TOPICALAPPLICATION OFANALGESIC FOR PAIN RELIEF

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/055,030, filed May 21, 2009, the contents of which are incorporated by reference in the entirety.

BACKGROUND OF THE INVENTION

[0002] A significant fraction of the general population suffers from various medical conditions that result in chronic pain. Musculoskeletal and rheumatic complaints account for approximately 15% of the patients seen by primary care physicians. These complaints include muscle pain and weakness, regional pain syndrome such as back or neck pain, rheumatoid arthritis, gout, ankylosing spondylitis and lupus erythematosus. More aggressive muscle pain associated with muscle inflammatory activity is less common and occurs in patients with the autoimmune disorders, polymyalgia rheumatica, and polymyositis. As one example, fibromyalgia, a chronic condition characterized by widespread pain/stiffness associated with fatigue, digestive disturbances, cognitive dysfunction, and many other symptoms, is estimated to affect well over 2% of the population in the United States. Because of the high prevalence of pain caused by different conditions, there exists a need for new, effective, and ready-to-use methods for pain amelioration and management. This invention fulfills this and other related needs.

BRIEF SUMMARY OF THE INVENTION

[0003] In one aspect, this invention provides a method for reducing pain in a patient. This method includes the step of administering an effective amount of an analgesic to the patient at a location that is a fibromyalgia tender point, a myofascial trigger point, or a Chinese medicine acupoint.

[0004] In some embodiments, the administration step involves applying a patch containing the analgesic, such as a capsaicin patch, to the patient. In some embodiments, the application may take place at multiple locations: for instance, a patch (e.g., capsaicin patch) is applied to the patient at various points on the skin and, for at least some of these points, each is a fibromyalgia tender point, a myofascial trigger point, or a Chinese medicine acupoint.

[0005] For the patches used in the present invention, they are in some cases round-shaped patches and their diameters are no greater than 2.5 cm. As an example, the diameter of a typical patch is between 0.5 to 2 cm. In some cases, the patch has an adhesive material on one side.

[0006] In practicing the present invention, the analgesic composition {e.g., a capsaicin patch) is applied daily for a treatment period ranging from 1 day to 6-8 weeks. For each day, the active administration may take place for up to 12 hours, e.g., a patch can be applied according to a 12- hour on and 12 -hour off schedule.

[0007] A capsaicin concentration of 0.025% to 0.15% in a patch is typical. In one example, the patch is a hydrogel patch with a 0.1% concentration of capsaicin, and the patch is 2.5 cm in diameter of and has a lavender scent.

[0008] In a second aspect, the present invention provides a kit for reducing pain. The kit includes an analgesic in an effective amount for reducing pain, an illustration of at least some of fibromyalgia tender points, myofascial trigger points, or Chinese medicine acupoints on a human body, and instructions on applying the analgesic to at least one location that is a fibromyalgia tender point, myofascial trigger point, or Chinese medicine acupoint.

[0009] In some embodiments, the analgesic is provided in a patch, such as a capsaicin patch. The analgesic may be applied at multiple locations: for instance, a patch (e.g., capsaicin patch) can be applied to the patient at various points on the skin and, for at least some of these points, each is a fibromyalgia tender point, a myofascial trigger point, or a Chinese medicine acupoint. [0010] For the patches in the kit, they are in some cases round-shaped patches and their diameters are no greater than 2.5 cm. As an example, the diameter of a typical patch is between 0.5 to 2 cm. In some cases, the patch has an adhesive material on one side.

[0011] The capsaicin patches typically have a capsaicin concentration of 0.025% to 0.15%. In one example, the patch is a hydrogel patch. In another example, the capsaicin patch has a 0.1% concentration of capsaicin, and the patch is 2.5 cm in diameter and has a lavender scent.

BRIEF DESCRIPTION OF THE DRAWINGS [0012] Figure 1 illustrates the locations of the 18 tender points of fibromyalgia.

[0013] Figure 2 shows in vitro permeation of capsaicin across rat skin: shaded circle is capsaicin 0.075% (750 meg sample) CMC-Na patch, and non-shaded circle is 0.025% (250 meg

sample) capsaicin. Taken from Wang et al. , International Journal of Pharmacokinetics 234 (2001) 89-104.

