EP1140052A2 - Agents sensibilisants pour le traitement de lesions cutanees - Google Patents

Agents sensibilisants pour le traitement de lesions cutanees

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Publication number
EP1140052A2
EP1140052A2 EP99967615A EP99967615A EP1140052A2 EP 1140052 A2 EP1140052 A2 EP 1140052A2 EP 99967615 A EP99967615 A EP 99967615A EP 99967615 A EP99967615 A EP 99967615A EP 1140052 A2 EP1140052 A2 EP 1140052A2
Authority
EP
European Patent Office
Prior art keywords
sensitizing agent
composition
wart
poison
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99967615A
Other languages
German (de)
English (en)
Inventor
Harry Goldberg
Hugh Sampson
Howard B. Sosin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seer Pharmaceuticals LLC
Original Assignee
Panacea Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Panacea Pharmaceuticals LLC filed Critical Panacea Pharmaceuticals LLC
Publication of EP1140052A2 publication Critical patent/EP1140052A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • disorders of the skin can cause wide ranging effects. Some skin lesions are modestly annoying; others are devastating. Many skin lesions resist treatment with currently-available therapeutics and technologies. Skin lesions caused by viral infections tend to be particularly recalcitrant to treatment. Warts are but one example of a common, persistent viral skin lesion for which no reliable treatment is currently available.
  • wart therapies are available, most of which focus on destruction of the wart and surrounding tissue. For example, warts are often removed by cryotherapy or by surgery. In other cases, warts are treated with locally destructive agents such as salicylic acid, lactic acid, or trichloroacetic acid.
  • these approaches has the disadvantage that significant damage can be caused to neighboring tissue. Moreover, these treatments are frequently not effective, and recurrence rates can be high.
  • Additional approaches to treating warts range from attempting to alter the cutaneous environment to discourage wart growth (e.g., by applying retinoids, formalin, glutaraldehyde, or aluminum chloride), to discouraging wart proliferation through hypnotherapy.
  • the present invention provides a new approach to the treatment of skin disorders.
  • the invention is particularly useful for the treatment of viral skin lesions, most particularly for the treatment of warts.
  • the invention provides a system for stimulating a localized immune response in the area of the skin lesion, thereby inducing the immune system to attack.
  • a preferred method of stimulating such a localized immune response is to apply a sensitizing agent to the skin in the area of the infection.
  • the agent is delivered so that its distribution to other areas of the body is inhibited or blocked.
  • the agent may be applied for only a short period of time.
  • the agent is delivered by means of an applicator, such as a pen or a patch, that provides some physical containment of the agent.
  • the agent may also be delivered to a physically confined location.
  • the sensitizing agent is provided in combination with a neutralizer, that can be applied an appropriate amount of time after application of the agent, to terminate the agent's effects.
  • a neutralizer that can be applied an appropriate amount of time after application of the agent, to terminate the agent's effects.
  • the selection of neutralizer, as well as its preferred mode of application, may depend on the choice of sensitizing agent utilized in a particular inventive embodiment.
  • the sensitizing agent comprises a compound that is naturally found in the sap of poison ivy, poison oak or poison sumac.
  • the agent may be provided as a poison ivy, poison oak, or poison sumac extract, or may alternatively be prepared from non-natural sources (e.g., by chemical synthesis or biological synthesis other than in natural context).
  • the agent comprises urushiol and/or includes at least one catechol.
  • the sensitizing agent is a polynucleotide containing an unmefhylated CpG.
  • inventive methods and compositions are particularly applicable for the treatment of warts (e.g. common warts [verruca vulgaris], plantar warts, palmar warts, planar warts [verruca plana], mosaic warts [condyloma accuminatum; including venereal warts]) but may also useful for treatment of other skin lesions (e.g., nasal polyps, melanoma, herpes sores, basal cell carcinoma), including, in particular, other viral infections of the skin.
  • warts e.g. common warts [verruca vulgaris], plantar warts, palmar warts, planar warts [verruca plana], mosaic warts [condyloma accuminatum; including venereal warts]
  • other skin lesions e.g., nasal polyps, melanoma, herpes sores, basal cell carcinoma
  • the present invention provides a composition for treating dermal disorders, comprising (i) a sensitizing agent characterized by an ability to induce a local immune response when applied to a skin lesion; and (ii) a delivery means for applying the sensitizing agent to skin.
