WO1999018800A1 - Methods and kits for removing, treating or preventing lice - Google Patents

Abstract

Methods and kits for removing, treating or preventing head lice infestations in patients in need of such treatment are disclosed and include topically applying to the lice-infested are an effective amount of a pediculostatic agent for a time sufficient to immobilize the lice, so that they exhibit the immersion reflex, followed by combing to remove the lice and nits. The method optionally includes application of a pediculocide with the pediculostatic agent.

Description

METHODS AND KITS FOR REMOVING, TREATING OR PREVENTING LICE

5 This application is a continuation-in-part of provisional application Serial No. 60/062,024, filed October 10, 1997; a continuation-in-part of provisional application Serial No. 60/074,681, filed February 13, 1998 and a continuation-in-part of provisional

₁₀ application Serial No. 60/079,576, filed March 26, 1998, each of which is incorporated herein in its entirety by reference. Benefit to each of these application is claimed under 35 USC § 119(e) .

₁₅ 1. FIELD OF THE INVENTION

The present invention relates to methods and kits for the treatment, removal or prevention of pedicular parasite infestations. More particularly, the methods and kits relate to the use of agents which rapidly immobilize __n head lice to facilitate their removal from the hair and scalp.

2. DESCRIPTION OF THE PRIOR ART

Pediculosis is a scalp infection which is produced by Pediculus humanus capi tis . Cases of pediculosis are quite frequent both in their endemic and epidemic forms. As the lice feed on human skin and blood, they inject their digestive juices and fecal material into the skin. These materials, as well as the puncture wound itself, __n cause skin irritation and lesions from the resulting scratching, and can cause a serious infection with ganglionic inflammation. Lice are also vectors of certain disease states such as exanthematic or epidemic thyphus and recurrent fever. The adult female louse has a life span of about one month and lays up to ten nits a day which are firmly attached to hair through an excreted cement . The nits hatch to release instars in about seven to nine days, and the instars become mature adults in another week. To cure someone of head lice requires a solution which eliminates all 3 stages of the louse life cycle.

Currently utilized treatment methods are based on the application of pediculicides, which are pharmaceutical agents that kill lice. A significant disadvantage of using these agents is that lice can become resistant . The need for further treatment increases the exposure to these harsh agents and increases the cost. Moreover, many of these compounds have unpleasant odors or other undesirable properties, causing noncompliance with the treatment by the patient, leading to re-infestation of the individual, and spreading of the infestation to others. In addition, the harshness of these agents make them unsuitable for use as prophylactics.

Home remedies such as application of corn oil, olive oil, eucalyptus oil, neem oil, coconut oil, mayonnaise, or petroleum jelly for a period of time sufficient to kill the lice (e.g. overnight) are not practical or completely effective.

A disadvantage of prior methods is the requirement of removing the nits from the hair in a separate treatment step. The removal of nits has typically been done by hand using special fine-tooth combs. Patent No. 4,927,813 teaches compositions containing formic acid which facilitate removal of nits from the hair; however, formic acid is a known caustic agent .

Use of combing alone to treat head lice has the disadvantage that the lice can hold onto the hair shafts using their claws or escape by crawling away from the area being combed. This labor intensive method requires daily combing, is painful, and is unpleasant since the lice are active, visible and crawling.

3. SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide methods and kits for the treatment or removal of lice infestations using agents which are effective even against lice resistant to other treatments. Another object of the invention is to provide methods and kits for the treatment or removal of lice infestations which are rapid, convenient, inexpensive, and cosmetically attractive.

Still another object is to provide methods and kits which can eradicate nits as well as adults and instars. Yet another object is to provide methods which can be repeated as needed as a prophylactic for persons at risk of initial lice infection or re-infection.

These and other objects are furnished by the present invention, which in one aspect provides a method for the treatment or removal of lice and/or nits, particularly head lice and/or nits, in animal subjects. According to the method, an effective amount of a pediculostatic agent is applied to a lice-infested area of an animal subject, preferably a human subject, for a time sufficient to trigger an immersion reflex in the lice, and removing the lice and/or nits, preferably while the pediculostatic agent remains on the infested area. To avoid dilution of the pediculostatic agent, the agent is preferably applied to the dry hair of the lice-infested area, typically in an amount sufficient to completely soak or saturate the hair and skin.

A pediculostatic agent is one that elicits the "immersion reflex" in lice whereby they become immobilized due to strategics to avoid suffocation. The lice remain immobilized while in contact with the pediculostatic agent. In a preferred embodiment of the method of the present invention, the pediculostatic agent induces the immersion reflex within about 2 hours, preferably within about 5 minutes and most preferably within about 6 seconds. In the preferred method, the lice are removed using a fine-toothed delousing comb. In the most preferred method, both the lice and nits are removed using the delousing comb. In an alternative embodiment of the invention which is particularly effective for removing the nits of lice, the lice-infested area is pre-treated with the pediculostatic agent prior to treatment and removal. According to this alternative embodiment, a pediculostatic agent is applied to the dry hair of a lice-infested area of an animal subject, preferably a human subject, for a period approximately 4-12 hours, or even longer. During this time, a substantial number of the lice may suffocate and die. For convenience, the pediculostatic agent can be applied overnight, being kept on the hair with the aid of a shower cap or other non- absorbent covering. Following this pre-treatment, an additional amount of the pediculostatic agent is applied to the lice-infested area for a period of time sufficient to trigger the immersion reflex in the lice, and the lice and/or nits are removed, preferably by combing with a fine-toothed delousing comb while the pediculostatic agent remains on the infected area.