[0014] Figure 3 shows in vitro permeation of capsaicin across rat skin: capsaicin 0.1% hydrogel patch.

DEFINITIONS

[0015] An analgesic is a compound that is capable of reducing pain in a patient without causing loss of consciousness. Analgesics are sometimes generally referred to as painkillers. Examples of analgesics include aspirin, acetaminophen (Tylenol), ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), the COX-2 inhibitor celecoxib, and narcotics including morphine, oxycodone, and hydrocodone (Vicodin). One analgesic useful for this invention is capsaicin, 8- methyl-N-vanillyl-6-nonenamide, or (CH ₃ ) ₂ CHCH=CH(CH ₂ ) ₄ CONHCH ₂ C ₆ H ₃ -4-(OH)-3- (OCH ₃ ), the active component in chili peppers.

[0016] Fibromyalgia is a soft tissue or muscular rheumatism, often called a rheumatic syndrome, with widespread pain in muscles, tendons, and other connective tissues, resulting in muscle pain without muscle weakness. Tender points of fibromyalgia exist at these nine bilateral muscle locations:

- Low Cervical Region: (front neck area) at anterior aspect of the interspaces between the transverse processes of C5-C7;

- Second Rib: (front chest area) at second costochondral junctions; - Occiput: (back of the neck) at suboccipital muscle insertions;

- Trapezius Muscle: (back shoulder area) at midpoint of the upper border;

- Supraspinatus Muscle: (shoulder blade area) above the medial border of the scapular spine;

- Lateral Epicondyle: (elbow area) 2 cm distal to the lateral epicondyle; - Gluteal: (rear end) at upper outer quadrant of the buttocks;

- Greater Trochanter: (rear hip) posterior to the greater trochanteric prominence;

- Knee: (knee area) at the medial fat pad proximal to the joint line.

[0017] To diagnose fibromyalgia, a doctor will apply pressure with an approximate force of 4 kg to the tender points. If the patient has pain in 11 of these 18 tender points in combination with meeting other diagnosis criteria, then the doctor may diagnose Fibromyalgia. The 18 tender points are shown in Figure 1. [0018] The concepts of myofascial pain syndrome (myofascial referring to the combination of muscle and fascia) and myofascial trigger points were first introduced by Janet Travell, M.D. The myofascial pain syndrome is described as a focal hyperirritability in muscle that can strongly modulate central nervous system functions. It is distinguished from fibromyalgia, as the latter is characterized by widespread pain and tenderness and is described as a central augmentation of nociception giving rise to deep tissue tenderness that includes muscles. Myofascial pain is associated with muscle tenderness that arises from trigger points, or focal points of tenderness, which are usually a few millimeters in diameter and can be present at multiple sites in a muscle and the fascia of muscle tissue. Biopsy tests may find that trigger points are hyperirritable and electrically active muscle spindles in general muscle tissue. Myofascial trigger points can be identified based on these general characteristics:

- Pain related to a discrete, irritable point in skeletal muscle or fascia, not caused by acute local trauma, inflammation, degeneration, neoplasm or infection.

- The painful point can be felt as a knot or band in the muscle, and a twitch response can be elicited on stimulation of the trigger point. - Palpation of the trigger point reproduces the patient's complaint of pain, and the pain radiates in a distribution typical of the specific muscle harboring the trigger point.

- The pain cannot be explained by findings on neurological examination.

[0019] Acupuncture points, or acupoints, in traditional Chinese medicine are locations on the body that are the focus of acupuncture, acupressure, sonopuncture, and laser acupuncture treatments. There are several hundred acupoints that are distributed along meridians (which are connected points across the body that affect a specific organ or a body part), as well as numerous other "extra points" not associated with a particular meridian. The precise locations and nomenclature can be found in various publications including standard acupuncture nomenclature published by the World Health Organization and the national standardized acupuncture point

locations published by the government of the People's Republic of China. When an acupoint is referred to as an "associated Chinese medicine acupoint" or "associated acupoint" in this application, it means that the pain being treated is within the organ or body part that this particular acupoint is deemed to affect. [0020] As used here, the term "gel" refers to a colloid that is in a more solid form than a solution, i.e., a solid three-dimensional network that spans the volume of a liquid medium. This internal network structure may result from physical or chemical bonds, as well as crystallites or other junctions that remain intact within the extending fluid. Virtually any fluid can be used as an extender or the dispersion medium: when water is the medium, the colloidal gel is called hydrogel or aquagel. Hydrogel is usually a network of natural or synthetic polymer chains that are water-insoluble but highly absorbent. It also possesses a degree of flexibility very similar to natural tissue, due to its significant water content.

