Methods for treating inflammatory dysfunction of oral mucosa

Abstract

Provided herein, inter alia, is a method for treating inflammatory dysfunction of the oral mucosa comprising topically administering an effective amount of a resin toxin (RTX).

Description

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 347,285, filed on May 31, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] Throughout this application, various publications, patents and / or patent applications are cited. The disclosures of these publications, patents and / or patent applications are hereby incorporated into this application by reference in their entirety to more fully describe the current state of the art to which this disclosure relates. Technical Field

[0003] The present disclosure provides a method for treating inflammatory disorders of the oral mucosa, the method comprising topically administering an effective amount of resiniferatoxin (RTX). Background Art

[0004] RTX acts as a super potent analog of capsaicin, the main spicy ingredient of red peppers. RTX is a tricyclic diterpene isolated from certain species of Euphorbia. High vanillyl is an important structural feature of capsaicin and is the most significant feature that distinguishes resiniferatoxin from typical phorbol-related compounds. Natural RTX has the following structure:

[0005]

[0006] RTX and analog compounds such as tinyatoxin and other compounds (20-homovanillyl esters of diterpenes such as 12-deoxyphorbol 13-phenylacetate 20-homovillate and michelatoxin 20-homovillate) are described in U.S. Pat. Nos. 4,939,194; 5,021,450; and 5,232,684. Other resiniferatoxin-type phorboid vanilloids have also been identified (Szallasi et al. (1999) Brit. J. Pharmacol. 128:428-434).

[0007] RTX is known as a TRPV1 agonist. TRPV1, i.e., transient receptor potential cation channel V subfamily member 1 (also known as vanilloid receptor-1 (VR1)), is a polymeric cation channel expressed primarily in nociceptive primary afferent neurons (Caterina et al. (1997) Nature 389:816-824; Tominaga et al. (1998) Neuron 21:531-543). Activation of TRPV1 usually occurs in nerve endings by applying painful heat and is upregulated during certain types of inflammatory stimulation. Activation of TRPV1 in peripheral tissues by chemical agonists causes calcium channel opening and pain sensory transduction (Szalllasi et al. (1999) Mol. Pharmacol. 56:581-587). However, direct application of certain TRPV1 agonists to the cell bodies of neurons (ganglia) expressing TRPV1 opens calcium channels and triggers a cascade of events leading to programmed cell death ("apoptosis") (Karai et al. (2004) J. of Clin. Invest. 113: 1344-1352).

[0008] Transient receptor potential vanilloid 1 (TRPV1) has been reported to be associated with inflammation (Amaya, F. et al. (2003) Brain Res. 963:190-196), cancer (Asai, H. et al. (2005) Pain 117:19-29; Shinoda, M. et al. (2008) J Pain 9:687-699) and neuropathic pain (Rashid, M. et al. (2003) J Pharmacol. Exp. Ther. 304:940-948). In orofacial pain, TRPV1 has been reported to be associated with pulp inflammation (Tarsa, L. et al. (2010) Neuroscience 167:1205-1215), temporomandibular disorder (TMD) (Ro, J. et al. (2009) Pain 144:270-277), oral cancer (Nagamine, K. et al. (2006) Pain 7:659-670), and IAN injury pain (Kim, H. et al. (2008) Journal of Pain 9:280-288).

[0009] Inflammatory dysfunction of the oral mucosa is associated with inflammation and pain of the oral mucosa. Inflammatory dysfunction of the human oral mucosa can be attributed to a series of diseases, some of which are immune-mediated, such as Behcet's disease, burning mouth syndrome, oral lichen planus, pemphigus and pemphigoid, recurrent aphthous stomatitis, stomatitis, Sjogren's syndrome, etc. These diseases are often chronic and usually seriously affect the quality of life of individuals. Common causes of inflammatory dysfunction of the oral mucosa include, for example, viral infections, yeast infections, bacterial infections, chemotherapy or radiotherapy treatments for cancer, weakened or defective immune systems, etc. People suffering from oral mucosal diseases may develop painful mouth ulcers or ulcers on the mucosal lining (the "skin" in the mouth, including cheeks and lips).

[0010] An inflammatory dysfunction of the oral mucosa of cats can be attributed to feline chronic gingivostomatitis (FCGS) or caudal stomatitis and affects 0.7% to 12% of all cats. FCGS is a debilitating oral inflammatory disease that can persist for years, ultimately leading to euthanasia. FCGS can be multifactorial (caused by viral infection, dental disease, and / or hypersensitivity) and can affect the gingival, oral, palate, sublingual, and pharyngeal tissues. FCGS can be refractory to medical treatment (immunosuppressive therapy) and surgical treatment (full-mouth extraction).

[0011] Pain associated with inflammatory dysfunction of the oral mucosa is generally considered to be deep pain requiring intervention, either systemic or local treatment directed directly or invasive or surgically directed treatment at the site of pain. Treatments include topical solutions (applied directly to the gums and teeth to treat dental pain), local injections (injected into the gums to treat dental pain or injected into trigger points), various systemic analgesics (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs and anesthetics), various other systemic agents (steroids, phenytoin, carbamazepine, calcium channel blockers, beta-blockers and tricyclic antidepressants) and surgical procedures (tooth extraction, etc.).

[0012] Although there are some treatments for pain associated with inflammatory dysfunction of the oral mucosa, they are not always effective. In addition, although some treatments are effective in treating the pain itself (e.g., U.S. Patent No. 5,296,225 and U.S. Patent Publication No. US20150051271), none of them can treat the underlying neurogenic inflammation.

[0013] Therefore, there is a need in the art for improved treatments of pain and inflammation associated with inflammatory dysfunction of the oral mucosa that address not only the sensitivity to pain, but also the underlying neurogenic inflammation that causes such pain. Summary of the invention

[0014] The present disclosure is intended to meet this need and / or provide other benefits. Provided herein are methods of topically administering RTX to a subject in need thereof to treat inflammatory disorders of the oral mucosa. The present disclosure is based in part on the recognition that oral topical administration of RTX to treat inflammatory disorders of the oral mucosa can provide effective pain relief as well as treat underlying neurogenic inflammation.

[0015] In one aspect, provided herein is a method for treating an inflammatory disorder of the oral mucosa, the method comprising topically administering a therapeutically effective amount of resiniferatoxin (RTX) to a subject in need of treatment for the inflammatory disorder of the oral mucosa.

[0016] In one aspect, provided herein is a composition for use in a method for treating an inflammatory disorder of the oral mucosa, the composition comprising resiniferatoxin (RTX), the method comprising topically administering a therapeutically effective amount of the composition to a subject in need of treatment of the inflammatory disorder of the oral mucosa.

[0017] In an embodiment, said inflammatory dysfunction of said oral mucosa is associated with neurogenic inflammation. In an embodiment, said inflammatory dysfunction of said oral mucosa is associated with pain.

[0018] In embodiments, said neurogenic inflammation is reduced. In embodiments, said pain is reduced.

[0019] In embodiments, the pain is orofacial pain. In embodiments, the pain is due to alveolar disorders, cancer, neuropathic pain, or idiopathic pain. In embodiments, the pain is due to alveolar disorders. In embodiments, the pain is due to cancer. In embodiments, the pain is due to neuropathic pain. In embodiments, the pain is due to idiopathic pain. In embodiments, the pain is due to stomatitis. In embodiments, the pain is due to chronic gingivostomatitis (CGS). In embodiments, the pain is due to feline chronic gingivostomatitis (FCGS). In embodiments, the idiopathic pain is due to burning mouth syndrome.

[0020] In embodiments, the pain is due to radiation therapy or chemotherapy. In embodiments, the pain is due to radiation therapy. In embodiments, the pain is due to chemotherapy. In embodiments, the pain is due to radiation therapy-induced mucositis.

[0021] In an embodiment, the pain is due to alveolar structural disorder. In an embodiment, the pain is due to tooth pain or oral mucosal pain. In an embodiment, the pain is due to tooth pain. In an embodiment, the pain is due to oral mucosal pain.

[0022] In embodiments, the subject is a mammal. In embodiments, the mammal is a cat, dog, horse, pig, ruminant, cattle, sheep, goat, or a domesticated mammal. In embodiments, the mammal is a cat. In embodiments, the mammal is a dog. In embodiments, the mammal is a horse. In embodiments, the mammal is a pig. In embodiments, the mammal is a ruminant. In embodiments, the mammal is cattle. In embodiments, the mammal is a sheep. In embodiments, the mammal is a goat. In embodiments, the mammal is a domesticated mammal. In embodiments, the mammal is a human.

[0023] In an embodiment, RTX is administered in a pharmaceutical formulation comprising said RTX and a pharmaceutically acceptable carrier. In an embodiment, said pharmaceutically acceptable carrier comprises water. In an embodiment, said pharmaceutically acceptable carrier comprises polysorbate 80. In an embodiment, said pharmaceutically acceptable carrier comprises polyethylene glycol. In an embodiment, said pharmaceutically acceptable carrier comprises a sugar or a sugar alcohol. In an embodiment, said pharmaceutically acceptable carrier comprises mannitol. In an embodiment, said pharmaceutically acceptable carrier comprises dextrose. In an embodiment, said pharmaceutically acceptable carrier comprises a pharmaceutically acceptable buffer.

[0024] In an embodiment, the pharmaceutically acceptable buffer is a phosphate buffer, and / or the pH of the formulation is about 6.0-7.6 or about 7.2. In an embodiment, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable salt. In an embodiment, the pharmaceutically acceptable salt is NaCl.