  • a sensitizing agent characterized by an ability to induce a local immune response when applied to a skin lesion
  • a delivery means for applying the sensitizing agent to skin is selected from the group consisting of nasal polyps, melanomas, herpes sores, basal cell carcinomas, and warts.
  • compositions further include a neutralizer that substantially blocks further action by the sensitizing agent, which neutralizer is provided separate from the sensitizing agent for application to the skin lesion subsequent to application of the sensitizing agent.
  • the neutralizer is a specific inhibitor of the particular sensitizing agent.
  • compositions include a sensitizing agent that is a compound naturally produced by a plant selected from the group consisting of poison ivy, poison oak, and poison sumac; preferably, the compound comprises one or more components of plant sap, for example an urushiol.
  • compositions include a sensitizing agent comprising a polynucleotide containing an unmethylated CpG motif, lipopolysaccharide, lipid A, heat-killed bacteria, pertussis virus epitopes, cytokines, cholera toxin, proholeragenoid, cholera toxin B subunit, and fungal polysaccharides.
  • compositions may be provided in combination with and/or in the context of a delivery means, for example comprising a first end including a reservoir in which the sensitizing agent is located, and a handle constructed and arranged for ease of grasping and manipulating.
  • the delivery means may be constructed, for example, as a pen applicator, a cotton-tipped swab, a bulb-type applicator, or a patch.
  • the present invention also provides methods of treating skin lesions with the inventive compositions.
  • Particularly preferred methods include methods of treating warts by applying one or more components of the sap of a poisonous plant. Definitions
  • Extract the term '"extract ' ", as used herein, means a substance or collection of substances prepared from a natural source by removing one or more natural elements of the source.
  • An extract may be a crude preparation in that only a small number of natural elements have been removed, or alternatively may be a substantially pure preparation in that all natural elements other than a selected natural element or collection thereof have been substantially removed.
  • “Individual”-- the term "individual' ' , as used herein, means the person or animal on whom inventive compositions are applied or with respect to whom inventive methods are practiced.
  • the individual is preferably a mammal, more preferably a human or a domestic animal (e.g., a dog, a cat, a bird, a horse, a cow, a sheep, a goat, etc.) Most preferably, the individual is a human.
  • Lesion-- a “lesion”, as that term is used herein, is any disturbance of the skin.
  • Preferred lesions according to the present invention are caused by viral infection.
  • warts, nasal polyps, melanomas, herpes sores, and basal cell carcinomas are all lesions according to the present invention.
  • the lesion is a wart such as a common wart (verruca vulgaris), a plantar wart, a palmar wart, a planar wart [verruca plana], or a mosaic warts [condyloma accuminatum; including venereal warts].
  • Neutralizing agent is a compound, composition, or treatment, that substantially terminates the effects of a sensitizing agent.
  • a neutralizing agent may act by substantially removing the sensitizing agent from the skin.
  • a detergent or soap can be an effective neutralizing agent.
  • a neutralizing agent may block the biological action of a sensitizing agent.
  • the choice of neutralizing agent may vary depending on the particular sensitizing agent being employed. Particularly preferred neutralizing agents are specific inhibitors of a chosen sensitizing agent).
  • “Patch”— a “patch " is any entity capable of delivering a sensitizing agent to the skin.
  • a patch may be a matrix or a container, may be a simple gauze pad or a complex multilayer device. Adhesive bandages are included within the term "patch” as that term is used herein.
  • Pen a "pen” , as that term is used herein, is a sensitizing agent delivery device comprising at least one substantially elongated member.
  • the chamber preferably terminates in a first end and a second end, at least one of which includes a sensitizing agent reservoir.
  • the elongated member is substantially hollow and sensitizing agent can be loaded within it; in other preferred embodiments, the elongated member includes a sensitizing agent reservoir at its first end and a neutralizing agent reservoir at its second end.
  • Reservoir a “reservoir”, as that term is used herein, is an area in which an active agent (i.e., a sensitizing agent or a neutralizing agent) is located for application onto an individual. It is not necessary that the reservoir have any significant depth; a flat surface will constitute a reservoir if an agent is localized on it.
  • the reservoir may include a means for retaining the agent, which means may comprise, for example, an absorptive pad, a depression, a cavity, etc.