[0021] The term "effective amount," as used herein, refers to an amount that produces therapeutic effects for which a substance is administered. The effects include the prevention, correction, reduction, delay of onset, or inhibition of progression of the symptoms of a disease/condition (such as pain) and related complications to any detectable extent. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations ( 1999)).

DETAILED DESCRIPTION OF THE INVENTION

I. INTRODUCTION

[0022] The present invention relates to the discovery that administration of an analgesic at one or more locations on a patient's body can reduce pain the patient is experiencing. The suitable location or locations are selected from (1) fibromyalgia tender points; (2) myofascial trigger points; or (3) Chinese medicine acupoints. As an example, an adhesive patch containing an analgesic can be applied to the pre-selected location or locations over the period of a few days to several weeks. In contrast to the standard of care treatment methods for some chronic pain conditions such as myofascial pain syndrome where a physician may perform injection of analgesics at trigger point(s) or acupuncture at acupoint(s), the topical application of analgesics,

such as the use of an analgesic patch, provides a much more convenient treatment option that is readily usable by patients in an in-home, self-care fashion.

II. ANALGESIC COMPOSITIONS AND ADMINISTRATION THEREOF

[0023] Various well known external analgesics are suitable for the present invention. They include but are not limited to those disclosed in the Tentative Final Monograph for External

Analgesic Drug Products for over-the-counter human use, U.S. Federal Register Vol. 48, No. 27, Feb. 28, 1983. These monographed external analgesics include counter-irritants that produce redness, for example, Allyl isothiocryanate 0.5-5%, Methyl salicylate 10-60%, and Turpentine oil 6-50%; irritants that produce cooling, for example, Camphor 3% to 11%, or Menthol 1.25- 16%; irritants that produce vasodilation, for example Histamine dihydrochloride 0.025-0. 10%, or Methyl nicotinate 0.25-1%; and irritants that do not produce redness, for example, Capsaicin 0.025-0.25%, Capsicum containing 0.025-0.25% capsaicin, or Capsicum oleoresin containing 0.025-0.25% capsaicin.

[0024] The pain relief method of this invention is generally suitable for pain management for any medical condition that involves chronic pain in soft tissue or joints. Fibromyalgia and myofascial pain syndrome are two examples of such conditions.

[0025] The analgesic compositions used in the present invention may be prepared in a number of forms for application to the skin (i.e., topical application) of a patient. For example, the composition may be applied in a gel, cream, ointment, liquid, spray liquid, paint-/brush-on preparation, solidifying emulsion or cream (e.g. , facial mask), aerosol, powder, oil, balm, salve, or adhesive patch. The topical compositions may be in the form of meltable solids, semi-solids, solutions, suspensions, or emulsions. In addition the composition may be impregnated on a bandage, hydrocolloid dressing, treatment patch, or on cloth wipe products. In one embodiment, the topical composition may have resistance to moisture and subsequent washing off from the skin. In other embodiments, the topical composition may be in a time-release formula such that the analgesic is released gradually over an extended period of time.

[0026] In certain embodiments, the topical compositions comprise a dermatologically acceptable carrier that is compatible with the active ingredients, e.g., capsaicin. An effective and safe carrier typically varies from about 50% to about 99% by weight of the topical compositions, often from about 75% to about 99% or about 75% to about 95% by weight of the compositions.

[0027] The topical compositions useful in the present invention can be formulated as solutions. Solutions typically include an aqueous or organic solvent (e.g., from about 50% to about 99.99% or from about 90% to about 99% of a cosmetically acceptable aqueous or organic solvent). Examples of suitable organic solvents include: propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, and mixtures thereof.