Pediculostatic agents useful in the kits and methods of the present invention are water-soluble compounds or compositions, or aqueous-based compositions, that are capable of triggering an immersion reflex in lice. The compositions can be any of a variety of forms common in the pharmaceutical arts for topical application to animals, including solutions, lotions, sprays, creams, ointments, salves, gels, etc. Preferred pediculostatic agents are those that are viscous enough to remain on the - treated area, those that do not readily evaporate and/or those that are easily removed by rinsing with water, optionally with the aid of soaps, Cleansers and/or shampoos .

In one embodiment, the pediculostatic agent is a surfactant or an aqueous-based composition comprising a surfactant. Non-limiting examples of suitable surfactants include anionic agents, cationic agents, amphoteric agents, zwitterionic agents, nonionic agents and mixtures thereof. Non-limiting examples of such agents include sodium lauryl sulfate, sorbitan tristearate, sorbitan monostearate, sorbitan monopalmitate, and butylene glycol distearate. A preferred aqueous-based surfactant pediculostatic agent is l-30wt% sodium lauryl sulfate.

In another embodiment, the pediculostatic agent is a polar organic compound or an aqueous-based composition comprising a polar organic compound. Non-limiting examples of suitable polar organic compounds, which are typically liquids infused heat, include (Ci-C_3o) alkanols (e.g., ethanol, propanol, isopropanol, etc.), (C^Cz_.) alkylene glycols (e.g., ethylene glycol, propylene glycol, etc.), polyalkylene glycols, polyalkylene oxides other polyols (e.g., glycerol) and mixture thereof. Preferred aqueous-based pediculostatic agents according to this aspect of the invention are l-50wt% ethanol, 1- 80wt% propylene glycol and l-70wt% isopropyl alcohol. n still another embodiment, the pediculostatic agent is a commonly available substances such as honey, vinegar, mustard, gelatin, yogurt, skin Cleansers, skin conditioners, hair conditioners, shampoos, personal lubricating jelly, sunscreen, mouthwash or toothpaste, or an aqueous-based composition comprising one or more of these substances.

In a particularly preferred embodiment, the pediculostatic agent is an aqueous-based composition comprising a surfactant and an alkanol . A particularly preferred alkanol-surfactant pediculostatic agent according to this aspect of the invention is the alkanol- surfactant formulation sold under the tradename CETAPHIL^® Cleanser (Gallderma Laboratories, Inc., Fortworth, TX) . Optionally, a conventional pediculocidal active ingredient can be incorporated into the pediculostatic formulations described herein. The pediculocidal active ingredients can be used at levels effective to achieve their intended result, typically from about 0.25% to about 2.5%. Non-limiting examples of suitable pediculocidal agents include natural or other pyrethrins (with or without piperonyl butoxide) , permethrin, lindane, malathion, carbaryl, ivermectin and combinations thereof. In an alternative embodiment, a pediculostatic agent can be applied first, followed by application of a pediculicidal composition to the infested area, or vice versa. If the pediculocidal agent is applied first, the hair of the infested area is preferably dried prior to application of the pediculostatic agent. The pediculostatic agent is optionally combined with a dye for temporarily marking the treated area in order to verify that the agent has been applied. The dye is preferably a fluorescent dye or other detectable agent capable of binding to the chitoness nits. In still another aspect, the invention provides diagnostic methods for monitoring the severity of a lice infestation or determining whether the infestation is due to an original infection or re-infection. According to the invention, a pediculostatic agent is applied to the dry hair and skin of an area of the body having or suspected of having a lice infestation, as previously described. While the pediculostatic agent remains in the - hair, the hair is combed with a fine-tooth comb, preferably a delousing comb, and the pediculostatic agent

⁵ removed by combing and placed on a paper towel or other type of paper or cloth material . The towels can then be inspected for the presence of infant lice, adult lice or nits. Depending on the type of lice or nits removed, the treatment regimen can be monitored or adjusted as

¹⁰ necessary to effect total eradication of the lice infestation. The methods can also be used to diagnose lice infestations prior to development of symptoms, and/or to determine whether a lice infestation is the result of an initial infestation, where only adult lice

¹⁵ are observed, or re-infestation, when instars and nits are observed.

In a final aspect, the invention provides a kit for the treatment or removal of lice and/or nits. The kit comprises an amount of a pediculostatic agent sufficient

20 for at least one application and a fine-toothed delousing comb for removing lice and nits. Alternatively, the kit can contain individual components that when mixed together, with or without the addition of water, provide an amount of a pediculostatic agent sufficient for at 5 least one application. The kit can optionally contain additional components, such as shower caps or other non- absorbent coverings, pediculostatic agents, dyes that can be mixed with the pediculostatic agents, etc.

³⁰4. DETAILED DESCRIPTION OF THE INVENTION

The prior art teaches that the only effective topical agents to treat and cure head lice are pediculocides. If lice are temporarily inactivated and later recover from exposure, the agent is considered 35 ineffective by those skilled in the art. There is no mention of either the concept or examples of treatments using water-soluble agents which merely stun or immobilize the lice; in fact, the prior art teaches away from using such agents. it has now been surprisingly discovered that a pediculostatic agent, that is one that triggers the immersion reflex, can be used in novel methods for the treatment or removal of lice and/or nits which overcome the disadvantages of the prior art methods. The immersion reflex is a self preservation behavior which lice have developed to protect themselves against drowning when they are immersed in water. Lice are obligate air breathers and cannot derive oxygen when underwater. This reflex allows them to greatly increase the amount of time they can survive without access to air. During submersion, breathing air through the spiracles and tracheoles is blocked by water. As the lice become anoxic, they rapidly switch into a state of profound suspended animation in order to decrease their need for oxygen, thus prolonging their survival. They become completely immobile, unresponsive to stimuli, and even cease gut motility. If the reflex continues too long, however, then eventually the lice run completely out of oxygen and die from anoxia. The methods and kits of the invention take advantage of the immersion reflex to provide regimens for lice removal and treatment that are safe, effective, and non- toxic. Since the methods and kits do not require application of a pediculocidal agent for success, they are highly unlikely to engender resistance in the lice.