  • sensitizing agent means any compound that, when applied to the skin of an individual, elicits a local immune response in that individual, in the area of application of the compound.
  • sensitizing agents include compounds that are naturally produced by poison ivy, poison oak, or poison sumac. Such compounds include urushiols.
  • Alternative preferred sensitizing agents include, for example, polynucleotides containing unmethylated CpG motifs (see, for example, U.S. Patent No. 5,830,877 to Carson et al. and published PCT applications WO 96/02555, WO 98/18810, WO 98/16247, and WO 98/40100, each of which is inco ⁇ orated herein by reference.
  • the polynucleotide is between 2 and 100 nucleotides (nt) or basepairs (bp) long and contains a consensus motif represented by the formula 5'-X 1 X 2 CGX 3 X 4 -3', where (i) C and G are unmethylated; (ii) X,. X 2 . X 3 . and X 4 are nucleotides; and (iii) a GCG trinucleotide is not present at or near the 5' or 3' terminus.
  • X 2 is adenine, guanine, or thymine
  • X 3 is cytosine or thymine
  • X, + X 4 together comprise between about 0 and 26.
  • One or more nucleotide residue within the polynucleotide may be a stabilized residue such as, for example, a phosphorothioate residue.
  • Particularly preferred polynucleotides are within the range of 8-40 nt or bp long.
  • Still other preferred sensitizing agents include any of a variety of different compounds that can stimulate a local immune response when applied topically.
  • immunostimulatory agents include, for example, lipopolysaccharide (LPS) (see, for example, Johnson et al., 1956), lipid A, and heat-killed bacteria (see, for example,
  • cytokines e.g., IL-12, IL-18, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , TGF- ⁇ , etc.
  • cholera toxin proholeragenoid
  • cholera toxin B subunit fungal polysaccharides (e.g., schizophyllan, muramyl dipeptide, muramyl dipeptide derivatives, phorbol esters, microspheres, non-Helicobacter pylori bacterial lysates, labile toxin of Escherichia coli, block polymers, saponins, and ISCOMs).
  • Figure 1 depicts the chemical structure of poison oak urushiol, which is a mixture of four pentadecylcatechols and four heptadecylcatechols. This Figure is reproduced from Armstrong et al., HerbalGram 34:36, 1995.
  • FIGS 2-4 show various embodiments of applicators for use in accordance with the present invention.
  • Figure 5 shows an exemplary protective disk that may be used to localize administered sensitizing agent according to the present invention.
  • Figure 6 shows an infrared (IR) profile of a concentrated extract of poison ivy.
  • Figure 7 shows an ultraviolet (UV) profile of a concentrated extract of poison ivy.
  • FIG. 8 shows a thin layer chromatography (TLC) profile of a concentrated extract of poison ivy.
  • Figure 9 shows a UV spectrum of the urushiol fraction isolated from an extract of poison ivy by column chromatography using an LH-sephadex resin.
  • Figure 10 shows a TLC profile of the urushiol fraction isolated from an extract of poison ivy by column chromatography using an LH-sephadex resin.
  • the present invention provides compositions for treating skin lesions including warts or other viral infections of the skin.
  • the inventive compositions include a sensitizing agent in a sufficient quantity to stimulate an immune reaction at the site of its application.
  • the agent should be of appropriate character, or administered in appropriately small quantity or for an appropriately short time, that no substantial systemic immune reaction is initiated.
  • Preferred sensitizing agents for use in the practice of the present invention include compounds that are naturally produced by poison ivy, poison oak, and/or poison sumac.
  • preferred sensitizing agents include compounds that are naturally found in the sap of these plants.
  • One known component of poison ivy, poison oak, and poison sap is urushiol, a mixture of phenolic compounds with long (15-17 carbons) hydrocarbon side chains (see, for example, Figure 1). The side chain may be saturated or unsaturated with 1-3 double bonds (Dawson, Recent Chemical Progress 15:39, 1954; Dawson, Transac. NYAcad. Sci. 18:427, 1956).
  • Urushiol produced by poison oak plants is comprised primarily of compounds with 17-carbon side chains; that produced by poison ivy and poison sumac plants is comprised primarily of compounds with 15-carbon side chains.
  • the urushiol-containing sap of each of these poison plants elicits a dramatic local immune response when contacted with skin, typically resulting in a characteristic rash.
