc is an essential mineral and is re- levels, using two different method. The first method quired for proper functioning of the immune system io involves lowering the concentration of the zinc (see, e.g., Bach 1981). Therefore, if zinc as used compound in the aqueous solution. The second herein permeates through the skin or vaginal mem- method involves the use of other carrier sub- branes into the bloodstream, it may have an addi- stances such as ointments and emulsions, many of tional beneficial effect of helping the immune sys- which are specifically formulated to mask the irritat- tem function properly, especially in people who 75 ing effects of certain active ingredients in various suffer from low levels of zinc (see Weiner 1984). formulations. For example, many cosmetic formula- By contrast, zinc chloride caused a high level tions, shampoos, and other topical mixtures contain of irritation in the forearm test, and was not tested various types of alcohol or detergent which would further. Zinc sulfate did not cause any irritation in severely irritate the skin if applied in concentrated the forearm or male genital tests, but it caused 20 form, but which are quite acceptable if present in substantial irritation when applied to the shallow low quantities in creams or ointments that contain areas of a vagina and was not tested during inter- other ingredients designed to soothe the skin. course. All three salts were tested at relatively high Any zinc salt or other zinc compound can be concentrations, to provide a cautious appraisal; if tested for anti-viral activity using in vitro tests. In zinc gluconate caused no irritation at a relatively 25 vitro tests involve cell cultures rather than intact high concentration, then it should not cause irrita- animals; see, e.g., Gordon et al 1975. If an in vitro tion at lower concentrations. assay involves anchorage-dependent cells (such as Zinc oxide was also tested and confirmed to be fibroblasts or other skin cells), the typical steps non-irritating in the vagina during intercourse. Zinc involve (1) growing a layer of cells on a solid or oxide is the main active ingredient in Desitin oint- 30 semi-solid nutrient such as agar, to form a "lawn" ment, which is spread on babies bottoms and geni- of cells across the surface of the culture plate; (2) tals to cure diaper rash, so it was expected to be spreading a liquid solution containing viral particles non-irritating. However, unlike zinc gluconate and (such as herpes simplex type I or II) across the zinc sulfate, the Applicant is not .aware of any layer of cells; (3) incubating the cells and viruses published reports indicating that zinc oxide has 35 for an appropriate period ot time, and (4) determin- anti-viral properties. Its anti-viral activity can be ing how many clusters of cells were killed by the determined through routine experimentation as de- viruses, as evidenced by rounded zones scribed below, and if zinc oxide is shown to have ("plaques") that have been cleared of viable cells. anti-viral properties, it will be suitable for use ac- The result of such a test is usually expressed in cording to this invention. 40 terms of "plaque-forming" viruses per volume of Various other salts of zinc, particularly organic solution. If a certain zinc compound reduces the salts formed by combining zinc with various or- number of plaques (i.e., if it allows more cells to ganic molecules having carboxylic acid groups, are survive), then that compound has in' vitro anti-viral preferred candidates for evaluation to determine activity. whether they are both non-irritating and anti-virally 45 In vitro assays involving cells that are not effective. Zinc gluconate is the salt that results anchorage-dependent (such as white blood cells) from combining one molecule of zinc (which is are done in an analogous manner, using liquid divalent) with two molecules of gluconic acid nutrients and viral "titers" (i.e., solutions with vary- (C5HS(OH)6COOH), which is an oxidation product ing concentrations of viruses). Instead of measuring of glucose, a sugar molecule with six carbon so immobile plaques, the viable cells that remain in atoms. Zinc salts formed by combining zinc with the solution after the viral challenge can be mea- carboxylic acid derivatives or other oxidation pro- sured. Most titer assays, rather than counting the ducts of various other carbohydrates (such as other number of viable cells that remain in a test tube at sugar molecules with more than about four or five the end of the challenge, are designed to deter- carbon atoms) are therefore preferred candidates 55 mine the concentration of viruses which effectively for testing to evaluate their suitability for use as wipe out a cell culture. If a specific zinc compound described herein. Any such molecule which has a allows a cell culture to withstand a concentration of higher dissociation constant at physiological pH viruses higher than the cells can withstand without 11 EP 0 402 078 A2 12 the zinc compound, then the compound has in ever, genetically engineered animals such as mice vitro anti-viral activity. have been developed which carry human-derived Some viruses