Moreover, since the methods and kits are non-toxic, they provide safe prophylactic treatment for the entire at- risk group, thereby providing effective means of eradicating lice outbreaks and re-infestations. In general, the method of treating or removing lice and/or nits according to the present invention comprises applying a pediculostatic agent to a lice-infested area of the body, typically the scalp, for a time sufficient to trigger the immersion reflex in the lice by oxygen deprivation. Before the pediculostatic agent is removed, the hair and scalp are combed using a fine-toothed comb, for example a delousing comb as described in U.S. Patent No. 5,131,418, to remove the lice and/or nits from the host.

In one embodiment of the present invention, the frequency of treatment or application is once every 2 days to once every 30 days. A preferred schedule is 3 times in 2 weeks. However, the treatment can be repeated at intervals as necessary to completely remove the lice and/or nits.

The treatment can also be used as needed as a prophylactic measure to prevent initial infestation or repeated as needed for persons at risk of re-infection. Because the pediculostatic agents of the invention are non-toxic and do not engender resistance, the treatment methods described herein can be repeated indefinitely, if necessary.

A critical feature of the methods of the invention is that the pediculostatic agent be applied full strength, i.e., in substantially undiluted form. This can be accomplished by applying the agent to the dry hair of the infested area, preferably in an amount sufficient to completely soak or saturate the area and/or hair, and massaging the agent in. As those of skill will appreciate, hair can experience varying degrees of wetness, from dripping wet to completely dry. As used herein, the expression "dry hair" is intended to encompass not only hair that is completely dry, but also hair that is moist or damp, and hair that is substantially dry such as is obtained by towel-drying the hair following shampooing. The critical aspect of the invention is that the hair be sufficiently dry such that the pediculostatic agent is not substantially diluted when applied to the hair. Hair of the appropriate level of dryness can be obtained by squeezing, toweling or otherwise drying wet hair until water ceases dripping from the hair. In preferred embodiments of the invention, the pediculostatic agent is applied to towel dry hair, more preferably to completely dry hair. Thus, if the pediculostatic agent is applied following shampooing, the hair should be wrung out or towel dried, preferably completely dried, prior to application. The time interval between application of the pediculostatic agent and combing to remove the lice and/or nits will depend upon the Immersion Reflex Index of the particular pediculostatic agent, which is defined as the time, in minutes, within which the immersion reflex is triggered in a louse upon being contacted with the agent. Typically, combing can be commenced after a period of time equal to the Immersion Reflex Index of the particular pediculostatic agent used. However, longer intervals between application and combing can be used, and in some cases are even preferred. Most preferably, the pediculostatic agent remains in the hair for a period of time equal to about 5 to 30 times the Immersion Reflex Index of the particular pediculostatic agent being used prior to combing.

It has been discovered that the longer a louse remains immobilized by a pediculostatic agent, the longer it takes the louse to revive after the pediculostatic agent has been rinsed away or otherwise removed. If the pediculostatic agent is applied for a sufficiently long duration, i.e., on the order of 10 to 5000 times the Immersion Reflex Index of the agent, the agent can be removed prior to removal of the lice and/or nits by combing, provided the removal can be effected while the lice are still substantially stunned or immobilized. If lice are covered by a pediculostatic agent according to the invention for a sufficiently long duration, they suffocate and die. While killing the lice is not necessary for success of the methods described herein, in some embodiments it may be desirable to kill some of the lice prior to, after, or concomitant with, removal by combing. Lice may be killed by prior, concurrent or post application of one or more commercially available pediculocidal agents, as will be discussed more thoroughly below, or by pre-treatment with a pediculostatic agent according to the invention for a time period sufficient to suffocate and kill some or all of the lice.

Quite surprisingly, it has been discovered that when certain pediculostatic agents of the invention are applied for durations long enough to kill some of the lice, the added benefit of easy nit removal is achieved. Thus, in preferred embodiments of the invention the pediculostatic agents are first used as pre-treatments, preferably for durations sufficient to kill some of the lice, followed by re-application for lice and/or nit removal.

According to this embodiment, a pediculostatic agent according to the invention is applied to a lice-infested area of the body, typically by applying to the dry hair of the infected area an amount of the agent sufficient to completely soak or saturate the infested area and/or hair. The agent is then allowed to remain on the area for a period sufficient to kill some of the lice. The actual amount of time the pediculostatic agent must remain on the infested area will depend in part on the Immersion Reflex Index of the particular agent used; however, typically times on the order of 2000 to 10,000 times the Immersion Reflex Index are sufficient. For the - preferred CETAPHIL"¹ Cleanser pediculostatic agent of the invention, it has been found that a duration of at least about 4 hours, preferably 9 to 12 hours, is sufficient. For convenience, the pediculostatic agent can be applied at bedtime, and the application site covered with, for example a shower cap, or other non-absorbant covering during sleep. Following this pre-treatment, a small amount of pediculostatic agent is re-applied to the infested area and massaged in. The agent is left on the area for a duration sufficient to trigger the immersion reflex in lice, and the lice and/or nits are then removed by combing as previously described. The same or different pediculostatic agent may be used for the pre-treatment and treatment .

Optionally, prior to re-application, the pediculostatic agent may be removed, for example by rinsing and/or shampooing, with or without combing prior to removal. If the pediculostatic agent from the pre- treatment step is removed according to this alternative embodiment, the hair surrounding the infested area should be dried prior to re-application, and an amount sufficient to soak or saturate the area should be re- applied. However, re-application without first removing the pre-treatment is preferred.