  • the present invention demonstrates that this sap is also capable of stimulating a response in a host that results in the disappearance of skin lesions (e.g., warts) to which the sap is applied.
  • Preferred sensitizing agents for use in accordance with the present invention therefore, contain a sufficient collection of sap components to produce a substantial reduction in a skin lesion when applied to that lesion in a subject's skin.
  • Poison oak, poison ivy, and poison sumac are classified into either the Rhus or the Toxicodendron genus within the family Anacardiaceae.
  • Urushiols are found in a number of plants in addition to poison ivy, poison oak. and poison sumac.
  • Other members of the family Anacardiaceae including the cashew genus (Anacardium) and the mango genus (Mangifera). Contact with these plants elicits a dermatitis similar to that occurring after exposure to poison ivy, oak. or sumac in sensitive individuals. Cross sensitivity to plants of these various families is well known.
  • the agent responsible for inducing the poison plant immune response i.e., the urushiol
  • the agent responsible for inducing the poison plant immune response is also likely to be the agent responsible for inducing the reaction that results in skin lesion cure.
  • certain preferred embodiments of the invention include compositions comprising one or more urushiols. Given the potency of most urushiols, large amounts are not required to induce the rash response. For example, some individuals respond to molecular traces of urushiol ( ⁇ 2 ⁇ g), and 80-90% of adult Americans respond to ⁇ 50 ⁇ g of purified material (Epstein et al., Arch. Dermatol. 109:356, 1974). It is likely that similar levels will be sufficient to induce the inventive response as well.
  • urushiol and “urushiols” are intended to encompass biologically active analogs and derivatives of urushiol. As discussed herein, one property of such biologically active compounds is the ability to elicit a contact dermatitis in sensitive individuals.
  • the sensitizing agent comprises a compound that is naturally found in the sap of poison ivy, poison oak or poison sumac.
  • the compound is provided as an extract of poison ivy, poison oak, or poison sumac.
  • extraction as the term is used pharmaceutically, entails separation of the medicinally active components of plant or animal tissue from the inactive components using selective solvents in standard extraction procedures. Such procedures are described, for example, in Nairn, J.G. in Remington 's Pharmaceutical Sciences, 18th ed., 1990 and in the United States Pharmacopeia - National Formulary, (e.g., U.S.P. XXII/NF XVII, U.S.
  • Preparation of extracts typically involves placing the solid ingredients, e.g., plant tissues, in a closed container with a solvent and allowing the mixture to stand for a variable period of time to allow soluble matter to dissolve. The mixture may be mixed or agitated while standing. Alternatively, or in addition to the process described above, a solvent can be allowed to percolate through a compacted mass of raw material and the percolate collected. The solid material can be compressed and the expressed fluid added to the percolate. Following collection of the liquid, the active constituents may be concentrated by evaporation of much of the solvent. In some instances heat is used in the preparation of extracts although this is generally to be avoided.
  • Typical solvents include water and alcohol, e.g., ethanol.
  • tests are useful, in addition, to standardize extract preparation so that uniform batches of extract can be produced from raw materials that may van' in terms of their concentration of active ingredient(s) or the ease with which they may be extracted.
  • a biological assay of activity may be used.
  • spectra of various types may be obtained, e.g.. infrared (IR) or ultraviolet (UV) spectra.
  • IR infrared
  • UV ultraviolet
  • Spectroscopic methods suitable for analysis of extracts are described, for example, in Jerry Workman (Editor), Art W. Springsteen, Applied Spectroscopy : A Compact Reference for Practitioners, Academic Press, New York, 1998, which is herein inco ⁇ orated by reference.
  • Other techniques suitable for the analysis of crude and purified extracts at various stages of preparation include thin layer chromatography, gas chromatography and/or mass spectrometry. These techniques are described in Practical Thin-Layer Chromatography : A Multidisciplinary Approach, Bernard Fried and Joseph Sherma (Editors), CRC Press, Boca Ratan, 1996 GC/MS : A Practical Thin-Layer Chromatography : A Multidisciplinary Approach, Bernard Fried and Joseph Sherma (Editors), CRC Press, Boca Rat
  • urushiol-containing composition e.g., sap or other plant extract, synthetic composition, etc.
  • Sensitizing agents may be formulated in any fashion suitable to local administration to a skin lesion such as a wart. It is preferred that the agent be formulated in a way that minimizes the risk of its unintended distribution elsewhere in the body.