[0028] The topical compositions may be formulated to contain an emollient, typically from about 2% to about 50% of an emollient or emollients. As used herein, "emollients" refer to materials used for the prevention or relief of dryness, as well as for the protection of the skin. Lotions typically comprise from about 1% to about 20% (e.g., from about 5% to about 10%) of one or more emollients and from about 50% to about 90% (e.g., from about 60% to about 80%) of water, whereas a cream typically comprises from about 5% to about 50% (e.g., from about 10% to about 20%) of one or more emollients and from about 45% to about 85% (e.g., from about 50% to about 75%) of water. An ointment is a further option, comprising a simple base of animal or vegetable oils or semi-solid hydrocarbons, from about 2% to about 10% of one or more emollients plus from about 0.1% to about 2% of at least one thickening agent. A wide variety of suitable emollients and thickening agents or viscosity-increasing agents are known and may be used herein. Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32- 43, 72-73 (1972) and the International Cosmetic Ingredient Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55 (The Cosmetic, Toiletry, and

Fragrance Assoc, Washington, D.C., 7th Edition, 1997) (hereinafter "ICI Handbook") contains numerous examples of suitable materials.

[0029] The topical compositions useful in the present invention can be formulated as emulsions. If the carrier is an emulsion, from about 1% to about 10% (e.g., from about 2% to about 5%) of the carrier may be an emulsifϊer or emulsifϊers. Emulsifiers may be nonionic, anionic, or cationic. Suitable emulsifiers are disclosed in, e.g., U.S. Pat. Nos. 3,755,560, 4,421,769, McCutcheon's Detergents and Emulsifiers , North American Edition, pp. 317-324 (1986), and the ICI Handbook, pp. 1673-1686.

[0030] The topical compositions used in this invention can also be formulated as a gel (e.g. , an aqueous, alcohol, alcohol/water, or oil gel using one or more suitable gelling agents). Suitable gelling agents for aqueous and/or alcoholic gels include, but are not limited to, natural gums,

acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g. , hydroxymethyl cellulose and hydroxypropyl cellulose). Suitable gelling agents for oils (such as mineral oil) include, but are not limited to, hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/styrene copolymer. Such gels typically comprise between about 0.1% and 5%, by weight, of such gelling agents.

[0031] In some cases, the topical compositions can also be formulated into a solid delivery system {e.g., a wax-based stick, soap bar composition, powder, or a wipe containing powder).

[0032] Liposomal formulations are also useful compositions of the subject invention. Examples of liposomes are unilamellar, multilamellar, and paucilamellar liposomes, which may or may not contain phospholipids. Such compositions can be prepared according to the method described in Mezei & Gulasekharam, Journal of Pharmaceutics and Pharmacology, Vol. 34 (1982), pp. 473-474, or a modification thereof. Epidermal lipids of suitable composition for forming liposomes may be substituted for the phospholipid. The liposome preparation may then be incorporated into one of the above carriers (e.g., a gel or an oil-in- water emulsion) in order to produce the liposomal formulation. Other compositions and uses of topically applied liposomes are described in, e.g., WO96/31194 and U.S. Pat. No. 5,260,065.

[0033] The topical compositions useful in this invention may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water- soluble materials conventionally used in compositions for use on skin, hair, and nails at their art- established levels. Various other materials may also be present in the compositions, including adsorbants, humectants, proteins and polypeptides, preservatives and an alkaline agent. Examples of such agents are disclosed in the ICI Handbook, pp. 1650-1667.

[0034] The compositions of the present invention may also comprise chelating agents (e.g., EDTA) and preservatives (e.g., parabens). Examples of suitable preservatives and chelating agents are listed in pp. 1626 and 1654-55 of the ICI Handbook. In addition, the compositions may contain conventional cosmetic adjuvants, such as dyes, opacifiers (e.g., titanium dioxide), pigments, and fragrances.