[0025] In an embodiment, the RTX is administered at a dose of about 0.1 μg to about 100 μg. In an embodiment, the concentration of RTX in the pharmaceutical preparation is in the range of 0.02 to 300 μg / ml. In an embodiment, the concentration of RTX in the pharmaceutical preparation is in the range of 0.02-0.1 μg / ml, 0.1-1 μg / ml, 1-5 μg / ml, 5-10 μg / ml, 10-20 μg / ml, 20-50 μg / ml, 50-100 μg / ml, 100-150 μg / ml, 150-200 μg / ml, 200-250 μg / ml or 250-300 μg / ml. In an embodiment, the concentration of RTX in the pharmaceutical preparation is in the range of 0.1-50 μg / ml.

[0026] In an embodiment, the RTX is topically administered in a volume of 0.5-5 ml. In an embodiment, the RTX is topically administered in a volume within the range of 0.5-1.0 ml, 1.0-1.5 ml, 1.5-2 ml, 2-3 ml, 3-4 ml or 4-5 ml.

[0027] In an embodiment, a general or local anesthetic is administered prior to administration of RTX. In an embodiment, an analgesic is administered after administration of RTX. In an embodiment, the analgesic is an opioid or a nonsteroidal anti-inflammatory drug (NSAID). In an embodiment, the analgesic is an opioid. In an embodiment, the analgesic is a nonsteroidal anti-inflammatory drug (NSAID). In an embodiment, the RTX is administered to multiple sites.

[0028] In one aspect, provided herein is a method for treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the method comprising topically administering a therapeutically effective amount of resiniferatoxin (RTX) to a subject in need of treatment for the neurogenic inflammation.

[0029] In one aspect, provided herein is a composition for use in a method for treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the composition comprising resiniferatoxin (RTX), the method comprising topically administering a therapeutically effective amount of the composition to a subject in need of treatment for the neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1A Shown are the body weights of each cat at the beginning of the study (Day 0) and at the end of the study (Day 8).

[0031] Figure 1B Shown is the amount of food consumed by each cat as a % of its ration over the eight days of the study (no data were collected on Day 2).

[0032] Figure 2A -E Time-dependent VSOM scores demonstrated the effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatment (qualitative assessment). Figure 2A Time-dependent VSOM scores demonstrated the effectiveness of 6.25 μg RTX treatment. Figure 2B Time-dependent VSOM scores demonstrated the effectiveness of 12.5 μg RTX treatment. Figure 2C Time-dependent VSOM scores demonstrated the effectiveness of 25 μg RTX treatment. Figure 2D Time-dependent VSOM scores (by group) demonstrated the effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatment (qualitative assessment). Figure 2E. The Maximum Possible Effect % (MPE %) graph shows the % change in VSOM from day 0 (before treatment) to day 28, demonstrating the effectiveness of 6.25 μg, 12.5 μg and 25 μg RTX treatment (qualitative assessment).

[0033] Figure 3A The effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatment was demonstrated by the increase in SDAI score in each cat (semi-quantitative assessment).

[0034] Figure 3B The graph of the Maximum Possible Effect % (MPE %) shows the % change in SDAI from Day 0 (pre-treatment) to Day 28 for each cat, demonstrating the effectiveness of the 6.25 μg, 12.5 μg and 25 μg RTX treatments (semi-quantitative assessment).

[0035] Figure 3C Baseline SDAI scores for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX) are shown.

[0036] Figure 4 The effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatment was demonstrated by the SDAI score on day 0 (before treatment) and day 28 for each cat. DETAILED DESCRIPTION

[0037] Certain embodiments of the present invention will now be described in detail, examples of which are shown in the accompanying drawings. Although the present invention will be described in conjunction with the embodiments shown, it should be understood that it is not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents that may be included in the present invention defined by the appended claims.

[0038] Before describing the teachings of the present invention in detail, it should be understood that the present disclosure is not limited to specific compositions or process steps, as such compositions or process steps may vary. It should be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include plural referents. Thus, for example, reference to "conjugate" includes multiple conjugates, and reference to "cell" includes multiple cells, etc. It should be understood that the use of alternatives (e.g., "or") in this article is used to mean any one or two of the alternatives or any combination thereof.

[0039] The term "and / or" as used herein will be deemed to mean that each of the specified features or components is explicitly disclosed with or without the other. For example, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0040] As used herein, the terms "comprising," "including," "having," and "containing," and grammatical variations thereof, as used herein, are intended to be non-limiting, such that one or more items in a list are not exclusive of other items that can be substituted or added to the listed items. It should be understood that when aspects are described with the language "comprising," wherever herein, other similar aspects described with respect to "consisting of" and / or "consisting essentially of" are also provided.

[0041] As used herein, the terms "mcg," "μg," and "ug" are interchangeable and refer to micrograms.

[0042] As used herein, the term "about" refers to a value or composition within an acceptable error range of a specific value or composition as determined by a person of ordinary skill in the art, which will depend in part on how to measure or determine the value or composition, that is, the limitations of the measurement system. For example, according to the practice of the art, "about" or "approximately" can mean within one or more than one standard deviation. Alternatively, according to the limitations of the measurement system, "about" or "approximately" can mean a range of up to 10% (i.e., ± 10%) or more. For example, about 5 mg may include any number between 4.5 mg and 5.5 mg. In addition, particularly in terms of biological systems or processes, the term can mean up to an order of magnitude or up to 5 times of a value. When a specific value or composition is provided in the present disclosure, unless otherwise stated, the meaning of "about" or "approximately" should be assumed to be within the acceptable error range of the specific value or composition. In an embodiment, "about" covers changes within 10%, 5%, 2%, 1% or 0.5% of the stated value.

[0043] Numerical ranges include the numbers defining the range. Measured and measurable values ​​are understood to be approximate, taking into account significant figures and measurement-related errors. Moreover, in the absence of an explicit exclusion such as "excluding the endpoints", all ranges should be interpreted as including the endpoints; thus, for example, "in the range of 1 to 10" includes the values ​​1 and 10 and all integers and (where appropriate) non-integer values ​​greater than 1 and less than 10.

[0044] The use of "comprise / comprises / comprising", "contain / contains / containing", and "include / includes / including" are not intended to be limiting. It should be understood that both the general description and the detailed description above are exemplary and explanatory only and do not limit the present teachings. Unless specifically noted in the above specification, embodiments reciting "comprising" various components in the specification are also contemplated as "consisting of" or "consisting essentially of" the recited components; embodiments reciting "consisting of" various components in the specification are also contemplated as "including" the recited components or "consisting essentially of" the recited components; and embodiments reciting "consisting essentially of" various components in the specification are also contemplated as "consisting of" or "including" the recited components (this interchangeability does not apply to the use of these terms in the claims).

[0045] The section headings used herein are merely for organizational purposes and should not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined in this specification, this specification shall prevail. Although the present teachings are described in conjunction with various embodiments, the present teachings are not intended to be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, variations, and equivalents, as will be appreciated by those skilled in the art.

[0046] definition

[0047] As used herein, the term "inflammatory dysfunction of the oral mucosa" refers to inflammation and pain associated with oral mucosal diseases, some of which are immune-mediated, such as Behcet's disease, burning mouth syndrome, oral lichen planus, pemphigus and pemphigoid, recurrent aphthous stomatitis, Sjögren's syndrome, caudal stomatitis, stomatitis, chronic gingivostomatitis (CGS), feline chronic gingivostomatitis (FCGS) or oral cancer. These diseases are often chronic and usually have a serious impact on the quality of life of an individual. Common causes of inflammatory dysfunction of the oral mucosa include, for example, viral infections, yeast infections, bacterial infections, chemotherapy or radiotherapy treatments for cancer, weakened or defective immune systems, etc. Mammals suffering from oral mucosal diseases may develop painful oral ulcers or ulcers on the mucosal lining (the "skin" in the oral cavity, including cheeks and lips).

[0048] As used herein, the term "orofacial pain" refers to pain caused by alveolar structural disorder, such as tooth pain or oral mucosal pain. Oral mucosal pain may be attributed to neurogenic inflammation (which may be the result of various oral mucosal diseases). Tooth pain may be the result of pulp pain, periodontal pain or gingival pain. As used herein, "orofacial pain" also refers to pain caused by idiopathic oral pain, such as burning mouth syndrome or persistent idiopathic alveolar pain. As used herein, "orofacial pain" may also refer to neuropathic pain or pain caused by local or systemic inflammation. In addition, as used herein, the term "orofacial pain" refers to pain caused by cancer (e.g., oral cancer) or cancer treatment (e.g., radiotherapy). In an embodiment, orofacial pain may be attributed to mucositis induced by radiotherapy or chemotherapy. In an embodiment, orofacial pain may be attributed to stomatitis. In an embodiment, orofacial pain may be attributed to chronic gingivostomatitis.

[0049] The term "neuropathic pain" refers to pain caused by damage or disease affecting sensory neurons.

[0050] A "ruminant" is a mammal with a rumen. Examples of ruminants include, but are not limited to, cattle, sheep, antelope, deer, and giraffes.

[0051] The term "effective amount", "therapeutically effective amount" or "effective dose" or related terms can be used interchangeably and refer to the amount of a therapeutic agent (RTX) that is sufficient to affect a measurable improvement or even complete regression of pain and neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa when applied to a subject. For example, an effective dose sufficient to inhibit neurogenic inflammation and stop pain is administered in a subject. The therapeutically effective amount of the therapeutic agent (RTX) provided herein will vary according to the subject and disease condition being treated, the subject's weight, the severity of the subject's disease condition, etc., which can be easily determined by a person of ordinary skill in the art. In one embodiment, the therapeutically effective amount will depend on certain aspects of the subject to be treated and the disorder to be treated, and can be determined by a person of ordinary skill in the art using known techniques. In addition, as known in the art, it may be necessary to adjust body weight, overall health, time of administration, drug interactions, and the severity of the disease.