  • the sensitizing agent may be formulated for short-duration contact with the lesion and/or may be provided in combination with a neutralizing agent that substantially reduces the risk of undesirable spread of reaction.
  • a neutralizing agent that substantially reduces the risk of undesirable spread of reaction.
  • the particular neutralizing agent selected will depend on the character of the sensitizing agent being employed.
  • the neutralizing agent is a specific inhibitor of the sensitizing agent.
  • the neutralizing agent is a general actor, for example that is capable of removing the sensitizing agent from its site of application (e.g., the neutralizing agent is a soap or a detergent).
  • a detergent or other agent capable of removing the urushiol, can be an effective neutralizing agent. It is important when utilizing a detergent to control application such that solubilized urushiol is not spread to other parts of the body.
  • Preferred detergents for use as urushiol neutralizing agents include, for example, common soap.
  • preferred neutralizing agents include, for example, inhibitors of NFKB activation (e.g., PDTC, gliotoxin, etc.), which have been shown to block the immunostimulatory effects of such polynucleotides (see, for example, published PCT application WO 98/18810).
  • a detergent or other agent capable of removing the polynucleotide from its site of application may alternatively or additionally be employed.
  • the sensitizing agent of the present invention may be formulated for delivery by any of a variety of applicators.
  • Figures 2-4 present certain embodiments of appropriate applicators for use in accordance with the present invention. These depicted embodiments should be understood to be merely exemplary; those of ordinary skill in the art can readily appreciate that any of a variety of different delivery means is suitable for the practice of the present invention, so long as the sensitizing agent becomes applied to the area of the skin lesion in sufficient amount and for a sufficient period of time that an appropriate local immune reaction is induced.
  • Figure 2 presents one possible "pen” applicator embodiment according to the present invention.
  • the applicator 100 includes a first end 110 comprising a pad reservoir 120 impregnated with a sensitizing agent, an elongated handle member 130, and a second end 140.
  • the applicator also includes a removable cap
  • the pad reservoir 120 protrudes from the first end 110 of the applicator 100 in a manner analogous to the point on a felt-tipped pen.
  • Such a configuration can be convenient for the pu ⁇ oses of controlling administration of the sensitizing agent to a defined area of skin, but is not required.
  • alternative configurations such as, for example, a rounded mound or even a substantially flat surface constituting substantially the entire surface of the first end 110.
  • the elongated handle member 130 shown in Figure 2 is presented as a substantially straight, cylindrical member. Those of ordinary skill in the art will readily appreciate that alternative constructions are equally suitable and may be preferable in certain cases.
  • the member 130 may be angled with respect to the first end 110.
  • the member 130 may be formed for comfortable grasping by a hand.
  • the member 130 may have one or more areas adapted to accept one or more fingers wrapped around the member 130.
  • the type of applicator depicted in Figure 2 may include a second pad reservoir at its second end, impregnated with a neutralizing agent. Such an applicator would be used by first applying the sensitizing agent with the first end of the applicator, then waiting an appropriate period of time and reversing the applicator so that the neutralizing agent may be applied from the second end.
  • individual sensitizing agent and neutralizing agent applicators are provided separately. Such applicators may be provided together, for example in a kit, but would be used individually, in series.
  • FIG. 3 presents an alternative embodiment of an applicator of the present invention.
  • the applicator 100 shown in this Figure is a "bulb-type" applicator comprising a first end 110 from which sensitizing agent is delivered, an elongated reservoir chamber 160 in which sensitizing agent is disposed, and a compression bulb 170 or other means for exerting expulsive force through the chamber 160 so that sensitizing agent is delivered from the first end 110.
  • the bulb-type applicator is provided already loaded with sensitizing agent.
  • the first end 110 of the applicator is preferably capped or plugged so as to prevent leakage of the sensitizing agent prior to delivery.
  • a cap may be provided that fits securely over the first end 110.
  • Such a cap could be a single-use (i.e., designed so as not to be replaceable), or could be replaceable (for example, a screw-on).
  • the first end 110 of the applicator is placed in softened wax so that an airtight wax cap 180 is formed that prevents leakage of the sensitizing agent from the applicator.
  • the sensitizing agent is to be applied to a skin lesion
  • the plugged first end 110 is simply removed from the applicator (e.g., by cutting) so that a new, open first end is created. Depression of the bulb 170 then ejects the sensitizing agent through the new opening.