[0035] In one embodiment the composition is delivered in a stick or bar, which is rubbed upon the skin wherein the active ingredient (e.g. , capsaicin) is deposited on the skin. In one embodiment, the active ingredient (e.g., capsaicin) is impregnated into in a patch or fabric for

prolonged contact with the skin. Natural or synthetic material, preferably flexible, breathable, and hypoallergenic, can be used to provide a base or backing of the patch containing the analgesic composition. Optionally, the patch is adhesive, e.g. , comprises an adhesive material on one side of the patch so that the patch will adhere to the skin without additional fastening device. [0036] In one embodiment, the active ingredient (e.g., capsaicin) is incorporated into a pumpable or sprayable solution, suspension, or emulsion, which forms a continuous or discontinuous coating, an adhesive firm, or a nonwoven fabric when sprayed onto the skin. In one such embodiment, the active ingredient can be incorporated into a polymer-containing solution, suspension, or emulsion, which forms a solid mesh or entrapment upon application, adheres to the skin and solidifies. Additional ingredients incorporated into a sprayable composition may include but are not limited to fibers, a binder, and a diluent. The fibers may be synthetic or natural, such as cotton, wool, silk, cashmere, linen seaweed cellulose, ramie cellulose, mink fur, rabbit hair, aramid, chitosan, carbon, glass, metal, ceramic, or other fibers, in dimensions sufficiently small to flow through a nozzle. The diluent may be any suitable solvent, such as acetone, water, ethyl acetate, or the like. The binder may be any suitable polymer or mixture of polymers that is soluble in the diluent, and solid at room temperature, such as polyvinyl acetate, polyvinyl butyrate, polyvinyl alcohol, and natural latex. The binder aids with adhesion of the sprayed fibers to one another. Preferably the fibers have a length about 20 microns to about 200 microns, and a length to diameter ratio of at least about 3:1. One such suitable sprayable composition is disclosed in WO 03/104540.

[0037] When the analgesic composition is delivered in the form of a cream or lotion, the cream or lotion preferably has the qualities of superior adhesion to the skin or superior resistance to wash-off by water or perspiration. Suitable wash-off resistant substance is known in the art and is disclosed, for example, in WO 2005/070371, U.S. Pat. No. 6,756,059, and published U.S. Patent Application Publication No. 2005/0232876. Furthermore, U.S. Patent Application

Publication No. 2006/0064068 describes a film-forming barrier composition that forms, over the skin, a thin film coating resistant to wash-off by water or body fluids. The analgesic composition of this invention may be formulated in accordance with these known methods for effective administration. Additional ingredients may be added to the topical analgesic compositions include protectants (e.g., UV blockers), insect repellants, and moisturizers.

[0038] The topical composition of this invention is optionally formulated to achieve an extended time release profile for improved delivery of the analgesic. For instance, hydrophilic matrix is known to provide for a controlled pharmacokinetic release profile. A hydrophilic matrix may encompass one or more natural or synthetic materials that are hydrophilic, but not necessarily water-soluble. Examples of a hydrophilic matrix include polymer(s) having affinity for absorbing water such as cellulose ethers (e.g., hydroxypropyl methylcellulose), mono or disaccharides (e.g., dextrose or lactose), starch, derivatives thereof, alone or in various combinations. In one embodiment, the analgesic composition used in this invention is provided in an adhesive patch that comprises an analgesic -containing hydrogel and can be directly applied to a patient's skin. Such patches can be made in any shape, preferably with an area comprising the adhesive surrounding an area exposing the analgesic composition to the patient's skin. The longest dimension of the patch is typically no greater than 3-5 cm. Frequently, the patch is round and its diameter is no greater than 2.5-3 cm, for example, between to 0.5 to 2 cm.

[0039] Depending on the nature and severity of the condition being treated, it may be recommended that an analgesic composition be applied at one or more locations on the patient's body. At least some of these locations are selected from the following three categories: fibromyalgia tender points, myofascial trigger points, and Chinese medicine acupoints. These selected locations may include varying number of points from one or more of the three categories, but need not includes at least one point from every category. In other words, the selected locations may consist of various points from just one or two categories. In general, particular tender points or trigger points relevant to the fibromyalgia or myofascial pain are selected for applying the analgesic composition. For instance, application at the lower cervical region (i.e., points 6 and 7 in Fig. 1) or at the gluteal/greater trochanter area (i.e., points 8 and 9 in Fig. 1 ) may be appropriate for treating neck pain or lower back pain. Chinese medicine acupoints, especially associated acupoints, i.e., those deemed to affect a specific organ or a body part relevant to the pain being treated, may also be selected for the purpose of analgesic administration. For instance, application of analgesic at acupoints GB 21 and BL 54 are commonly used for treating neck and lower back pain. Application of an analgesic composition at one to four locations on a patient is typical, most often at two to three locations. [0040] In addition to these locations selected from the three above-mentioned categories, the analgesic composition may also be applied to other locations that fall outside of these categories, as directed by an attending physician.