infect only certain types of cells; T-cells, to enable researchers to perform tests in- in general, herpes viruses infect anchorage-depen- volving the HIV virus on those animals. The tests dent cells such as skin cells and nerve cells, while 5 described herein can be performed on any animal the AIDS virus infects only certain types of blood species or strain which is susceptible to a specific cells. Therefore, a suitable combination of cells and type of sexually transmitted virus being tested. viruses must be used in any specific test. Alternately, it is possible to determine anti-viral For the purposes of this invention, a zinc com- effects in tests involving humans who are already pound is regarded as having in vitro anti-viral w infected by a certain type of sexually transmitted activity if it significantly inhibits one or more types virus. Such tests would involve contacting the geni- of sexually transmitted virus. It is not necessary for tals with zinc-containing lubricant for a desired pe- a zinc compound to inhibit all types of sexually riod of time, such as ten or twenty minutes, prefer- transmitted viruses in order to be useful as de- ably while massaging the lubricant into the genita- scribed herein to help reduce the spread of that 75 lia, to simulate the motions of intercourse. Subse- type of virus. Similarly, a sexual lubricant contain- quently, genital tissue or sexual fluids are sampled ing zinc is regarded as having anti-viral activity if it to determine whether the number of infective viral inhibits the replication, recurrence, or transmission • particles is reduced compared to untreated control of one or more types of sexually transmitted virus subjects. Alternately, in the case of herpes, the in in vivo tests. Even if an anti-viral sexual lubri- 20 treatment can be performed on people suffering cant directly inhibits only one type of herpes virus, from active outbreaks of lesions, preferably during it is still useful in two different respects. First, it can the "rising red" phase of the outbreak. The sub- directly inhibit the spread of that particular virus. jects are monitored after the treatment to deter- And second, it can indirectly help reduce the mine whether the lesions caused less pain, disap- spread of AIDS, by reducing, in a large population 25 peared more rapidly, and recurred less frequently of people at risk, the number of people who suffer compared to untreated control groups. If a specific from herpes lesions. Such lesions serve as entry or formulation containing a zinc compound and a sex- exit ports for the AIDS virus during intercourse and ual lubricant is shown to be effective in reducing therefore increase the spread of AIDS among peo- the severity, duration, or recurrence of herpes out- ple exposed to the AIDS virus. 30 breaks, then that formulation has in vivo anti-viral Any zinc compound that has been shown to be activity. Even though it will not offer completely anti-virally effective in in vitro assays, and which reliable protection against becoming infected, it can causes low levels of skin and mucous membrane reduce the number of people who contract sexually irritation in tests as described above, is a good transmitted viral diseases after sexual intercourse candidate for screening using in vivo tests on lab 35 with infected people. animals after it is mixed with a sexual lubricant as Anyone buying such a lubricant should be described herein. Alternately, several zinc com- clearly warned that the lubricant does not offer pounds (including zinc gluconate) have been completely effective and reliable protection against shown to provide substantial relief to people suffer- infection. Nevertheless, in the absence of effective ing from herpes infections. Those compounds have 40 vaccines or cures for herpes or AIDS, most rational been shown to have anti-viral activity when mixed people who are sexually active and non-monogam- with aqueous solutions, and they can be used as ous would prefer to take the precaution of using a described herein in aqueous lubricants such as lubricant shown to have anti-viral activity. gels. However, before being mixed with any hy- In an alternate preferred embodiment of this drophobic carrier or emulsion, they should be test- 45 invention, zinc can be included in a sexual lubricant ed for anti-viral activity in that particular carrier which also contains one or more other active substance, using lab animals. agents. For example, US patent 4,507,281 Animal tests involving infection through the (invented by Asculai and Rapp, assigned to Exovir, genitals (to simulate sexual transmission) are nor- Inc. of Great Neck, New York) described a corn- mally done by inserting cell-free viral solutions, or so position for treating herpes infections, containing infected cells containing viruses, into the vaginas of interferon and "an anti-viral surface active agent" female animals or into the urethral mucosa of male such as nonoxynol. As further described in Asculai animals. Tests involving herpes virus are com- et al 1978 and in US patents 4,020,183 and monly done on mice and guinea pigs; see, e.g., 4,139,630 (both by Asculai et al), non-ionic surface