  • Figure 4 presents yet another applicator embodiment for use in accordance with the present invention.
  • the applicator depicted in Figure 4 is of the "dermal patch" type.
  • Dermal patches are well known in art (to give but a few examples, see U.S. Patent No. 5,147.339; U.S. Patent No. 4,666.441 ; each of which is inco ⁇ orated herein by reference).
  • Any available patch is suitable for the practice of the present invention.
  • a patch should include a reservoir 190 in which the sensitizing agent is loaded, and a means of affixing the patch to the skin in the area of the lesion, so that the reservoir is sufficiently well positioned over the lesion that the sensitizing agent contacts the wart and/or neighboring tissue.
  • Any available affixing means may be employed; preferred affixing means include adhesive bandages.
  • the affixing means 200 comprises adhesive tabs extending from the reservoir 190 so that the patch, once applied, is secured to the skin.
  • Preferred patches may include means of enhancing transdermal delivery of the sensitizing agent.
  • a variety of such means is known in the art.
  • known transdermal delivery patches often include an added substance that assists the penetration of the active ingredient (i.e., the sensitizing agent in the present invention) through the skin. Often, this substance is termed an "enhancer".
  • an enhancer Many such enhancers are known in the art (to give but one example, see U.S. Patent No. 5,023,252, inco ⁇ orated herein by reference), some of which are water soluble, and some of which are water insoluble.
  • the enhancer also acts as an encapsulating means, that assists the transport of the active ingredient into the skin (e.g., liposome enhancers- see, for example, U.S. Patent No. 5.718,914, inco ⁇ orated herein by reference). Any known enhancer that is compatible with the selected sensitizing agent is useful in accordance with the present invention.
  • One advantage of applying the sensitizing agent of the present invention by means of a dermal patch is that the occlusion caused by covering the lesion with the patch may itself enhance the resolution of the lesion (see, for example, U.S. Patent
  • An additional advantage is that the patch covers the lesion during the period of time that it is contacted with the sensitizing agent, and therefore reduces the likelihood that sensitizing agent will inadvertently be contacted with other areas of the individual's body.
  • a neutralizing patch i.e., a patch containing neutralizing agent
  • Sensitizing agents may be applied by any available means including, for example, by stick-type applicators (e.g., cotton-tipped swabs), by direct contact with a source of sensitizing agent (e.g., with the broken stem of a poison ivy, poison oak, or poison sumac plant), by hand (preferably a protected hand, e.g., covered with a glove), etc.
  • a source of sensitizing agent e.g., with the broken stem of a poison ivy, poison oak, or poison sumac plant
  • hand preferably a protected hand, e.g., covered with a glove
  • Bottles, tubes, boxes, or other containers of sensitizing (and/or neutralizing agent) may be provided to the individual performing the application, and that individual may select the particular mode by which agent will be applied to lesion.
  • applicators for use in accordance with the present invention may be designed for single-use or multiple-use applications.
  • Dermal patch-type applicators will typically be single-use; pen or bulb applicators may be either single-use or multiple-use.
  • a multiple-use applicator it may be useful to utilize materials and arrangements that allow for sterilization (e.g., by autoclaving, contacting with alcohol, or other means) between applications of surfaces that contact skin.
  • the applicator may be designed to release or apply sensitizing agent on a designated surface (e.g., a pad to subsequently be applied to the lesion, or directly to the lesion), so that the applicator itself does not actually contact skin.
  • applicators may also generally be desirable to use applicators in combination with one or more barrier means that limit the spread of the sensitizing agent (and/or neutralizing agent) from the immediate area to which it is applied.
  • barrier means that limit the spread of the sensitizing agent (and/or neutralizing agent) from the immediate area to which it is applied.
  • a protective barrier e.g.. an adhesive disc whose opening is positioned over the lesion
  • the ability of the sensitizing agent (and/or neutralizing agent) to spread from its site of application to other areas of the body can be limited by adjusting parameters of the formulation itself, such as viscosity and volatility. In general, spreading is more controllable with more viscous preparations. Also, the more rapidly a preparation volatilizes, the less likely it is to spread while in liquid form. Of course, if the sensitizing agent (and/or neutralizing agent) can still be transferred by contact even after volatilization of other components of the formulation, other precautionary measures may desirably be taken as well.