[0052] As used herein, the terms "subject" and "patient" refer to humans and non-human animals, including vertebrates, mammals and non-mammals. In one embodiment, the subject can be a human, non-human primate, ape, ape-like, rodent (e.g., mouse and rat), cow, pig, horse, dog, cat, goat, wolf, ranidae or fish.

[0053] The term "administering or administered" and grammatical variants refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration of the formulations disclosed herein include non-parenteral routes (i.e., local), such as topical, epidermal or mucosal routes of administration. In one embodiment, the formulation is topically applied to the oral mucosa in the oral cavity in the form of a solution, suspension, cream, lotion, gel, paste, spray, powder or ointment. Administration can also be performed, for example, once, multiple times and / or over one or more extended periods of time.

[0054] "Treatment" should be broadly understood and encompass any beneficial effect, including, for example, delaying, slowing down or preventing the deterioration of symptoms associated with inflammatory dysfunction of the oral mucosa or at least partially treating such symptoms. As discussed in detail below, treatment also encompasses improvements in patient function that bring about any form. In an embodiment, treatment also means an extension of survival compared to the expected survival without treatment. The term also means including mitigation or elimination of a disorder, disease or condition; or one or more symptoms associated with a disorder, disease or condition; or mitigation or elimination of the cause of the disorder, disease or condition itself. Those subjects in need of treatment include those already suffering from a disease or condition.

[0055] A "pharmaceutically acceptable vehicle" for therapeutic purposes is a physical embodiment that can be administered to a subject. Pharmaceutically acceptable vehicles include, but are not limited to, solutions, suspensions, creams, lotions, gels, pastes, sprays, powders, or ointments. An example of a pharmaceutically acceptable vehicle is a buffered isotonic solution, such as phosphate buffered saline (PBS).

[0056] As used herein, the term "or a combination thereof / or combinations thereof" refers to any and all permutations and combinations of the terms listed before the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and if the order is important in a particular context, BA, CA, CB, ACB, CBA, BCA, BAC, or CAB is also included. Continuing with this example, explicitly included are combinations containing repetitions of one or more items or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. The skilled person will understand that, unless the context indicates otherwise, the number of items or terms in any combination is generally not limited.

[0057] As used herein, "well tolerated" refers to a response to the administration of RTX, wherein the subject has few or no clinical side effects (e.g., only mild or moderate side effects, or only mild side effects). Mild side effects (e.g., minor events that do not require special medical intervention; only asymptomatic laboratory test results; clinically insignificant); moderate side effects (e.g., events that require only minimal intervention; local intervention; non-invasive intervention; blood transfusion; elective interventional radiological procedures; or therapeutic endoscopy or surgery). Side effects include adverse and unexpected signs, symptoms or diseases associated with the use of RTX. Examples of side effects include, but are not limited to, toxicity and distress indicated by, for example, high or low body temperature, hypotension, hypertension, hypocapnia and ventricular arrhythmias, drowsiness, responsiveness, loss of appetite and / or weight loss.

[0058] Overview

[0059] In chronic pain states, vanilloid (TRPV1) receptors on neurons are upregulated, lowering the stimulation threshold and leading to increased pain perception. TRPV1 agonists, such as capsaicin, will activate and depolarize TRPV1 receptors, initially causing a burning sensation due to stimulation of the nerve. After the TRPV1 receptors are completely depolarized, the nociceptive area is desensitized and becomes analgesic, particularly for neuropathic pain (Bley, K. (2010) TRPV1 agonist approaches for pain management.: Gomtsyan A, Faltynek CR, eds., Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders. New York: Wiley, 325-47). Capsaicin, a TRPV1 agonist with a lower potency than RTX, has been approved for the treatment of postherpetic neuralgia (Acorda Therapeutics, 2009). RTX, the most potent TRPV1 receptor agonist, is 1000-10,000 times more potent than capsaicin or 16 billion on the Scoville scale.

[0060] Vanilloid receptor-1 (TRPV1) is a polycation channel that is primarily expressed in nociceptive primary afferent neurons (see, e.g., Caterina et al., (1997) Nature 389:8160824; Tominaga et al., (1998) Neuron 531-543). Activation of the receptor typically occurs when the nerve endings are exposed to heat pain (TRPV1 transduces heat pain) or during inflammation or exposure to vanilloids. It has been widely reported that activation of afferent nerves expressing TRPV1 induces the secretion of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) (see Nicoletti et al. (2012) Int J Immunopathol Pharmacol 25(4):849-57; Bhatia (2010) Antioxidant Redox Signal 12(10):1191-202; Fernandes et al. (2009) Handb Exp Pharmacol 194:393-416; Scardina et al. (2004) Minerva Stomatol 53(1-2):21-32; Harrison et al. (2001) Int J Biochem Cell Biol 33(6):555-76). The released SP, but not CGRP, binds to neurokinin (NK) 1 receptors on blood vessels in sensory endings, causing vasodilation and increased vascular permeability, which allows loss of protein and fluid (plasma extravasation), thereby promoting regional accumulation of monocytes and leukocytes, leading to inflammation (see Roberts et al. (2004) Brain Res 995(2):176-83; Andrews et al. (1989) Br J Pharmacol 97(4):1232-8; and McConalogue et al. (1998) Mol Biol Cell 9(8):2305-24).

[0061] Activation of TRPV1 by agonists such as resiniferatoxin or capsaicin results in calcium channel opening and pain sensory transduction (see, e.g., Szalllasi et al., (1999) Mol Pharmacol 56:581-587). After initial activation of TRPV1, TRPV1 agonists desensitize TRPV1 to subsequent stimuli. This desensitization phenomenon has been exploited to produce analgesia to subsequent nociceptive stimuli.

[0062] It has been shown that topical application of resiniferatoxin (RTX), a potent vanilloid receptor agonist, to nerve endings in the skin induces long-term insensitivity to chemical pain stimuli (e.g., U.S. Publication No. US20210007998; U.S. Patent No. US5,296,225). However, such topical application is limited to the surface of the skin and only addresses the sensation of pain, not the underlying neurogenic inflammation.

[0063] The present disclosure provides topical formulations of RTX that can be applied to the oral mucosa or oral cavity and can treat not only pain associated with inflammatory dysfunction of the oral mucosa, but also the underlying neurogenic inflammation affecting the gingival, cheek, palate, sublingual or pharyngeal tissues causing the pain.

[0064] Exemplary methods and compositions for use

[0065] Provided herein are topical formulations of RTX for application to the oral mucosa or oral cavity to control or alleviate pain-related oral mucosal inflammatory dysfunction and underlying neurogenic inflammation.

[0066] In one aspect, provided herein is a method for treating an inflammatory disorder in the oral mucosa, the method comprising topically administering a therapeutically effective amount of RTX to a subject in need of treatment of the inflammatory disorder in the oral mucosa.

[0067] In another aspect, provided herein is a composition for use in a method for treating an inflammatory disorder of the oral mucosa, the composition comprising RTX, the method comprising topically administering a therapeutically effective amount of the composition to a subject in need of treatment of the inflammatory disorder of the oral mucosa.

[0068] In yet another aspect, provided herein are methods and compositions for interrupting the neurogenic inflammatory process occurring in the oral cavity and / or treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the method comprising topically administering to a subject a therapeutically effective amount of RTX.

[0069] In yet another aspect, provided herein is a method for treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the method comprising topically administering a therapeutically effective amount of RTX to a subject in need of treatment for the neurogenic inflammation.

[0070] In an embodiment, the subject has one or more symptoms of an inflammatory dysfunction of the oral mucosa before treatment, and the treatment alleviates or eliminates the one or more symptoms. For example, the symptoms of an inflammatory dysfunction of the oral mucosa include orofacial pain, neurogenic inflammation, idiopathic pain, neuropathic pain, oral ulcers or ulcers, blisters, or discomfort when eating.

[0071] The compositions and methods described herein are suitable for any subject for whom RTX is effective (e.g., capable of binding and activating TRPV-1 or a homolog thereof) and in need of treatment for an inflammatory dysfunction of the oral mucosa. In an embodiment, the subject is a mammal. In an embodiment, the mammal is a human. In an embodiment, the mammal is a cat. In an embodiment, the mammal is a dog. In an embodiment, the mammal is a monkey. In an embodiment, the mammal is a ruminant. In an embodiment, the mammal is a horse, a cow, a pig, a sheep, a goat, or a domesticated mammal.

[0072] The compositions and methods described herein are suitable for any subject for whom RTX is effective (eg, is capable of binding to and activating TRPV-1 or a homolog thereof) and who is in need of treatment for neurogenic inflammation.

[0073] Administration and formulation

[0074] RTX can be topically applied to the oral mucosa or oral cavity. Depending on the number of inflammatory sites in the oral cavity or on the oral mucosa, RTX can be topically applied to one or more sites. In an embodiment, RTX is topically applied to a single site. In an embodiment, RTX is topically applied to more than one site. In an embodiment, the RTX is applied to multiple sites.