It has been found that applying a saturating quantity of CETAPHIL^* Cleanser to the hair of an infested area for a duration of 8-12 hours (with the aid of a shower cap) followed by re-application of a small amount of CETAPHIL^® Cleanser for a period of at least 2 minutes, followed by removing the dead and/or immobilized lice by combing with a delousing comb while the CETAPHIL^* Cleanser remains on the hair is particularly effective for removal of lice and nits.

Pediculostatic agents useful in the methods and kits of the present invention are characterized by their ability to induce an immersion reflex in lice, as determined by the following in vi tro Immersion Reflex

Test:

1. Contact a louse with an agent suspected of being a pediculostatic agent; and ° 2. Measure the length of time required for the louse to exhibit the immersion reflex, i . e . , to become immobile. The Immersion Reflex Index is the time, in minutes, within which the immersion reflex is triggered in the louse . 5 The pediculostatic agents of the present invention typically have an Immersion Reflex Index of no more than

120 minutes. For preferred agents, the Index is 5 minutes or less. For the most preferred agents, the Index can be as low as 0.1 minute, or even lower. 0 The pediculostatic agents of the present invention comprise all water-soluble pharmaceutically acceptable compositions suitable for topical application to the hair, body and scalp of animals and humans and which induce an immersion reflex effect in lice. In a preferred 5 embodiment, the pediculostatic agent is a liquid or is incorporated into a liquid or semisolid composition which is flowable or spreadable over the scalp. These compositions are convenient in use, and are an effective medium for coating the lice and scalp. 0 There are a number of acceptable water-soluble and/or aqueous-based formulations suitable for use in the present invention, including but not limited to, solutions, lotions, sprays, creams, ointments, emollients, salves, and gels. Descriptions of non- 5 limiting examples of suitable formulations may be found in the PHYSICIAN'S DESK REFERENCE, Medical Economics Co., Pub., Oradell, N.J. and in THE NATIONAL FORMULARY, American Pharmaceutical Association, Pub., Washington, DC, each of which is incorporated herein by reference in its entirety.

The pediculostatic agent is preferably transparent or translucent in order to facilitate observation of the area being treated, and is preferably easily removed, such as by rinsing with water, or is readily washed out using a shampoo. In general, the pediculostatic agent used in the present invention is a liquid or semisolid that presents a barrier that prevents the transfer of oxygen to the lice.

While the pediculostatic agents of the invention are water-soluble or aqueous-based, water by itself is not a preferred pediculostatic agent. Bathing or swimming in water may cause a few lice to be dislodged, but others will likely remain attached. In either case, lice are unlikely to succumb to suffocation or drowning because of the immersion reflex, unless their host also perishes. Lice breathe air, but not in the same manner as do vertebrates. Water may not enter through the spiracles or fill the tracheoles of lice due to its high surface tension. Also, since water applied to the scalp would evaporate or run off, it would be necessary to immerse the scalp during the combing process; it is inconvenient and impractical to immerse the scalp in water for the required period. However, it has been found that aqueous compositions containing surfactants are effective pediculostatic agents. While not intending to be bound by any particular theory of operation, it is believed that the surfactant increases the ability of the water to effectively coat the lice, thereby blocking their breathing apparatus, and also to spread upon the surfaces of the hair and scalp. In a preferred embodiment, the pediculostatic agent of the present invention is a surfactant or an aqueous- based composition containing one or more surfactants. Non-limiting examples of suitable classes of surfactants include wetting agents, surface tension depressants, detergents, dispersing agents, emulsifiers, and quaternary ammonium antiseptics.

Non-limiting examples of suitable surfactants include anionic agents, cationic agents, amphoteric agents, zwitterionic agents, and nonionic agents. The literature contains numerous examples of compositions containing surfactant systems which are suitable for use in the present invention. Examples are found in U.S. Patent Nos. 5,288,483; 4,495,079; 5,034,218; 5,656,280; 5,284,833; 5,562,912; and 5,480,633, each of which is incorporated herein in its entirety by reference. A preferred anionic surfactant for use in the present invention is sodium lauryl sulfate, which can conveniently be used in an aqueous solution at a concentration from 1 to 30% by weight.

Non-limiting examples of nonionic surfactants include fatty alcohols such a lauryl alcohol, cetyl alcohol and stearyl alcohol, glyceryl esters such as mono, di and tri glycerides, fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, and sucrose. Propylene glycol can be conveniently used in an aqueous solution at a concentration from 1 to 80% by weight. A preferred concentration is 10 to 50% propylene glycol. Other examples of suitable surfactants are Span 65

(sorbitan tristearate) , Span 60 (sorbitan monostearate) ,

Span 40 (sorbitan monopalmitate) , sodium bis- (2- ethylhexyl) sulfosuccinate, butylene glycol distearate, and Tween 80 (polysorbate 80) . An antifoaming agent can be optionally included in the composition, an example of which is silicone fluid.

All polar, water-soluble solvents which are pharmaceutically acceptable for topical application are included as pediculostatic agents of the present invention. These solvents can be used neat or in the form of aqueous-based compositions containing the solvent. Non-limiting examples of these solvents include (C₁-C₂₀) alcohols such as ethanol which can be used in aqueous dilutions of from 1 % to 50% by weight, or isopropyl alcohol, which can be used in aqueous dilutions of from 1 % to 70% by weight. Examples of polyhydroxylated solvents suitable as pediculostatic agents include propylene glycol, ethylene glycol, and glycerin.