  • Warts with Poison Ivy Sap Four patients, ranging in age from 4 to 47 years and suffering from between 1 and 4 warts, were enrolled in the present study. Each wart had been present for between 1 and 12 years, and three of the four patients had been treated unsuccessfully on 1-4 occasions. In total, 13 warts were treated.
  • This Example summarizes a procedure that has been developed to extract poison ivy leaves and the analytical methods that have been developed to examine the resultant extracts.
  • the focus of the analytical method development program has been to first identify and then quantify the level of urushiol, as well as other components that have not been identified, in the extract, and to follow those levels during storage of the extract as a measure of chemical stability.
  • the terms urushiol and urushiols may be used interchangeably, recognizing that, as discussed above, they are a family of related compounds comprised of catechols derivatized with long-chain polyunsaturated alkyl groups.
  • poison ivy leaves stored frozen since the time of fresh harvest, are suspended in 95% denatured ethanol under refrigerated conditions (approximately 4°C) in a tightly closed jar flushed with nitrogen to avoid introduction of oxygen.
  • the ratio used is 250 grams of leaves in 2 L of ethanol.
  • the suspension is left under refrigerated conditions without agitation for four days, following which the extract is filtered through a nylon cloth into a 3L flask in order to remove solids.
  • the extract is concentrated under reduced pressure by rotary evaporation to approximately 250 mL.
  • the final concentrate is stored in sealed bottles, under nitrogen, in aliquots of approximately 50 mL.
  • the storage temperature is maintained at no higher than
  • the extract has been characterized by several analytical methods well known in the art of analytical chemistry, including infrared spectroscopy (IR), ultraviolet spectroscopy (UV), thin-layer chromatography (TLC), and column chromatography using an LH- sephadex resin. Data obtained by these analytical methods are utilized to compare extraction consistency as well as chemical stability of extracts during storage. Data obtained using these methods are both qualitative and quantitative in nature.
  • the urushiol fraction has been positively identified and quantified. The relative levels of other, unidentified, components are followed by their chromatographic and spectroscopic behavior.
  • IR and UV spectra of the concentrated extract prepared as described above were obtained using standard techniques. In the concentrated extract, it appears that components other than urushiol dominate the spectroscopic profile in both the IR and UV spectra, as may be expected.
  • IR and UV spectra obtained by analysis of the unfractionated, concentrated extract are shown in Figures 6 and 7 respectively.
  • Figure 9 shows the UV spectrum of the urushiol-containing fraction obtained by purification of unfractionated, concentrated extract using LH-sephadex. It is not possible at this time to unambiguously assign any IR or UV peak maxima to the presence of urushiol itself.
  • Thin-layer chromatography provided definite evidence of the presence of urushiol in the extract.
  • silica gel 60 plates to which the concentrated extract had been applied, were developed with methylene chloride. Several components (yellow to green in color) were visible on the developed plate.
  • the developed plate was sprayed with a 1% solution of ferric chloride in methanol, resulting in the reduction of ferric ion to metallic iron by the phenolic urushiols, giving rise to a dark spot on the plate where urushiol is present ( Figure 8).
  • This method may also be utilized to provide semi- quantitative evidence for the amount of urushiol in the extract.
  • lanes 1 and 8 are controls consisting of unfractionated extract.
  • Each pair of lanes 2 - 7 represents samples from fractions of the 2% and 16% methanol gradients from three different chromatographic runs.
  • lanes 2, 4, and 6 represent fractions from the 2% methanol gradient from three separate runs while lanes 3, 5, and 7 represent fractions from the 16% methanol gradient from the same runs, i.e., lanes 2 and 3, 4 and 5, and 6 and 7 represent samples obtained from the same three runs.
  • the extraction procedure that has been developed is simple, convenient, and reproducible.
  • the analytical methods which have been developed to analyze these extracts provide both qualitative and quantitative data for components of the extracts.
  • Example 4 Delivery of a Sensitizing Agent from a Bulb-type Applicator
  • the bulb 170 of a bulb type applicator substantially as depicted in Figure 3 is depressed slightly prior to insertion of the applicator first end 110 into a composition comprising an extract of poison ivy.
  • the bulb 170 is released so that a predetermined amount of extract is loaded into the chamber 160.
  • the first end 110 is subsequently placed in softened, high-melting-point wax so that an airtight seal is formed.