Tennican et al 1980. Tests involving the AIDS virus 55 active agents with ether or amide linkages between (HIV) are presently done mostly on monkeys and the hydrophilic and hydrophobic portions of the apes (see, e.g., Miller et al 1989), since most other molecule rapidly reduce the infectivity of herpes animals are not susceptible to HIV infection. How- simplex viruses. Nonoxynol is sold without a pre- 13 EP 0 402 078 A2 14 scription, for use during intercourse as a sper- EXAMPLE 2: ZINC SULFATE micidal contraceptive; it causes low levels of genital irritation in most people. It can be used in Zinc sulfate in crystalline form was purchased combination with zinc ions as described herein, to from Sigma Chemical Company (St. Louis, Mis- provide a doubly effective anti-viral sexual lubri- 5 souri). One gram was ground into a fine powder cant. using a mortar and pestle, then 15 ml of K-Y Jelly Similarly, an ointment sold in the United States was added and the two were thoroughly mixed. under the generic name "Triple Antibiotic" contains Although the mixture did not cause any irritation to polymyxin, bacitracin, and neomycin. Other oint- the male's forearm or genitals, it caused a substan- ments, which often require a prescription for pur- io tial level of irritation when applied in a passive test chase, contain beta-lactam antibiotics such as peni- to the female's mucous membranes. Therefore, it cillin or ampicillin. Sexual lubricants which contain was not tested during intercourse. an anti-viral zinc compound and one or more such bacteriocidal compounds can inhibit the spread of viral diseases as well as non-viral diseases such as 75 EXAMPLE 3: ZINC CHLORIDE gonorrhea and syphilis. Those skilled in the art will recognize", or may Zinc chloride in crystalline form was purchased ascertain using routine experimentation, various from Sigma Chemical Company (St. Louis, Mis- equivalents to the specific embodiments of the souri). One gram was ground into a fine powder invention described herein. Such equivalents are 20 using a mortar and pestle, then dissolved in water within the scope of the invention, which is limited and applied to the forearm of the male. It caused a solely by the claims below. burning sensation within a few minutes, and was not tested further.

EXAMPLES 25 EXAMPLE 4: ZINC OXIDE

EXAMPLE 1: ZINC GLUCONATE Zinc oxide ointment (Walgreens Pharmaceuti- cal Laboratories, Chicago, IL) was tested in a geni- Zinc gluconate was purchased from Ruger 30 tal irritation experiment. Zinc oxide was selected Chemical Company (Irvington, New Jersey). It because it is known to cause little or no irritation. came in the form of a white powder interspersed An ointment sold under the trade name "Desitin" with small hard granules. To remove the abrasive (Pfizer, Inc., New York City), which contains 40% granules, it was ground into a fine powder using a zinc oxide, has been spread on the buttocks and mortar and pestle for several minutes when dry 35 bottoms of babies for years, to control diaper rash and again after the gel was added. Approximately and other skin irritations. Desitin also contains cod odor that 0.5 gram of zinc gluconate was used with about 15 liver oil, which gives it a rather strong fish milliliters of K-Y LUbricating Jelly. Although the renders it undesirable as a sexual lubricant (except mixture displayed a very slight roughness when possibly for cats). It is also too viscous to make a rubbed hard between the forefinger and thumb, no 40 suitable sexual lubricant. abrasion was noticeable by either partner during Other zinc oxide ointments have also been intercourse. used on the skin for years; such ointments are The two volunteers were a male in his 30's and often spread on the nose to prevent sunburn. One his wife, both of whom are monogamous and free such ointment, sold at Walgreen's (Walgreen Lab- in of any symptoms of genital herpes. The male test- 45 oratories, Chicago, IL), contains 20% zinc oxide ed the mixture of zinc gluconate and K-Y Jelly on an ointment base of white wax, petrolatum, and his forearm first, then on his genitals, using water mineral oil. first and then K-Y Jelly in both locations. They then In skin irritation tests using 20% zinc oxide tested the mixture on the mucous membranes of ointment, preliminary tests on the forearm or other her vagina by spreading it on the membranes that so non-sensitive areas were deemed unnecessary. are close to the outlet of the vaginal canal, in a The male mixed approximately equal portions of passive test. It caused no irritation, so it was tested 20% zinc oxide ointment (Walgreens) with K-Y during intercourse. Both people wiped off the ex- Jelly to reduce the viscosity of the zinc ointment. cess with a tissue after intercourse, but neither He tested it on himself first to ensure that it didn't showered or made any effort to wash off the lubri- 55 cause any irritation, then he and his wife used it as cant until the following day. The mixture caused no a sexual lubricant during intercourse. Other than significant irritation to either person. being a bit sticky and viscous, it did not cause any significant irritation to either person.