[0075] In embodiments, the entire dose of RTX is topically applied to one site in a single application. In embodiments, the entire dose of RTX is topically applied to one site in more than one application. In embodiments, the entire dose of RTX is topically applied to one site in two applications. In embodiments, the entire dose of RTX is topically applied to one site in three applications. In embodiments, the entire dose of RTX is topically applied to one site in four applications. In embodiments, the entire dose of RTX is topically applied to one site in five applications. In embodiments, each lesion in the oral cavity receives one layer of RTX. In embodiments, each lesion in the oral cavity receives two layers of RTX. In embodiments, each lesion in the oral cavity receives three layers of RTX. In embodiments, each lesion in the oral cavity receives four layers of RTX. In embodiments, each lesion in the oral cavity receives five layers of RTX. In embodiments, the RTX solution is allowed to drip into the gingival sulcus.

[0076] In embodiments, the method further comprises administering a general or local anesthetic prior to administering RTX. In embodiments, the method further comprises administering a general anesthetic prior to administering RTX. In embodiments, the method further comprises administering a local anesthetic prior to administering RTX.

[0077] In an embodiment, the subject is anesthetized prior to administration of RTX. In an embodiment, the local anesthetic is administered by injection. In an embodiment, the local anesthetic is administered topically.

[0078] In an embodiment, the local anesthetic is an aminoamide anesthetic, such as lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine, ropivacaine, or levobupivacaine. In an embodiment, the topical local anesthetic is benzocaine, lidocaine, cocaine, proparacaine, or oxybuprocaine.

[0079] Discomfort following treatment may be managed with an analgesic. In an embodiment, the method further comprises administering an analgesic after administering RTX. In an embodiment, the analgesic is an opioid or a nonsteroidal anti-inflammatory drug (NSAID). In an embodiment, the analgesic is a nonsteroidal anti-inflammatory drug (NSAID). In an embodiment, the analgesic is an opioid. In an embodiment, the opioid is buprenorphine.

[0080] In an embodiment, an analgesic is administered no more than 5 days after the administration of RTX. In an embodiment, an analgesic is administered no more than 4 days after the administration of RTX. In an embodiment, an analgesic is administered no more than 3 days after the administration of RTX. In an embodiment, an analgesic is administered no more than 2 days after the administration of RTX. In an embodiment, an analgesic is administered no more than 1 day after the administration of RTX. In an embodiment, no analgesic is administered after the administration of RTX.

[0081] In embodiments, for topical administration, RTX can be formulated into solutions, lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, the formulation may include one or more thickeners, wetting agents and stabilizers. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax or mineral oil, lanolin, squalene, and the like.

[0082] In an embodiment, the pharmaceutical formulation provided herein is formulated as an ointment for topical application, comprising RTX and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the ointment provided herein comprises RTX and one or more excipients or carriers, and the excipients or carriers are selected from the group consisting of water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 80, myristyl alcohol, sorbitan monostearate, lactic acid and benzyl alcohol. In another embodiment, the ointment provided herein comprises RTX and water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 80, myristyl alcohol, sorbitan monostearate, lactic acid and benzyl alcohol.

[0083] In an embodiment, the pharmaceutical preparation provided herein is formulated as a gel for topical administration, comprising RTX and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the gel provided herein comprises RTX and one or more excipients or carriers, and the excipients or carriers are selected from the group consisting of water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide and docusate sodium. In another embodiment, the gel provided herein comprises RTX and water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide and docusate sodium.

[0084] In an embodiment, the pharmaceutical formulations provided herein are formulated as solutions for topical administration, comprising RTX and one or more pharmaceutically acceptable excipients or carriers.

[0085] In an embodiment, RTX is administered with a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutically acceptable carrier comprises water. In an embodiment, the pharmaceutically acceptable carrier comprises polysorbate 80. In an embodiment, the pharmaceutically acceptable carrier comprises polyethylene glycol. In an embodiment, the pharmaceutically acceptable carrier comprises a sugar or a sugar alcohol. In an embodiment, the pharmaceutically acceptable carrier comprises mannitol. In an embodiment, the pharmaceutically acceptable carrier comprises dextrose. In an embodiment, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable buffer. In an embodiment, the pharmaceutically acceptable carrier comprises a phosphate buffer. In an embodiment, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable salt. In an embodiment, the pharmaceutically acceptable carrier comprises NaCl. In an embodiment, the pharmaceutically acceptable carrier comprises an organic solvent, such as ethanol or DMSO, for example, as a minority or residual component to aid in dissolving the RTX prior to dilution in a primarily aqueous composition.

[0086] The concentration of RTX in the formulation can be any suitable value for delivering the intended dose. In an embodiment, the concentration of RTX in the pharmaceutical formulation is in the range of 0.02 to 300 μg / ml. In an embodiment, the concentration of RTX in the pharmaceutical formulation is in the range of 0.02-0.1 μg / ml, 0.1-1 μg / ml, 1-5 μg / ml, 5-10 μg / ml, 10-20 μg / ml, 20-50 μg / ml, 50-100 μg / ml, 100-150 μg / ml, 150-200 μg / ml, 200-250 μg / ml, or 250-300 μg / ml. In an embodiment, the concentration of RTX in the pharmaceutical preparation is 0.5 μg / ml-0.6 μg / ml, 0.6 μg / ml-0.7 μg / ml, 0.7 μg / ml-0.8 μg / ml, 0.8 μg / ml-0.9 μg / ml, 0.9 μg / ml-1.0 μg / ml, 1.0 μg / ml-1.1 μg / ml, 1.1 μg / ml-1.2 μg / ml, 1.2 μg / ml-1.3 μg / ml, 1.3 μg / ml-1.4 μg / ml, 1.4 μg / ml-1.5 μg / ml, 1.5 μg / ml, 1.6 μg / ml, 1.7 μg / ml, 1.8 μg / ml, 1.9 μg / ml, 2.0 μg / ml, 2.1 μg / ml, 2.2 μg / ml, 2.3 μg / ml, 2.4 μg / ml, 2.5 μg / ml, 2.6 μg / ml, 2.7 μg / ml, 2.8 μg / ml, 2.9 μg / ml, 3.1 μg / ml, 3.2 μg / ml, 3.3 μg / ml, 3.4 μg / ml, 3.5 In one embodiment, the concentration of RTX in the pharmaceutical preparation is in the range of 0.1-50 μg / ml, 1-50 μg / ml or 12.5 μg / ml. In an embodiment, the concentration of RTX in the pharmaceutical formulation is in the range of 0.1 to 100 μg / ml, such as 0.1 to 50 μg / ml or 1 to 25 μg / ml, or about 0.1, 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40 or 50 μg / ml.

[0087] In an embodiment, the RTX is delivered in a composition having a volume of 0.1 ml-1 ml, 1 ml-10 ml, 10 ml-20 ml, 20 ml-30 ml, 30 ml-40 ml, 40 ml-50 ml, 50 ml-60 ml, 60 ml-70 ml, 70 ml-80 ml, 80 ml-90 ml, or 90 ml-100 ml. In an embodiment, the RTX is delivered in a composition having a volume of 0.5 ml-5 ml. In an embodiment, the RTX is delivered in a composition having a volume in the range of 0.5-1.0 ml, 1.0-1.5 ml, 1.5-2 ml, 2-3 ml, 3-4 ml, or 4-5 ml.

[0088] Starting from a concentrated stock solution, an RTX formulation can be prepared for delivery to a subject by diluting in a suitable diluent, such as normal saline.

[0089] The formulation may have any pH suitable for topical administration. In an embodiment, the pH of the pharmaceutical formulation comprising RTX and a pharmaceutically acceptable carrier is in the range of 6.0 to 7.6. In an embodiment, the pH of the pharmaceutical formulation comprising RTX and a pharmaceutically acceptable carrier is in the range of 6.0 to 6.4, 6.3 to 6.7, 6.4 to 6.8, 6.8 to 7.2, 7 to 7.4, or 7.2 to 7.6. In an embodiment, the pH of the pharmaceutical formulation comprising RTX and a pharmaceutically acceptable carrier is about 6.5 or about 7.2.

[0090] In an embodiment, the preparation comprises polysorbate 80 and dextrose. In an embodiment, the concentration of polysorbate 80 is 0.03-7% w / v. In an embodiment, the concentration of polysorbate 80 is 2-4% w / v, and / or the concentration of dextrose is 4-6% w / v. In an embodiment, the concentration of polysorbate 80 is 3% w / v, and / or the concentration of dextrose is 5% w / v. The preparation may further comprise a buffer, such as a phosphate buffer (e.g., sodium phosphate buffer). In an embodiment, the concentration of phosphate buffer is 10-50mM. In an embodiment, the concentration of phosphate buffer is 10-30mM. In an embodiment, the concentration of phosphate buffer is 10mM. In an embodiment, the concentration of phosphate buffer is 30mM. The pH of the preparation may be in the range of 7-7.5, such as about 7.2. In an embodiment, in any of the foregoing formulations, the concentration of RTX may be 1-30 μg / ml, such as 3.12 μg / ml or 12.5 μg / ml. In an embodiment, the formulation further comprises a phosphate buffer, such as at a concentration and pH as shown in Table 1 for phosphate buffer. In an embodiment, the formulation further comprises NaCl, such as at a concentration as shown in Table 1 for NaCl. When both are present, the phosphate buffer and NaCl may (but need not be) present in a combination of the concentrations and phosphate buffer pHs shown for the individual formulations.

[0091] The following table shows exemplary formulations of RTX.