The pediculostatic agents of the present invention can be used singly or in combination, and can optionally include other components such as thickeners, penetration enhancers, conditioners, osmotic adjusters, acids, bases, buffering agents, skin protectants, stabilizers, antioxidants, coloring agents, preservatives, and fragrances . Thickeners can be included in the pediculostatic agents of the invention for decreasing the tendency of the composition to flow away from the treated area. Non-limiting examples of thickeners include cetyl alcohol, stearyl alcohol, petrolatum, glyceryl monooleate, myristyl alcohol and isopropyl palmitate. Other hydrophillic thickeners include polysaccharide gums, an example of which is xanthan gum. Non-limiting examples of preservatives include methyl paraben, propylparaben, and butylparaben . A non-limiting example of an acid is citric acid. Non-limiting examples of coloring agents include FD&C Green No. 8, FD&C Green No.

3, D&C Violet No. 2, and D&C Red No. 3. Commercially available products such as soaps, Cleansers, lotions, moisturizers, conditioners and shampoos that are non-toxic and pharmaceutically acceptable for topical application may also be used as pediculostatic agents. These are preferably applied in their undiluted state and without agitation in order to minimize the ^'formation of foam. The presence of air in the foam or suds can provide oxygen to the lice and therefore lessen the ability of the agent to stun the lice.

In another embodiment of the invention, the pediculostatic agent includes commercially available skin Cleansers, skin conditioners, shampoos, personal lubricating jelly, sunscreen, mouthwash, toothpaste, and other products. Also included are commonly available products including honey, vinegar, mustard, gelatin, yogurt, or other foodstuffs which may be applied for a period of time sufficient to stun the lice, followed by physically removing the lice from the hair by combing. The preferred agent is one which can be easily removed after the treatment by rinsing with water.

In a preferred embodiment of the invention, the pediculostatic agent is an aqueous-based composition containing one or more surfactants and one or more alkanols. An example of a suitable alkanol-surfactant pediculostatic agent is BABY MAGIC baby shampoo (Mennen Co., Morristown, N.J.) which contains water, polysorbate 20, sodium lauryl sulfate, lauroamphoglycinate, polysorbate 80, PEG-150 distearate, fragrance, citric acid, and quaternium 15. In use, the shampoo is applied in the absence of water in order to avoid foaming, for a period sufficient to stun the lice, followed by combing.

Another example of an alkanol-surfactant pediculostatic agent suitable for use in the present invention is SUAVE⁸¹ Baby Care bath soap tear-free formula (Helene Curtis, Inc., Chicago, IL) which contains water, PEG-80, sorbitan laurate, sodium tridecyl sulfate, cocamidopropyl hydroxysultaine, disodium lauroamphodiacetate, PEG-150 distearate, sodium lauryl-13 carboxylate, aloe vera gel, quaternium-15 , DMDM hydantoin, methylchloro isothiazolinone, methylisothiazolinone, fragrance, citric acid, D&C Violet No. 2, D&C Red No. 3.

The most preferred composition for use as a pediculostatic agent in the invention is a mixture of water, cetyl alcohol, propylene glycol, sodium lauryl sulfate, stearyl alcohol, methyl paraben, propylparaben, and butylparaben sold commercially as a nonirritating, non-greasy skin Cleanser under the trademark CETAPHIL^* Cleanser (Galderma Laboratories, Inc., Fort Worth, TX) . CETAPHIL" Cleanser is additionally advantageous since it aids in the removal of the nits . While the mechanism for this property is not fully understood, a component or components in CETAPHIL^® Cleanser may dissolve or loosen the cement which holds the nits to the hair shaft, and may also make the shaft slippery, thus facilitating the removal of the nits during combing.

CETAPHIL^® Cleanser has the ability to rapidly trigger the "immersion reflex" in head lice. Both in vivo and in vi tro, lice coated in CETAPHIL³¹ Cleanser became immobilized within 6 seconds. On the patients' scalp, the lice became totally immobilized, floating on the scalp in the Cleanser. They were easily removed by forceps without any effort to escape or to grasp the hair shaft to stay m place. Under the microscope, they were immobile, did not respond to being touched, and lost their normally visible gut motility. They remained immobilized as long as they were in the Cleanser. This phenomenon was observed for periods ranging from 6 seconds to 4 hours .

At any point the louse could be removed from the Cleanser and usually awakened and resumed crawling. When immersed overnight in CETAPHIL^Φ Cleanser (12 hours) the lice died.

The invention can also incorporate a system for verifying whether the pediculostatic agent has been applied. This is an important feature for certain populations where cross-contamination is known to occur such as in a grade school setting. The pediculostatic agent is optionally combined with a dye which will temporarily remain on and mark the hair and/or scalp ° after a treatment in order to verify that the agent has been applied. The dye is present at a concentration which will leave an observable mark (e.g. 0.1-1% by weight in the pediculostatic formulation) and preferably will remain on the treated area for at least 12 hours . The dye 5 is preferably fluorescent and is visible only under an ultraviolet light. Non-limiting examples of suitable dyes include those described in U.S. Patent Nos. 4,610,806 and 5,302,371.

Optionally, a pediculostatic agent and a 0 conventional pediculicide can be coadministered. In one embodiment of the method of the invention, a conventional pediculicidal active ingredient can be incorporated into the pediculostatic formulation described herein. The active ingredients can be used at levels of from about 5 0.25% to about 2.5%. Exemplary useful pediculocidal agents include natural pyrethrins (with or without piperonyl butoxide) , permethrin, lindane, malathion, carbaryl, and ivermectin and combinations thereof.