8 15 EP 0 402 078 A2 16

REFERENCES Godfrey, J.C., et al, Letters to the Editor, An- timicrobial Agents and Chemotherapy 32: 605- Al-Nakib, W., et al, "Prophylaxis and treatment 609(1988) of rhinovirus colds with zinc gluconate lozenges," J Gordon, Y.J., et al, "Irreversible inhibition of herpes Antimicrob. Chemother. 20: 893-901 (1987) 5 simplex virus replication in BSC-1 cells by zinc Asculai, S.S., et al, Antimicrob. Agents ions," Antimicrob. Agents Chemother. 8: 377-380 Chemother. 73:686(1978) (1975) Bach, J.-F., "The multi-faceted zinc dependency of Korant, B.D. and B.E. Butterworth, "Inhibition by the immune system," Immunology Today, pp. 225 zinc of rhinovirus protein cleavage: interaction of et seq., November 1981 10 zinc with capsid polypeptides," J. Virol. 18: 298- Becher, P., Emulsions: Theory and Practice, 2nd 306(1976) ed., Amer. Chem. Soc. Monograph #162 (Reinhold Korant, B.D., et al, "Zinc ions inhibit replication of Publ., New York, 1965) rhinoviruses," Nature 248: 588-590 (1976) Bracha, M. and M.J. Schlesinger, "Inhibition of Lieberman, H.A, et al, eds., Pharmaceutical Dos- Sindbis virus replication by zinc ions," Virology 72: 75 age Forms: Disperse Systems (Marcel Dekker, 272-277 (1976) New York, 1988) ' Brawner, T.A., et al, "A Combined Chemical-Phys- Marx, J., "The AIDS Virus Can Take On Many ical Treatment for Herpes Simplex Lesions in Guin- Guises," Science 241: 1039-1040 (26 August ea Pigs," Arch. Dermatol. Res. 265: 71-77 (1979) 1988) Brody, I., "Topical treatment of recurrent herpes 20 Miller, C.J., et al, "An SIV Model for the Heterosex- simplex ... zinc sulphate solution," Brit. J. Der- ual Transmission of AIDS," 1989 AAAS Annual matol. 104: 191-194 (1981) Meeting Abstracts p. 47 (Amer. Assn for the Adv. Douglas, R.M., et al, "Failure of effervescent zinc of Science; 1989) acetate lozenges to alter the course of upper res- Mindel, A., Herpes Simplex Virus (Springer Ver- piratory tract infections in Australian adults," An- 25 lager, New York, 1989). timicrob. Agents Chemother. 31: 1263-1265 Robinson, J.R. and Lee, V.H., eds., Controlled (1987) Drug Delivery (Marcel Dekker, New York, 1987) Eby, G.A., et al, "Reduction in duration of common Sergio, W., "Zinc Salts that may be Effective colds by zinc gluconate lozenges in a double-blind Against the AIDS Virus HIV," Medical Hypotheses study," Antimicrob. Agents Chemother. 25: 20-24 30 26(4): 251-253 (1988) (1984) Sharma, R., et al, "Antiviral effect of zinc ions on Eby, G.A., and W.W. Halcomb, "Use of topical zinc aphthovirus in BHK-21 cell line," Acta Virol. 