[0092] Table: Exemplary RTX solution formulations

[0093]

[0094]

[0095]

[0096] In an embodiment, the formulations in Table 1 comprise dextrose. In an embodiment, the concentration of dextrose is 0.05-5% w / v. In an embodiment, the concentration of dextrose is 0.8-5% w / v. In an embodiment, the concentration of dextrose is 0.05% w / v. In an embodiment, the concentration of dextrose is 0.8% w / v. In an embodiment, the concentration of dextrose is 3.0% w / v. In an embodiment, the concentration of dextrose is 5.0% w / v.

[0097] In an embodiment, the formulations in Table 1 comprise mannitol. In an embodiment, the concentration of mannitol is 0.8-3.0% w / v. In an embodiment, the concentration of mannitol is 0.8% w / v. In an embodiment, the concentration of mannitol is 3.0% w / v.

[0098] In embodiments, dextrose or mannitol is omitted from the formulations shown in Table 1.

[0099] In an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to any RTX concentration or concentration range disclosed herein. For example, in an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to 0.3-200mcg / ml. In an embodiment, the concentration of RTX in the formulations shown in Table 1 is 200mcg / ml. In an embodiment, the concentration of RTX in the formulations shown in Table 1 is 0.3-100mcg / ml. In an embodiment, the concentration of RTX in the formulations shown in Table 1 is 100mcg / ml. In an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to 0.3-50mcg / ml. In an embodiment, the concentration of RTX in the formulations shown in Table 1 is 25mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to 0.3-15mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to 0.5-10mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulations shown in Table 1 is adjusted to 0.6-1.5 mcg / ml. Dextrose or mannitol is omitted from any such formulations having adjusted RTX concentrations.

[0100] The preparation in table 1 can be prepared according to the following exemplary method, and these methods are provided for preparation 3 and 5, but can be modified by those skilled in the art to be applicable to other preparations.Preparation 3 can be prepared by adding 46mg sodium dihydrogen phosphate monohydrate, 94.7mg anhydrous disodium hydrogen phosphate and 860mg NaCl to a 100ml volumetric flask.Add 50ml water to dissolve the component in the volumetric flask, then add 1.0g polysorbate 80, to form a water-containing component.20mg RTX is added to the aqueous component in the volumetric flask, and pH is adjusted to 7.2 with hydrochloric acid / sodium hydroxide.Then add 30mL PEG 300, and the solution is subjected to ultrasonic treatment to dissolve solids.It should be noted that initially RTX will sometimes be precipitated at the interface of aqueous solution and PEG, but will return to the solution after ultrasonic treatment.With water, the whole mixture in the bottle is diluted to volume (100.00ml), and mixed by inversion process.Filter the complete preparation by 0.2μm polytetrafluoroethylene (PTFE) filter.

[0101] Preparation 5 can be prepared by adding 138mg sodium dihydrogen phosphate monohydrate, 284.1mg anhydrous disodium hydrogen phosphate and 540mg NaCl to a 100ml volumetric flask. Add 50ml water to dissolve the component in the volumetric flask, then add 3.0g polysorbate 80 and 800mg dextrose, to form a water-containing component. 20mg RTX is added to the aqueous component in the volumetric flask, and pH is adjusted to 7.2 with hydrochloric acid / sodium hydroxide. Then the solution is ultrasonically processed, to dissolve all solids. (Alternatively, RTX can be dissolved in a small amount of ethanol or DMSO initially, and then this solution is added to the aqueous component.) The whole mixture in the bottle is diluted to volume (100.00ml) with water, and mixed by inversion process. Complete preparation is filtered by a 0.2 μm PTFE filter.

[0102] A formulation according to formulation 11 was prepared using 200 mcg RTX, 300 mcg polysorbate 80 (commercially available polysorbate 80 was used), 5.4 mg sodium chloride, 500 mcg dextrose, 1.38 mg sodium dihydrogen phosphate monohydrate, 2.84 mg anhydrous disodium hydrogen phosphate, and 1 mL of water, and then the pH was adjusted to 7.2 with hydrochloric acid / sodium hydroxide. As described above, dextrose can be omitted.

[0103] A formulation according to formulation 13 was prepared using 25 mcg RTX, 30 mg polysorbate 80 (commercially available polysorbate 80 was used), 5.4 mg sodium chloride, 50 mg dextrose, 1.38 mg sodium dihydrogen phosphate monohydrate, 2.84 mg anhydrous disodium hydrogen phosphate, 1 mL water, and then the pH was adjusted to 7.2 with hydrochloric acid / sodium hydroxide. As described above, dextrose can be omitted.

[0104] Additional details on techniques for formulation and administration may be found in Gennaro, A., ed., Remington's Pharmaceutical Sciences, 18th ed., (1990) (Mack Publishing Co., Easton, Pa.).

[0105] dose

[0106] The methods described herein are applicable to any subject for whom RTX is effective (e.g., capable of binding and activating TRPV1 or its homologue) and in need of treatment of inflammatory dysfunction and / or neurogenic inflammation of the oral mucosa. In an embodiment, RTX is administered at a dose of 0.1-150 μg. In an embodiment, the dose range of RTX is 0.1-0.5 μg, 0.5-1 μg, 1-2 μg, 2-5 μg, 5-10 μg, 10-20 μg, 20-30 μg, 30-40 μg, 40-50 μg, 50-60 μg, 60-70 μg, 70-80 μg, 80-90 μg, 90-100 μg, 100-110 μg, 110-120 μg, 120-130 μg, 130-140 μg or 140-150 μg.

[0107] In an embodiment, RTX is administered in one dose. In an embodiment, RTX is administered in repeated doses. In an embodiment, RTX is administered in 1, 2, 3, 4, or 5 doses.

[0108] In an embodiment, RTX is administered daily. In an embodiment, RTX is administered every other day. In an embodiment, RTX is administered weekly.

[0109] Neurogenic inflammation and pain

[0110] Inflammatory dysfunction of the oral mucosa is associated with neurogenic inflammation and pain. In an embodiment, the inflammatory dysfunction of the oral mucosa is associated with neurogenic inflammation. In an embodiment, the inflammatory dysfunction of the oral mucosa is associated with pain.

[0111] In embodiments, the compositions and methods described herein may be used to reduce pain. In embodiments, the compositions and methods described herein may be used to eliminate pain. In embodiments, the pain is orofacial pain.

[0112] In embodiments, the pain is due to alveolar structural disorder, cancer, neuropathic pain, or idiopathic pain. In embodiments, the pain is due to alveolar structural disorder. In embodiments, the pain is due to cancer. In embodiments, the pain is due to neuropathic pain. In embodiments, the pain is due to idiopathic pain. In embodiments, the pain is due to stomatitis. In embodiments, the pain is due to caudal stomatitis. In embodiments, the pain is due to chronic gingivostomatitis (CGS). In embodiments, the pain is due to feline chronic gingivostomatitis (FCGS). In embodiments, the pain is due to radiation therapy. In embodiments, the pain is due to tooth pain or oral mucosal pain. In embodiments, the pain is due to tooth pain. In embodiments, the pain is due to oral mucosal pain. In embodiments, the pain is due to oral mucosal inflammation.

[0113] In an embodiment, the cancer is treated with radiation therapy. In an embodiment, the pain is due to radiation therapy or chemotherapy induced mucositis.

[0114] In an embodiment, the idiopathic pain is due to burning mouth syndrome.

[0115] Example

[0116] 1. A preliminary safety study of oral topically applied resiniferatoxin (RTX) for pain control associated with feline chronic gingivostomatitis (FCGS)

[0117] This example provides safety data associated with oral topical application of RTX.The primary objective of this study was to determine the initial tolerability of RTX as a monotherapy when applied topically to the oral cavity of cats under anesthesia.

[0118] Four cats were included in this study. Each cat presented with mild to moderate gingival inflammation. Cats were assigned to two treatment groups based on the severity of gingival inflammation. Group 1 cats with mild gingivitis were dosed with diluted RTX solution (12.5 μg / mL) applied topically to the maxillary and mandibular gingival tissues (buccal and palatal / lingual gingiva) on study day 0. Group 2 cats, those with current or recent moderate gingivitis, received the same treatment regimen on study day 0 with the addition of dosing on the palatal and sublingual tissues.

[0119] The total dose of RTX tested per cat (diluted to a total volume of 2 mL with sterile saline) was: 17.5 μg (Group 1 cats), 23.75 μg (Group 1 cats), or 25 μg (Group 2 cats) RTX. One cat (pudding) received 17.5 μg RTX, one cat (Clank) received 23.75 μg RTX, and two cats (Forbes and Bianca) received 25 μg RTX. A single RTX dose was applied topically within the oral cavity of each cat. RTX was applied to the entire oral cavity.

[0120] Cats were anesthetized during treatment administration and within 30 minutes after administration. Diphenhydramine (2 mg / kg, IM) was given as an anesthetic pretreatment at least 30 minutes before administration. A combination of medetomidine 0.03 mg / kg, ketamine 5 mg / kg, and butorphanol 0.2 mg / kg was then used for induction; dose volume 0.1 mL / kg, IM. After the use of lidocaine hydrochloride spray in the throat, intubation was performed and anesthesia was maintained using a mixture of isoflurane and oxygen. Standard anesthesia monitoring of vital signs was performed approximately every 5-10 minutes after administration, and precautions were taken to avoid hypothermia throughout the process. After administration, cats were kept under anesthesia for 30 minutes for additional monitoring. After the anesthetic was removed, the reversal drug atipamezole (0.2 mg / kg, IM) was administered.