In an alternative embodiment of the method of the ⁰ invention, a pediculostatic agent can be applied first, followed by application of a pediculocidal composition, or vice versa. Such compositions are well known in the art and include RID" (Pfizer Inc., New York, NY), NIX^® (Warner-Lambert, Harristown, NJ) , KWELL^* (Reed and ⁵ Carnick, Jersey City, NJ) , A-200° (Hogil, Purchase, NY) , PRONTO⁰⁶ (Del Pharmaceuticals, Uniondale, NY), LINDAINE^® (Alpharma, Baltimore, MD) , CLEAR^® (Care Technologies, Inc., Greenwich, CT) , and those described in U.S. Patent No. 5,292,504, which is incorporated herein by reference in its entirety.

When used together, the pediculostatic agent and conventional pediculocide act synergistically to increase the rate of rendering the louse totally immobile. Therefore, within a short period of time, preferably less than about 5 minutes, the lice can be removed using, for example, a fine-toothed delousing comb. When using both the pediculostatic agent and pediculicide together, combing is optional and not required. The lice will be rendered inactive due to being immobilized by the pediculostatic agent or being killed by the pediculostatic agent. The inactive lice can be removed, for example, by rinsing the hair. There currently is a major problem of reported resistance or potential evolving resistance to the previously successful pediculicides . On the other hand, all treated lice are susceptible to an immersion reflex agent . The co- administration of a pediculostatic agent by either of these two methods renders effective a pediculicide chemical which otherwise would be ineffective. i another embodiment, the invention provides a kit having at least an amount of a pediculostatic agent for one treatment (about 8 ounces) and at least one delousing comb suitable for removing adult lice and nits. Alternatively, the kit can contain ingredients in quantities suitable that when they are mixed together, either with or without the addition of water, provide an amount of pediculostatic agent sufficient for at least one application or treatment. The teeth of the comb have spacings such that hair can pass therethrough while nits and lice will be caught in the teeth of the comb. Examples of suitable combs are known in the art and include Acu-Med Lice Comb (Health Enterprises, North Attleboro, MA) , LiceMeister Lice Comb (National Pediculosis Association), Medi-Sweep Lice Comb (U.S. Patent No. 4,612,944), and dog and/or cat Flea Comb (Classic Products, Oxnard, CA) , each of which is incorporated herein by reference in its entirety. The comb is preferably constructed of rigid material such as metal or plastic. In a preferred embodiment, the comb is inexpensive and designed to be disposable after a single use, in order to prevent contamination. In another embodiment the comb has a removable, and preferably disposable, piece having a plurality of teeth which attaches to a handle portion such as described in U.S. Patent No. 5,636,646, incorporated herein by reference in its entirety.

Of course, other components such as pediculocidal agents, markers such as fluorescent dyes, shower caps, paper towels, etc. can also be included in the Kits of the invention. Typically, the kit will contain a quantity of pediculostatic agent and enough combs to completely eradicate a lice infestation, thereby providing an effective treatment for lice.

While the invention has been described in terms of removal, treatment or prophylaxis of head lice, it will be appreciated that the methods and kits of the invention can be used as described for the treatment, removal or prevention of other types of lice infestations, including body and pubic lice. Moreover, the methods and kits can e used to treat, remove or prevent infestations of other bugs which undergo an immersion reflect when immersed in water, such, as for example, ticks.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLE 1 : CETAPHIL^® Cleanser Triggers the Immersion Reflex in Lice Within Seconds

Ten crawling lice were obtained from patients with head lice and each one placed on a separate microscope slide for observation under a microscope at lOx or 40x power. Each louse was placed in a drop of CETAPHIL^® Cleanser for up to 4 hours. All of them exhibited the same response. Within 6 seconds of application, they stopped all spontaneous movement. Usually within 30 seconds, and always within 60 seconds, they would not respond to contact by a probe and ceased previously visible gastrointestinal motility. They remained in this state of suspended animation as long as they were kept in wet CETAPHIL^® Cleanser. If the louse was pulled to the side of the drop, it could be seen that the CETAPHIL^® Cleanser formed an adherent layer surrounding and conforming to the body and limbs. When the lice were removed from the CETAPHIL^® Cleanser and allowed to dry off, they usually awoke and all prior activity. Thus, the lice were stunned but were not killed by the Cleanser. The longer the louse was coated, the longer it took to awaken after removed from the Cleanser. After five of the lice were placed in the Cleanser overnight, they were all dead following 12 hours of immersion in the Cleanser.

To reliably kill head lice with the Cleanser, immersion for periods longer than 4 hours were required.

EXAMPLE 2: CETAPHIL^® Cleanser is More Effective At

Triggering the Immersion Reflex Than Water

A louse obtained from a patient with head lice was placed on a microscope slide and treated as described in EXAMPLE 1, except that water was used instead of CETAPHIL^® Cleanser. When the louse had water applied to it, it took 25 seconds for limb and head movement to stop. During a 3 minute observation period, the louse continued to show visible gut motility and remained reactive to the probe.

The louse was then removed from the water, allowed to dry off, and treated with CETAPHIL^® Cleanser as described in EXAMPLE 1. The same pediculostatic events and timing of them were observed as with the lice of EXAMPLE 1.

Based on this comparative experiment, CETAPHIL^® Cleanser acts quicker and more effectively as a pediculostatic agent than water. While not intending to be bound by any particular theory of operation, it is believed that the superiority of CETAPHIL^® Cleanser is due to its "stickiness." Whereas the water readily comes off the louse, the CETAPHIL^® Cleanser adheres to the louse .

EXAMPLE 3 : In Vivo Studies with a Pediculostatic

Agent On five separate patients, crawling lice were observed on the scalp and one drop of CETAPHIL^® Cleanser was placed on each louse. Prior to application, each louse responded immediately to attempts at being picked _Up with a forceps, rapidly crawling away and avoiding being picked up. Within 6 seconds of application of the Cleanser, all the lice ceased crawling, were floating immobile in the Cleanser, and did not respond to being touched with a probe . They were not grasping any of the surrounding hairs and made no attempt to move or escape.