  • the applicator is then packaged for shipment to the site of application.
  • the poison ivy extract is subsequently delivered from the applicator to a subject suffering from a skin lesion such as a wart.
  • an adhesive protective disk such as that depicted in Figure 5, is applied to the subject, so that the open center of the disc is positioned over the lesion and the lesion is otherwise surrounded by disk.
  • a variety of protective disks are commercially available. The size of the disk is selected to be appropriate to the size of the lesion being treated.
  • the plugged first end 110 of the applicator is removed with scissors, so that a new first end is created through which ivy extract can be delivered.
  • the new first end is then positioned over the exposed lesion in the center of the disk, and the bulb 170 is depressed so that ivy extract is expelled through the new first end of the applicator and onto the lesion.
  • the lesion is subsequently covered with an adhesive bandage.
  • any adhesive bandage is removed and the lesion is washed carefully to remove ivy extract.
  • the protective disk is then also removed, and the lesion is washed again.

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Abstract

La présente invention concerne des compositions et des méthodes destinées au traitement de lésions cutanées, consistant à mettre en contact la lésion avec une substance sensibilisante pouvant déclencher une réaction immunitaire locale chez l'individu atteint de cette lésion. Les compositions et les méthodes de l'invention peuvent convenir dans les contextes pharmaceutique et/ou vétérinaire.
EP99967615A 1998-12-22 1999-12-22 Agents sensibilisants pour le traitement de lesions cutanees Withdrawn EP1140052A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US218345 1980-12-22
US21834598A 1998-12-22 1998-12-22
PCT/US1999/030875 WO2000037067A2 (fr) 1998-12-22 1999-12-22 Traitement de lesions cutanees

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JP (1) JP2002532547A (fr)
AU (1) AU770464B2 (fr)
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DE10331974A1 (de) * 2003-07-14 2005-02-17 Uni-Klinikum Schleswig-Holstein Campus Kiel Verfahren zur Herstellung und Verwendung antimikrobielle Proteine induzierender Faktoren
KR101352238B1 (ko) * 2007-04-04 2014-01-15 더 보드 오브 트러스티스 오브 더 유니버시티 오브 아칸소 단순포진바이러스 감염 치료를 위한 비특이적 지연형 과민증 반응
US8273387B2 (en) 2009-08-26 2012-09-25 Mary Kay Inc. Topical skin formulations comprising plant extracts
NL2003419C2 (en) * 2009-09-01 2011-03-02 Shieldmark Zacco Composition for tropical application, uses thereof, applicator device and kit of parts.
US9597385B2 (en) 2012-04-23 2017-03-21 Allertein Therapeutics, Llc Nanoparticles for treatment of allergy
CN105188741A (zh) 2013-04-03 2015-12-23 阿勒丁医疗公司 新型纳米颗粒组合物
KR102533463B1 (ko) 2015-02-26 2023-05-16 스퀘어렉스 파마슈티컬 코포레이션 단순 포진 바이러스 감염을 치료하기 위한 비특이적 지연형 과민성 반응
JP7326343B2 (ja) * 2018-02-13 2023-08-15 ハプテン・サイエンシーズ・インコーポレイテッド ウルシオールを含むパッチ、それを含む試験パネル、及びそれを使用する方法

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WO1998018810A1 (fr) * 1996-10-30 1998-05-07 The University Of Iowa Research Foundation Molecules d'acide nucleique immunostimulantes

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DE3705151A1 (de) * 1987-02-18 1988-09-01 Brigitte Luenemann Warzenmittel
US5236707A (en) * 1991-11-08 1993-08-17 Dallas Biotherapeutics, Inc. Stabilization of human interferon
KR100215390B1 (ko) * 1997-02-13 1999-08-16 박호군 우루시올계 화합물의 항산화 활성을 포함한 항암제로서의 새로운 용도 및 그의 제조방법

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018810A1 (fr) * 1996-10-30 1998-05-07 The University Of Iowa Research Foundation Molecules d'acide nucleique immunostimulantes

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WO2000037067A2 (fr) 2000-06-29
WO2000037067A3 (fr) 2001-01-18
CA2357413A1 (fr) 2000-06-29
AU2387100A (en) 2000-07-12
AU770464B2 (en) 2004-02-19
WO2000037067A9 (fr) 2000-11-23

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