[0121] To assess RTX tolerability, adverse event monitoring was performed using the following parameters: measurement of vital signs during anesthesia; physical examinations in the morning (AM) and afternoon (PM) at 0.25, 0.5, 1, 2, 3, and 4 hours after recovery from anesthesia (i.e., removal of the endotracheal tube) and 1, 3, and 7 days after dosing; clinical observations twice daily; and daily food consumption measurements.

[0122] After administration of RTX, intermittent lip smacking or lip licking (Pudding and Clank, Group 1; Bianca and Forbes, Group 2), salivation (Pudding and Clank, Group 1; Bianca, Group 2) were observed in both groups. These observations occurred within 15 minutes to 2 hours after recovery from anesthesia and all disappeared on the second day after dosing. Additional findings included a mild increase in the severity of gingivitis in 1 cat from each treatment group (Pudding, Group 1; Forbes, Group 2) and a moderate increase in severity in 1 cat in Group 2 (Bianca), which also presented with lip redness. Changes in the severity of gingivitis were noted 15 minutes after recovery from anesthesia to 1 day after dosing. The mild changes in both cases resolved within 3 days after dosing without intervention. Cat (Bianca) showed a moderate increase in gingival inflammation (scored as moderate and significant compared to mild at baseline), returning to a moderate classification, which lasted until the end of the study.

[0123] Cats were followed for 8 days after RTX administration to assess the tolerability and safety of RTX. Figure 1B Although there appeared to be a transient decrease in food consumption, the cats' food consumption returned to normal by day seven. The body weights of the cats were determined before and 8 days after RTX administration. Figure 1A It is shown that despite a transient decrease in food consumption, body weight returned to normal (ie, body weight before RTX administration) by day 8.

[0124] This study demonstrated that RTX was well tolerated with only mild and transient adverse events such as transient lip licking / lip redness, transient salivation (15 minutes to 2 hours after application), mild increase in severity of gingivitis (up to 24 hours), and transient reduction in food consumption.

[0125] 2. Efficacy and safety of oral topically applied resiniferatoxin (RTX) for pain control associated with feline chronic gingivostomatitis (FCGS)

[0126] This example provides efficacy and safety data related to oral topical application of RTX to control pain associated with feline chronic gingivostomatitis (FCGS).The effects of RTX treatment on inflammation caused by feline chronic gingivostomatitis were also observed.

[0127] Primary Objectives: To demonstrate the efficacy of RTX in controlling oral pain associated with feline chronic gingivostomatitis (FCGS) in client-owned cats using the Veterinary Specific Outcome Measure (VSOM) and the Oral Inflammation Disease Activity Index (SDAI) at Day 28. To characterize the dose of RTX required for topical application to the oral mucosa to control pain associated with feline chronic gingivostomatitis (FCGS).

[0128] Inclusion criteria:

[0129] - Documented diagnosis of FCGS in cats.

[0130] - Cats have developed clinical signs of FCGS associated with oral pain for at least 3 months after being diagnosed with FCGS.

[0131] - Oral pain has a negative impact on quality of life.

[0132] - Medications commonly used to treat pain are acceptable, except for corticosteroids (see Exclusion Criteria), provided that these medications have been administered for at least 2 weeks prior to study inclusion and that no changes in treatment regimen are expected while the cat is on the study.

[0133] - The cat scored 10 or higher on a composite Veterinary Specific Outcome Scale (VSOM) (see paragraphs

[0094] and

[0095] below) of 3 activities selected by the investigator, with each question being scored at least 3 points.

[0134] Exclusion criteria:

[0135] -Cats less than 12 months old.

[0136] - Cat weighs less than 2kg.

[0137] -It is unlikely that a cat would survive a 30 minute anesthesia or sedation procedure.

[0138] - Cats are unlikely to survive 4 weeks due to health problems other than oral pain.

[0139] - A cat cannot be used for the entire duration of the study or the investigator deems a cat unsuitable for other reasons.

[0140] -Cats were involved in another study.

[0141] - The cat is pregnant or lactating.

[0142] - Cats underwent oral surgery within 30 days prior to screening.

[0143] - Cats received a cannabinoid agonist, such as cannabidiol (CBD) or anandamide, within 28 days of starting the study.

[0144] - Cats received oral corticosteroids within 1 week of study initiation, or injectable corticosteroids within 6 weeks of study initiation, and / or received essential medications or supplements during the study that could interfere with study objectives.

[0145] Twenty-eight cats, each weighing more than 2 kg and 12 months old, were included in this study. There was no significant trend in the age of the cats included in the study. Physical examinations were performed on the included cats (their physical examination findings such as general appearance, ears / eyes / mouth, abdomen / gastrointestinal, musculoskeletal, neuro-urogenital system, lymph glands, etc. were recorded). Their weight and vital signs were also recorded.

[0146] Validity variables

[0147] Veterinary Specific Outcome Scale (VSOM) - Qualitative assessment of common stomatitis features was performed before treatment began and on days 7, 14, and 28 (end of treatment). Cats were assessed for drooling, pain with feeding, pain with handling, and oral tissue swelling. Each clinical sign was scored from 1 to 5 (1 = no problem; 5 = impossible). The results are presented in Figures 2-4.

[0148] Treatment success was defined as a decrease of at least 2 points in the total VSOM score on day 28 compared to the VSOM score on day 0. A decrease of less than 2 points, no change, or an increase in the total score was defined as treatment failure. Any cat with an increase in VSOM alone, regardless of the total VSOM score, was considered a treatment failure. Based on this definition, the success rate on day 28 was 90.0% for Group 1 (6.25 μg RTX), 80.0% for Group 2 (12.5 μg RTX), and 88.9% for Group 3 (25 μg RTX). The results of each group were not statistically compared; due to the small number of cats in each group and the lack of randomization, only descriptive statistics were produced. However, there was no evidence of a relationship between treatment success and dose.

[0149] Figure 2A Shown are VSOM scores taken on day 0 (before treatment started), day 7, day 14 and day 28. The graph demonstrates the effectiveness of 6.25 μg, 12.5 μg and 25 μg RTX treatment. Figure 2B Those same VSOM scores organized by treatment group (6.25 μg, 12.5 μg, or 25 μg RTX) are shown, demonstrating that similar changes were observed in all groups at day 28. Figure 2C Shown is the % change in VSOM score from day 0 (before treatment) to day 28. This graph shows the Maximum Possible Effect % (MPE %), demonstrating that the MPE at day 28 ranged from 68% to 80%.

[0150] Oral Inflammatory Disease Activity Index (SDAI) - This semiquantitative assessment of oral inflammation was performed before treatment began (Day 0) and at Day 28 (end of treatment). Owners rated their cats' interest and ability to eat, perceived comfort, grooming behavior, and activity level. Each assessment was scored from 0 to 3 (0 = no problem; 3 = severe problem). The specifics of the assessment are shown in Table 1 below.

[0151] Table 1. Owner Assessment Questions

[0152]

[0153] The average of the scores in Table 1 (total score divided by 4) was entered into the "Owner Evaluation" box on the initial SDAI (Oral Inflammatory Disease Activity Index) tabulation worksheet in Table 2. The remaining questions of the SDAI survey were completed by the veterinarian before the start of treatment (Day 0) and on Day 28 (end of treatment). Each assessment was scored from 0 to 3 as follows (0 = no problem; 3 = severe problem):

[0154]

[0155] Table 2. Oral Inflammatory Disease Activity Index - SDAI

[0156] Stomatitis Disease Activity Index 0 1 2 3 1. Owner Assessment 2. Weight (compared to day 0) 3. Inflammation of maxillary buccal mucosa 4. Inflammation of mandibular buccal mucosa 5. Inflammation of maxillary attached gingiva 6. Mandibular attached gingivitis 7. Inflammation of the lateral palatolingual folds 8. Molar salivary gland inflammation 9. Oropharyngeal inflammation 10. Inflammation of the tongue and / or sublingual area Total score (maximum = 30)

[0157] Figure 3A The change in SDAI score before the start of treatment (day 0) and on day 28 is shown for each cat. Figure 3A The effectiveness of 6.25 μg, 12.5 μg and 25 μg RTX treatment was shown, even at the lowest dose of 6.25 μg. Figure 3B Shown is the % change in SDAI score from Day 0 (pre-treatment) to Day 28. This graph shows the Maximum Possible Effect % (MPE %), demonstrating that the MPE at Day 28 ranged from 30% to 85% (with most cats experiencing approximately 60% improvement). Figure 3C Baseline SDAI scores (Day 0) are shown for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX). Figure 4 Baseline SDAI scores (Day 0) and Day 28 SDAI scores are shown for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX). Figure 4 A trend towards smaller improvement was shown for the higher dose (25 μg) of RTX and a trend towards the greatest improvement at 12.5 μg.

[0158] For SDAI scores ( Figure 3A-3B and Figure 4 ), a smaller trend toward improvement was observed at higher doses. Figure 3C It is shown that the group treated with the highest dose (25 μg RTX) had the highest SDAI score before treatment. Therefore, the severity of inflammation before treatment may affect the overall response to treatment. The treatment is most effective for moderate disease.

[0159] Treatment success was defined as a 20% reduction in SDAI on day 28 compared to day 0 using the SDAI metric. Based on this definition, the percentage success rates for cohorts 1, 2, and 3 were 100.0%, 80.0%, and 44.4%, respectively. The difference in success rate for cohort 3 using both metrics may be due to a higher baseline SDAI score. However, these results confirm that increased inflammation measured by the SDAI is not associated with treatment success using behavioral metrics such as VSOM.