[0041] Optionally, the analgesic composition may also be applied to one or more additional locations that do not belong to these three categories. Moreover, the nature and severity of the condition being treated may also determine the schedule of administration. For instance, it may be desirable to apply the analgesic composition once per day and up to 2-4 times per day, over a continuous treatment period ranging from one day to several weeks, e.g., from 2 days to 8 weeks, or from 4-5 days to 4-5 weeks. In some cases, the analgesic composition (such as a capsaicin patch) is applied to a patient's skin daily on a 12-hour on /12-hour off schedule, for a therapeutic period of as little as 1 day to as long as 8 weeks. More often, the treatment period is at least 3-4 days and up to 3-4 weeks, e.g., 2-3 weeks.

III. KITS

[0042] The invention provides compositions and kits for practicing the methods described herein to reduce pain and associated symptoms in a patient, which can be used for treating a variety of medical conditions, especially those in which the patients afflicted experience prolonged soft tissue pain. [0043] Kits for carrying out the treatment methods of this invention typically include one or more containers that store the composition comprising an analgesic. For example, one, typically multiple, analgesic patches such as adhesive capsaicin patches are included in the kit. Optionally, such patches are hydrogel time-released patches. Because the analgesic composition is to be administered over a time period for some clinical indications, it may be provided in a dosage form and packaged for use over a course of several days to several weeks, for example, from 1-2 weeks to 4-6 weeks.

[0044] Typically, the kits also provide instruction manuals to guide users in selecting the locations on the body for applying the analgesic composition, duration and frequency of the application, in accordance with their clinical symptoms. The kits may optionally include a map of various locations on the body where analgesic compositions may be administered.

EXAMPLES

[0045] The following examples are provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results.

Example 1: Pharmacokinetic and Safety Testing of Capsaicin Patch

[0046] In vitro skin permeation experiments have been reported in the literature on capsaicin 0.25% and 0.75% hydrogels. These experiments have used the skin of rats. See Figure 2, taken from Wang et ah, "In vitro and in vivo evaluations of topically applied capsaicin and nonivamide from hydrogels" International Journal of Pharmacokinetics 234 (2001) 89-104.

[0047] The capsaicin 0.1% (500 meg) hydrogel patch by the present inventor was tested by one of the co-authors of the Wang et a publication. Because the size of the patch was larger than the delivery area of the experimental instrument, delivery of capsaicin was 100 meg. Based on this calculation, skin permeation from the capsaicin 0.1% hydrogel patch may be higher than the hydrogels in the published study. See Figure 3.

[0048] The study described above demonstrates that capsaicin delivered via the 0.1% capsaicin hydrogel easily penetrates the skin. Since there is a balance between the amount of skin permeation of capsaicin and skin irritation/toxicity, in vitro skin irritancy profiles of the patch to be used in the proposed study were explored, using the methodology of a previous study to evaluate skin brightness, skin erythema, and transdermal water loss to measure skin irritability/toxicity (Fang et ah, "In vitro topical application and in vivo pharmacodynamic evaluation of nonivamide hydrogels using Wistar rat as an animal model" Eur. J. Pharm. ScL 15 (2002) 417-423). The experiment demonstrates safety of the capsaicin 0.1% hydrogel patch since there is not significant skin brightness, skin erythema, or transepidermal water loss in the rat experimental model.

Table 1. Safety of capsaicin 0.1% hydrogel on rat skin

Skin condition Value δ Value ³

L* (skin brightness) 69.06±2.17 2.22±2.97 a* (skin erythema) -0.61±0.53 -1.28±2.13

Transepidermal water loss (g/m ² /h) 13.19±2.42 1.23±2.47 a δ value indicates the value of patch-treated skin area minus the non-treated skin area (control).

[0049] All patents, patent applications, and other publications, including GenBank Accession Numbers, cited in this application are incorporated by reference in the entirety for all purposes.