29: to prevent recurrent herpes simplex infection: re- 517 (1985) view of literature and suggested protocols," Medi- Shilts, R., And The Band Played On, St. Martin's cal Hypotheses 17: 157-165 (1985) 35 Press, New York, 1987 Fahim, M., et al, "New Treatment for Herpes Sim- Tennican, P.O., et al, "The Diverse Effects of Topi- plex Virus Type 2 [Ultrasound and Zinc, Urea, and cal and Systemic Administration of Zinc on the Tannic Acid Ointment] Part 1-Male Patients," J. Virulence of Herpes Simplex Genitalis," Life Sci- Medicine 9(3): 245-264 (1978) ences 24: 1877-1884 (1979). Also see Hospital Fahim, M., et al, "New Treatment for Herpes Sim- 40 Practice, January 1979, pp. 44-53. plex Virus Type 2. Part 2--Female Patients," J. Tennican, P., et al, "Topical Zinc in the Treatment Medicine 11(2&3): 143-167 (1980) of Mice Infected Intravaginally with Herpes Fahim, M.S. and Brawner, T.A, Treatment of Geni- Genitalis Virus," Proc. Soc. Exp. Biol. Med 164: tal Herpes Simplex Virus in Male Patients," Arch. 593-597 (1980) Androiogy4: 79-85 (1980) 45 Wahba, A, "Topical Application of Zinc Solutions: A Farr, B.M., et al, Two randomized controlled trials New Treatment for Herpes Simplex Infections of of zinc gluconate lozenge therapy of experimentally the Skin?" Acta Derm. Venerol. (Stockholm) 60: induced rhinovirus colds," Antinicrob. Agents 175-177(1980) Chemother. 31: 1183-1187 (1987) Weiner, R.G., "AIDS and Zinc Deficiency," J. Firpo, E.J., and E.L Palma, "Inhibition of foot and so Amer. Med. Assn 252: 1 409-1 41 0 (1 984) mouth disease virus and procapsid synthesis by Wormser, G., ed., AIDS and Other Manifestations zinc ions," Arch. Virol. 61: 175-181 (1979) of HIV Infection, Noyes Publications, Park Ridge, Fridlender, B., et al, "Selective inhibition of herpes NJ, 1987 simplex virus type 1 DNA polymerase by zinc Zaslavsky, V., "Inhibition of vaccinia virus growth ions," Virology 84: 551-554 (1978) 55 by zinc ions: effects on early RNA and thymidine Geist F.C., et al, "In vitro activity of zinc salts kinase synthesis," J. Virology 29: 405-408 (1979) against human rhinoviruses," Antimicrob. Agents Chemother. 31: 622-624 (1987) 17 EP 0 402 078 A2 18

Claims

1 . A sexual lubricant which comprises a water- soluble or a hydrophobic carrier substance and a zinc compound effective as an anti-viral agent 5 against herpes simplex virus, and which is non- irritating during sexual intercourse. 2. A lubricant according to Claim 1 wherein the zinc compound is mixed with a hydrophilic gel. 3. A lubricant according to Claim 2 wherein the 10 hydrophilic gel comprises a cellulose derivative mixed with water. 4. A lubricant according to Claim 1, wherein the hydrophobic substance comprises vegetable shortening. 15 5. A lubricant according to Claim 1 , wherein the hydrophobic substance consists of water-soluble droplets mixed with a hydrophobic carrier. 6. A lubricant according to any one of the preceding Claims wherein the zinc compound com- 20 prises a zinc salt formed of zinc and a carboxylic acid derivative of a carbohydrate. 7. A lubricant according to Claim 6 wherein the carbohydrate comprises a sugar having at least five carbon atoms. 25 8. A lubricant according to Claim 7 wherein the zinc compound comprises zinc gluconate.