[0160] Security variables

[0161] mortality rate ——There was no mortality rate in this study, whether it was natural death or euthanasia.

[0162] Adverse events and serious adverse events -

[0163] An adverse event (AE) was defined as any undesirable occurrence in a study animal during the study, whether expected or not, and whether or not the event was considered to be causally related to study treatment. Adverse events were reported at scheduled times during the study, from Day 0 to the last day of the study. Certain adverse events (defined as serious adverse events) were reported on an expedited basis to allow for possible study protocol modifications. A serious adverse event (SAE) was defined as any medical event that resulted in hospitalization for more than 24 hours or caused severe disability or morbidity or was life-threatening or resulted in death.

[0164] One SAE occurred during the study that was determined by the investigator to be medically significant. On Study Day 14, NIE-08 (Cohort 2; 6.25 ug / mL topical resiniferatoxin (12.5 ug dose)) reported extreme pain, which the investigators thought may be related to stress from travel or oral manipulation. The cat had increased screaming and was unable to eat food that was not pureed. The investigators considered the event severe on Study Day 14 and noted improvement in the event when the patient was permanently removed from the study on Study Day 17. However, this cat was included in the efficacy analysis as a treatment failure. HAM-01 (Cohort 1; 3.12 ug / mL (dose 6.25 ug) of topical resiniferatoxin developed respiratory signs unrelated to RTX administration by Day 9 and was removed from the study on Day 9. WEX-09 (Cohort 3; 12.5 ug / mL (dose 25 ug) of topical resiniferatoxin) was removed from the study because progressive pain was recorded as a SAE and was included in the efficacy analysis as a treatment failure.

[0165] The investigators described adverse events according to the following descriptions:

[0166] - Mild; asymptomatic or mild symptoms; clinical signs or diagnostic observations only; no intervention required.

[0167] - Moderate; minimal, outpatient or non-invasive intervention; moderate limitation in activities of daily living (ADL).

[0168] - Severe or medically significant but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; contraindicating; significantly limiting ADL.

[0169] Clinical signs clearly related to pain progression were not considered adverse events unless considered related to RTX administration. Patients who experienced adverse events received appropriate medical therapy as determined by the investigator.

[0170] Record the severity, causality, and outcome of the adverse event. Causality is a determination of whether it is reasonably possible that the drug caused or contributed to the AE. This relationship is described as “unlikely,” “possible,” “probable,” “certain,” or “unknown.”

[0171] Blood (4-5 mL) was collected at the beginning of the study for complete blood count (CBC) and serum biochemistry.

[0172] Most AEs were rated as mild. No consistent trends were evident between AEs and dose, severity, or causality. The incidence of AEs increased on study days 7 and 14, consistent with study visits, but decreased on study day 28.

[0173] Sedation and anesthesia

[0174] Prior to RTX treatment, fasted cats were pretreated with antihistamines for at least 30-45 minutes (antihistamines are used to counteract possible allergic reactions to polysorbate 80 in cats and dogs). Enrolled cats were anesthetized using standard feline sedation / anesthesia based on an analgesic / sedative / anesthetic mixture. Cats were monitored by auscultation and observation of chest movement. Heart rate and oxygenation were monitored using a pulse oximeter throughout the duration of the procedure. Blood pressure was monitored using an oscillometric non-invasive sphygmomanometer (e.g., tail cuff and / or limb). Body temperature (98 to 99°F) was maintained using a heated water blanket or equivalent thermal barrier (e.g., Vetko). Balanced IV solutions were used to maintain adequate hydration (approximately 2 mL / kg / hour intravenous (IV) infusion) and / or fluid boluses (2-5 mL / kg IV) as needed. RTX solution was administered after the cat reached an adequate level of anesthesia. A copy of the anesthesia record was included in the study file.

[0175] Before treatment with RTX, the location of oral lesions was recorded, and oral photographs were taken before treatment and on day 28 to record the oral lesions.

[0176] RTX preparation and application

[0177] RTX is provided in a 2R glass vial as a solution of 25 μg / mL (2.4 mL). The IVP is maintained in its original sterile glass container (vial) until use. The IVP is brought to room temperature before administration and gently swirled but not shaken before use. Dosages and preparation instructions are described in Table 3.

[0178] Each animal was randomly assigned to one of three groups. Ten cats were treated with 6.25 μg RTX (total) (diluted to a total volume of 2 mL with sterile saline) (Group 1). Nine cats were treated with 12.5 μg RTX (total) (diluted to a total volume of 2 mL with sterile saline) (Group 2). Nine cats were treated with 25 μg RTX (total) (diluted to a total volume of 2 mL with sterile saline) (Group 3).

[0179] Table 3. Animal Treatments - Topical Oral Application

[0180]

[0181] Apply the RTX solution directly to visible lesions and adjacent tissue using a clean cotton swab. Protect non-target administration areas (caudal mouth / pharynx) with a 4×4 gauze. Dry any target areas with sterile gauze or using an air-water irrigator. Gently press the saturated cotton swab along the target area for 10 seconds. Apply two to three layers to each lesion using the same cotton swab. Allow the area to dry for a few seconds and then move to the next lesion by exposing the area to air or by gently using an air-water irrigator. When possible, allow the RTX solution to drip into the gingival sulcus in the absence of active bleeding from the procedure. If the target area is actively bleeding, attempt to reduce or stop the bleeding before applying RTX.

[0182] After all lesions were treated, any remaining RTX solution was applied to tissue adjacent to the most severely infected area. Once all applied RTX had dried for at least 20 minutes, the treated area was cleaned with a 4x4 gauze lightly moistened with saline.

[0183] After oral topical application of RTX, cats were maintained under general anesthesia for at least 10 min (minimum total anesthesia time 30 min).

[0184] If reversal medications are used, such as atipamezole, their use is discouraged for at least 1 hour after application of the RTX solution. If acute reactions occur during administration (e.g., involuntary motor movements or respiratory efforts, increased cardiovascular changes, nociceptive responses), cats can receive short-acting analgesics such as, but not limited to, fentanyl (1-2 μg / kg IV) or sufentanil and / or propofol (0.5 mg / kg IV) to control motor movements as needed. The nature and extent of these reactions are reported as adverse events (AEs).

[0185] If an anaphylactic reaction (e.g., facial edema, auricular edema, excessive airway secretions, tachycardia, hypotension, urticaria, vomiting / regurgitation, diarrhea, erythema, and / or elevated temperature) was observed during treatment or recovery and if the cat was unstable and in a life-threatening state, dexamethasone sodium phosphate 0.2-0.4 mg / kg was administered IV over 1 minute. Because corticosteroids have potent anti-inflammatory effects, continued study of any cat receiving corticosteroids for the above conditions was re-evaluated. All medications used to treat adverse events following administration of RTX were reported.

[0186] Clinical observations after treatment

[0187] After treatment was completed, short-acting analgesics such as, but not limited to, buprenorphine were prescribed for up to 3 days as needed to control pain associated with treatment. Administration of buprenorphine reduced the number of adverse reactions. Cats in Group 1 were not treated with buprenorphine after RTX administration. Cats in Groups 2 and 3 were treated with buprenorphine after RTX administration.

[0188] On Day 0, beginning with the application of RTX to all oral lesions (Time 0), veterinarians performed clinical observations at 10, 30, 45, 60 (± 5 minutes) and 2 (± 10 minutes) and 4 (± 15 minutes) hours post-treatment application. Cats were observed 4 hours post-treatment application as needed or until abnormal observations resolved.

[0189] Clinical signs such as, but not limited to, panting, hypersalivation, tachycardia, and restlessness have been reported as adverse effects following administration of RTX to cats. These signs resolved within approximately 3 hours of treatment without the need for medical intervention.

[0190] Summary of results

[0191] Veterinary Specific Outcome Scale (VSOM) Results - On Day 7, Groups 2 and 3 had higher success rates than Group 1, which may have been influenced by the use of post-treatment buprenorphine in both groups. However, the success rate of Group 1 continued to increase, and by Day 28, this group had the highest success rate. On Day 14, all cats in Group 2 were successful, but 2 of them failed by Day 28. The treatment success rate on Day 28 (as defined above in the Effectiveness Variables - VSOM section) was 90.0% for Group 1 (6.25 μg RTX), 80.0% for Group 2 (12.5 μg RTX), and 88.9% for Group 3 (25 μg RTX).

[0192] Stomatitis Disease Activity Index (SDAI) Results - Cases were considered successful if the total SDAI score decreased by 20% or more between Day 0 and Day 28. An inverse relationship was observed between dose and percentage success rate, with the highest percentage success rate in Group 1 (6.25 μg RTX) and the lowest percentage success rate in Group 3 (25 μg RTX). The treatment success rates for Groups 1, 2, and 3 were 100.0%, 80.0%, and 44.4%, respectively.

[0193] However, as seen in Table 4, the mean total SDAI scores on Day 0 varied between treatment groups, with the highest baseline SDAI in Group 3. Cats were not randomized to groups, and variability in baseline SDAI scores should be considered when interpreting the percentages of successes and failures based on a ≥20% decrease in SDAI scores between Day 0 and Day 28.

[0194] Table 4. SDAI scores: mean group total scores on day 0

[0195] Day 0 Average SDAI overall score Group 1 13.50 Group 2 13.20 Group 3 17.44

[0196] Comparison of VSOM and SDAI Effectiveness Assessments: Cohort 3 had a significant difference in success rate using the VSOM versus the SDAI measure due to a higher baseline SDAI. However, this difference confirms that the extent of inflammation does not always correlate with a positive response to treatment, which is behaviorally assessed in the VSOM assessment. Because the primary goal of RTX administration is to provide oral pain relief to encourage eating and improve quality of life, rather than to reduce inflammation, the VSOM was determined to be the best measure for this study.