They could easily be picked up with a forceps and remained immobile. The immobility was immediately confirmed under the microscope while the lice were still coated with the Cleanser. EXAMPLE 4 : Clinical Use of a Pediculostatic Agent in the Treatment of Head Lice

A group of 31 patients with active head lice infestations were treated with CETAPHIL^® Cleanser combined with combing with a variety of different types of combs. All patients gave a history of symptoms of lice and/or recent exposure to a close family member or friend with lice. Some of the patients had previously tried commercially available lice treatments; one patient had tried multiple treatments with these commercially available remedies. All patients or their parents signed informed consent forms prior to entry into the study. The patients ranged in age from 2 years to 43 years, with most of the patients being 6-9 years old. All treatments were done at the patients' homes, usually by the parent. Treatment was done once weekly until no lice were present. Several different comb designs were used. For each week's treatment the patient was given a new comb and the previous week's comb was discarded. All of the patient's family members were treated with at least one treatment to see if they had lice or nits in their data collection. If identified as affected, then they were added to the study.

.ι Method of Application

All patients in the study were asked to follow the following protocol once weekly until requested to stop by the research director:

1) Start with dry hair; 2) Use a wide-toothed comb to detangle the hair; 3) Apply CETAPHIL^® Cleanser thoroughly throughout the scalp to totally soak the scalp and hair (usually this requires 6 oz . for short hair and 12 oz . for long hair) ; 4) Use a wide-toothed comb to detangle hair, if necessary;

5) After a period of from 2 to 60 minutes, use a fine-toothed delousing comb to thoroughly comb out all of the CETAPHIL^® Cleanser soaking the hair and scalp;

6) Put the removed Cleanser onto paper towels and place the towels and used comb into a Ziploc™ -type bag labeled with the patient's name and date of treatment;

7) Bring the labeled bag to the research director for analysis.

During the course of treatment, all patients were advised to wear clean clothes after each treatment, to launder all dirty clothes and to put clean sheets on the bed. Patients were also requested to sanitize all combs and brushes daily by soaking for 10 minutes in rubbing alcohol and to sanitize all hair ribbons, scrunchies, etc. and hats by placing in plastic bags for 14 days. Patients were further advised not to share combs, brushes, hats or other hair items with anyone and to avoid friends or classmates showing symptoms of lice infestation.

4.2 Data Analysis

Each bag received from patients was opened and all lice and nits present counted and recorded on a computerized data form. The total number of nits present, the number of instars present and the number of adult lice present were recorded.

4.3 Determination of Cure

Complete lice removal was defined as meeting three criteria:

1) No lice in the data collection from the paper towels returned after treatment; 2) No further symptoms of lice infestation; and 3) No recurrence of lice reported by the patients within 2 months of achieving a zero lice data collection result .

The number of applications to achieve complete lice removal, or cure, is defined as the number of applications that produced lice before the zero lice collection result was achieved. For example, if on the third application there were no lice in the towel data, then it took 2 applications to remove all the lice.

4.4 Results

All 31 patients achieved complete lice removal. Of the 31 patients, 7 achieved complete removal within 1 application; 19 achieved complete removal within 2 treatments; 4 achieved complete removal within 3 treatments; and 1 achieved complete removal within 4 treatments. On average, it took 2 treatments to achieve complete removal. Some of the patients had previously tried pediculocidal treatments without success . A sufficient number of nits were removed to allow the patients to return to school, whereas with the conventional pediculocidal treatments they could not. In some instances, parents had to manually remove a small number of residual nits in order for the patient to return to school. The raw data are shown in Table 1, infra:

TABLE 1

A total of 1033 lice and 2553 nits were removed, _n yielding an average of 33.3 lice and 82.4 nits per patient. All patients and parents described the process as pleasant. All reported immediate relief of itching after the first application. Frequently, they described the hair as much easier to comb out as compared to their

- _. prior experience with Nix^®, Kwell^® and Rid^®. Often they reported 50% or greater reduction in comb out time. Parents noted their children had 90% or better reduction in complaints of pain during combing. Metal pronged combs such as the Acu-Med Lice comb (Health Enterprises,

-,_ North Attleboro, MA) and the Licemeister (National

Pediculosis Association) were described as much easier to use for removing nits with CETABHIL Cleanser as compared with dry or water-damp combing.

Of interest, half the patients had families in which

-,_. an unsuspecting but affected member was identified by this method of detecting lice.

EXAMPLE 5: In Vitro Killing of Lice Using a Pediculostatic Agent

30 Five lice were placed in CETAPHIL^® Cleanser overnight, they all were dead following 12 hours of immersion in the CETAPHIL^® Cleanser. To reliably kill head lice with the Cleanser, immersion for periods longer than 4 hour were required.

35 EXAMPLE 6 : Clinical Treatment of Headlice Using

Overnight Pre-Treatment with a Pediculostatic Agent

In this study, 13 patients with active lice infestation were first pre-treated with CETAPHIL^®

Cleanser, followed by a regular treatment regimen. The patients ranged in age from 4 to 35 years. Ten patients had previously tried home remedies or commercially available Nix^®, Rid^® or Clear^® treatments without success.

Informed consent forms were obtained from all patient's parents .

For pre-treatment, CETAPHIL^® Cleanser was applied at bedtime to the dry hair and scalp to completely soak the hair and scalp and left on overnight under a shower cap .