[0197] Cats were weighed on Days 0, 7, 14, and 28. Twenty-four of the 28 cats were reported to be of normal weight. Two cats (one in Group 1 and one in Group 3) had abnormal (low) weight on Day 0 but were of normal weight on Day 28. One cat (Group 1) exhibited weight loss on Day 28 compared to Day 0. One cat (Group 2) exhibited weight loss on Day 14.

[0198] Cats' ability to eat was assessed on days 0, 7, 14, and 28. The ability to eat improved in most cats throughout the study. No differences in eating ability between the two groups were detected on day 28. Overall, the ability to eat improved in most cats across all groups that completed the study, with only one cat (in group 2) experiencing a decrease in eating ability.

[0199] in conclusion

[0200] Even low concentrations of RTX (6.25 μg) were effective in controlling pain and inflammation for 28 days.

[0201] Application of RTX to inflamed and vulnerable oral mucosa appears to be safe as cats did not show signs of systemic RTX exposure.

[0202] Studies have demonstrated that administration of buprenorphine up to 72 hours after treatment improves the tolerability of RTX treatment.

[0203] Adverse events were mostly related to post-treatment discomfort, which could be managed with standard pain therapy (buprenorphine administered once daily for 3 days). The most common AEs were weight loss, decreased appetite, hypersalivation, decreased ability to eat, and pain / oral pain.

[0204] The body weight of most cats was not adversely affected by RTX treatment. No information is available regarding the safe maintenance of thermal sensation.

[0205] The study demonstrated a high success rate across all cohorts using the VSOM metric and confirmed that behavioral metrics like the VSOM outperformed the SDAI, which also measures inflammation. The safety profile of this route of administration was acceptable, as most AEs were considered mild in severity and cats showed no signs of systemic exposure to RTX.

[0206] The complete disclosures of all publications cited herein are incorporated by reference in their entirety as if each publication were individually set forth in its entirety and incorporated herein.

[0207] Various modifications and alterations to the embodiments disclosed herein will become apparent to those skilled in the art without departing from the scope and spirit of the present disclosure.The illustrative embodiments and examples are provided as examples only and are not intended to limit the scope of the present invention.

Claims

1. A method for treating an inflammatory disorder of the oral mucosa, the method comprising topically administering a therapeutically effective amount of resiniferatoxin (RTX) to a subject in need of treatment of the inflammatory disorder of the oral mucosa.

2. A composition for use in a method for treating an inflammatory disorder of the oral mucosa, the composition comprising resiniferatoxin (RTX), the method comprising topically administering a therapeutically effective amount of the composition to a subject in need of treatment of the inflammatory disorder of the oral mucosa.

3. The method of claim 1 or the composition for use of claim 2, wherein the inflammatory dysfunction of the oral mucosa is associated with neurogenic inflammation.

4. The method or composition for use of claim 3, wherein the neurogenic inflammation is reduced.

5. The method of claim 1 or the composition for use of claim 2, wherein the inflammatory dysfunction of the oral mucosa is associated with pain.

6. The method or composition for use of claim 5, wherein the pain is reduced.

7. The method or composition of claim 5, wherein the pain is orofacial pain.

8. The method or composition for use of claim 3, wherein the subject is a mammal.

9. The method or composition for use of claim 8, wherein the mammal is a human.

10. The method or composition for use of claim 8, wherein the mammal is a cat, dog, horse, pig, ruminant, cattle, sheep, goat, or a domesticated mammal.

11. The method or composition for use according to any one of the preceding claims, wherein the RTX is administered at a dose of about 0.1 μg to about 150 μg.

12. The method or composition for use according to any one of the preceding claims, wherein the method comprises administering a pharmaceutical formulation comprising the RTX and a pharmaceutically acceptable carrier.

13. The method or composition for use according to claim 12, wherein the pharmaceutically acceptable carrier comprises water.

14. The method or composition for use according to claim 12 or 13, wherein the pharmaceutically acceptable carrier comprises polysorbate 80.

15. The method or composition for use according to any one of claims 12 to 14, wherein the pharmaceutically acceptable carrier comprises polyethylene glycol.

16. The method or composition for use according to any one of claims 12 to 15, wherein the pharmaceutically acceptable carrier comprises a sugar or a sugar alcohol.

17. The method or composition for use according to any one of claims 12 to 16, wherein the pharmaceutically acceptable carrier comprises mannitol.

18. The method or composition for use of any one of claims 12 to 17, wherein the pharmaceutically acceptable carrier comprises dextrose.

19. The method or composition for use according to any one of claims 12 to 18, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable buffer, optionally wherein the pharmaceutically acceptable buffer is a phosphate buffer, and / or the pH of the formulation is about 6.0-7.6 or about 7.

2.

20. The method or composition for use according to any one of claims 12 to 19, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable salt.

21. The method or composition for use according to any one of claims 12 to 20, wherein the pharmaceutically acceptable salt is NaCl.

22. The method or composition for use according to any one of claims 12 to 21, wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.02 to 300 μg / ml.

23. The method or composition for use of claim 22, wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.02-0.1 μg / ml, 0.1-1 μg / ml, 1-5 μg / ml, 5-10 μg / ml, 10-20 μg / ml, 20-50 μg / ml, 50-100 μg / ml, 100-150 μg / ml, 150-200 μg / ml, 200-250 μg / ml or 250-300 μg / ml.

24. The method or composition for use according to claim 22, wherein the concentration of RTX in the pharmaceutical formulation is in the range of 0.1-50 μg / ml.

25. The method or composition for use according to any one of the preceding claims, wherein the RTX is topically administered in a volume of 0.5-5 ml, optionally wherein the volume is in the range of 0.5-1.0 ml, 1.0-1.5 ml, 1.5-2 ml, 2-3 ml, 3-4 ml or 4-5 ml.

26. The method or composition for use of any one of the preceding claims, wherein the method further comprises administering a general or local anesthetic prior to administering the RTX.

27. The method or composition for use of any one of the preceding claims, wherein the method further comprises administering an analgesic after administering RTX.

28. The method or composition for use of claim 27, wherein the analgesic is an opioid or a nonsteroidal anti-inflammatory drug (NSAID).

29. The method or composition for use of any one of the preceding claims, wherein the pain is due to alveolar structural disorder, cancer, neuropathic pain, or idiopathic pain.

30. The method or composition for use of claim 29, wherein the pain is due to neuropathic pain.

31. The method or composition for use of claim 29, wherein the pain is due to idiopathic pain.

32. The method or composition for use of claim 31 , wherein the idiopathic pain is due to burning mouth syndrome.

33. The method or composition for use of any one of the preceding claims, wherein the pain is due to stomatitis.

34. The method or composition for use of any one of the preceding claims, wherein the pain is due to chronic gingivostomatitis (CGS).

35. The method or composition for use of claim 34, wherein the chronic gingivostomatitis is feline chronic gingivostomatitis (FCGS).

36. The method or composition for use of any one of the preceding claims, wherein the pain is due to cancer.

37. The method or composition for use of any one of the preceding claims, wherein the pain is due to radiation therapy.

38. The method or composition for use of any one of the preceding claims, wherein the pain is due to a disordered alveolar structure.

39. The method or composition for use of claim 38, wherein the pain is due to dental pain or oral mucosal pain.

40. The method or composition for use of any one of the preceding claims, wherein the pain is due to radiotherapy-induced mucositis.

41. A method for treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the method comprising topically administering to a subject in need of treatment for said neurogenic inflammation a therapeutically effective amount of resiniferatoxin (RTX).

42. A composition for use in a method for treating neurogenic inflammation associated with an inflammatory dysfunction of the oral mucosa, the composition comprising resiniferatoxin (RTX), the method comprising topically administering a therapeutically effective amount of the composition to a subject in need of treatment for the neurogenic inflammation associated with an inflammatory dysfunction of the oral mucosa.

43. The method of claim 41 or the composition for use of claim 42, wherein the neurogenic inflammation is reduced.

44. The method of claim 41 or the composition for use of claim 42, wherein the neurogenic inflammation is associated with pain.

45. The method or composition for use of claim 44, wherein the pain is reduced.

46. ​​The method or composition for use of claim 44, wherein the pain is orofacial pain.

47. The method or composition for use of claim 44, wherein the pain is due to alveolar structural disorder, cancer, neuropathic pain, or idiopathic pain.

48. The method or composition for use of claim 47, wherein the pain is due to neuropathic pain.

49. The method or composition for use of claim 47, wherein the pain is due to idiopathic pain.

50. The method or composition for use of claim 49, wherein the idiopathic pain is due to burning mouth syndrome.

51. The method or composition for use of claim 44, wherein the pain is due to stomatitis.

52. The method or composition for use of claim 44, wherein the pain is due to chronic gingivostomatitis (CGS).

53. The method or composition for use of claim 44, wherein the chronic gingivostomatitis is feline chronic gingivostomatitis (FCGS).

54. The method or composition for use of claim 44, wherein the pain is due to cancer.

55. The method or composition for use of claim 44, wherein the pain is due to a disordered alveolar structure.

56. The method or composition for use of claim 55, wherein the pain is due to dental pain or oral mucosal pain.

57. The method or composition for use of claim 44, wherein the pain is due to radiotherapy-induced mucositis.

58. The method or composition for use of any preceding claim, wherein the RTX is administered to multiple sites.

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