In the morning, a small amount of additional CETAPHIL

Cleanser was applied to the scalp and massaged in. After waiting for 2 minutes, thorough combing was done with a delousing comb as described in EXAMPLE 4. The data collection and evaluation processes were essentially as described in EXAMPLE 4.

All 13 patients achieved complete removal of lice and many nits following this simple treatment, as reported in Table 2, below:

TABLE 2

Head Lice and Nit Removal In 13 Patients

Overnight Application with Combing In the Morning

In total, 167 lice and 1507 nits were removed, giving and average of 12.8 lice and 116 nits per patient. All patients were pleased with the process. In contrast to their prior pediculocidal treatments, this method effectively removed lice and nits . Very few nits were observed after treatment .

Overnight pre-treatment resulted in more nits being removed per patient as compared with application of pediculostatic agent without pre-treatment.

EXAMPLE 7 : Prophylactic Use of Pediculostatic Agents CETAPHIL^® Cleanser is applied as in the previous examples, but on a weekly basis in order to prevent re- infestation or to prevent infestation for persons who are uninfected but at risk for catching head lice.

Current school policy is to immediately send children home who are discovered to have lice infestation. As an alternative, CETAPHIL^® Cleanser is applied to the scalp at school and left in place until the child returns home at the end of the day. The lice can then be removed by the child's parents.

While the foregoing has presented specific embodiments of the present invention, it is to be understood that these embodiments have been presented by way of example only. It is expected that others will perceive and practice variations which, though differing from the foregoing, do not depart from the spirit and scope of the invention as described and claimed herein.

Claims

We claim :

1. A method of removing lice or nits from a subject, comprising the steps of: a) applying to the dry hair of an area of the body suspected of having lice or nits an effective amount of a pediculostatic agent for a time sufficient to trigger an immersion reflex in lice; and b) removing the lice or nits prior to or concommitant with removal of the pediculostatic agent from the area.

2. The method of Claim 1, wherein the lice or nits are removed with a fine-toothed comb.

3. The method of Claim 1, wherein the pediculostatic agent has an Immersion Reflex Index of 120 or less.

4. The method of Claim 1, wherein the pediculostatic agent is selected from the group consisting of solutions, lotions, sprays, creams, ointments, salves and gels.

5. The method of Claim 1, wherein the pediculostatic agent is a surfactant or an aqueous composition comprising a surfactant.

6. The method of Claim 5, wherein the surfactant is selected from the group consisting of anionic agents, cationic agents, anphotoric agents, zwitler ionic agents, nonionic agents and combinations thereof.

7. The method of Claim 5, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan tristearate, sorbitan monostearate, sorbitan monopalmitate and butylene glycol distearate.

8. The method of Claim 1, wherein said pediculostatic agent is a polar organic compound or an aqueous composition comprising a polar organic compound.

9. The method of Claim 8 in which said polar organic compound is selected from the group consisting of (Ci- jo) alkylene glycols, polyethylene glycols, polyethylene oxides, (Ci-Czo) polyols, glycerol and combinations thereof .

10. The method of Claim 1 in which the pediculostatic agent is selected from the group consisting of honey, vinegar, mustard, gelatin, yogurt, skin Cleansers, skin conditioners, hair conditioners, shampoos, personal lubricating jelly, sunscreen, mouthwash, toothpaste and combinations thereof and aqueous compositions thereof.

11. The method of claim 1 in which the pediculostatic agent is an aqueous composition comprising an alkanol and a surfactant .

12. The method Claim 1 in which the pediculostatic agent is CETAPHIL^® Cleanser.

13. The method of Claim 1 in which the pediculostatic agent includes an effective amount of a pediculocidal agent .

14. The method of Claim 13 in which the pediculocidal agent is selected from the group consisting of pyresthrins, permethrin, lindane, malathion, carbaryl and ivermectin.

15. The method of Claim 1 further including the step of applying an effective amount of a pediculocidal agent to the area.

16. A method of removing lice or nits from a subject, comprising the steps of: a) applying to the dry hair of an area of the body of a subject suspected of having lice or nits an effective amount of a first pediculostatic agent for a period of about 2000 to 10,000 times the Immersion Reflex Index of the agent; thereafter b) applying to the area an additional amount of a second pediculostatic agent for a period of time sufficient to trigger an immersion reflex in lice; and thereafter c) removing the lice or nits prior to or concommitant with removal of the agent from the area.

17. The method of Claim 16 in which the first and second pediculostatic agents are CETAPHIL^® Cleanser; the agent is applied to the area for about 4 to 16 hours in step (a) ; and the agent is applied for a period of at least 2 minutes in step (b) .

18. A method for the prevention of active lice infestations, comprising: a) applying to the dry hair of an area of the body at risk of lice infestation an amount of a pediculostatic agent sufficient to soak or saturate the area for a period of time equal to about 5 to 30 times the Immersion

Reflex Index of the agent; and thereafter b) combining the hair with a fine-toothed comb to remove the agent and any lice or nits which could lead to active lice infestations.

19. A kit for the removal, treatment or prevention of lice or nits, comprising: a) an amount of a pediculostatic agent sufficient for at least one application; and b) a fine-toothed delousing comb.

20. The kit of Claim 19, further including an amount of a pediculocidal agent sufficient for at least one application.

21. The kit of Claim 19, further including an amount of a dye sufficient for at least one application.

22. A method of treating a lice infestation, comprising the steps of : a) applying to the dry hair of a lice-infested area of the body an effective amount of a pediculostatic agent ; b) allowing the pediculostatic agent to remain on the area for period of time equal to or greater than the immersion Reflex Index for the agent; c) combing the hair of the area to remove the agent and lice; and d) repeating steps (a) - (c) at intervals of 1 to 3 times weekly until the lice infestation is cured.

23. The method of Claim 23 in which nits are also removed.