Method for treating inflammatory dysfunction of oral mucosa

Abstract

In particular, methods for treating inflammatory dysfunction of the oral mucosa are provided herein that include the step of topically administering an effective amount of riciniferatoxin (RTX). This disclosure is aimed at meeting this need and / or providing other benefits. A method of topically administering RTX to a subject in need thereof for treating inflammatory dysfunction of the oral mucosa is provided herein. This disclosure is based in part on the recognition that oral topical administration of RTX for treating inflammatory dysfunction of the oral mucosa can not only provide effective pain relief, but also treat the underlying neurogenic inflammation.

Description

Technical Field

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

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

[0003] Technical Field The present disclosure provides a method for treating an inflammatory dysfunction of the oral mucosa, which includes the step of locally administering an effective amount of resiniferatoxin (RTX).

Background Art

[0004] Background RTX acts as a very potent analog of capsaicin, the main pungent ingredient of chili peppers. RTX is a tricyclic diterpene isolated from certain species of Euphorbia. The homovanillyl group is an important structural feature of capsaicin and the most important feature that distinguishes resiniferatoxin from typical phorbol-related compounds. Natural RTX has the following structure:

Chemical

[0005] RTX and analog compounds (e.g., diterpene 20-homovanillyl esters such as thiniatoxin and other compounds (12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate)) are described in U.S. Patent Nos. 4,939,194; 5,021,450; and 5,232,684. Other resiniferatoxin type phorbol vanilloids have also been identified (Szallasi et al. (1999) Brit. J. Pharmacol. 128:428-434).

[0006] RTX is known as a TRPV1 agonist. TRPV1 (transient receptor potential cation channel subfamily V member 1, also known as vanilloid receptor-1 (VR1)) is a multimodal cation channel prominently expressed in nociceptive primary afferent neurons (Caterina et al. (1997) Nature 389:816-824; Tominaga et al. (1998) Neuron 21:531-543). Activation of TRPV1 typically occurs at nerve endings via the application of noxious heat and is upregulated during certain types of inflammatory stimuli. Activation of TRPV1 in peripheral tissues by chemical agonists results in the opening of calcium channels and the transmission of pain sensation (Szalllasi et al. (1999) Mol. Pharmacol. 56:581-587). However, direct application of certain TRPV1 agonists to the cell bodies (ganglia) of neurons expressing TRPV1 induces a cascade of events that open calcium channels and lead to programmed cell death ("apoptosis") (Karai et al. (2004) J. of Clin. Invest. 113:1344-1352).

[0007] The transient receptor potential vanilloid 1 (TRPV1) has been reported to be involved in 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 involved in pulpitis (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 inferior alveolar nerve injury pain (Kim, H. et al. (2008) J Pain 9:280-288).

[0008] Inflammatory dysfunction of the oral mucosa is associated with oral mucosal inflammation and pain. Inflammatory dysfunction of the oral mucosa in humans can be caused by many diseases, some of which are immune-mediated (e.g., Behçet's disease, oral lichen planus, pemphigus and pemphigoid, recurrent aphthous stomatitis, stomatitis, Sjögren's syndrome and many others). These diseases tend to be chronic and often severely affect an individual's quality of life. Common causes of inflammatory dysfunction of the oral mucosa include, for example, viral infection, yeast infection, bacterial infection, chemotherapy or radiotherapy treatment for cancer, a weakened or insufficient immune system, and many others. People with oral mucosal diseases can develop painful mouth sores or ulcers in the mucosal inner layer (the "skin" inside the mouth, including the cheeks and lips).

[0009] Inflammatory dysfunction of the oral mucosa in cats can be caused by feline chronic gingivostomatitis (FCGS) or caudal stomatitis, affecting between 0.7% and 12% of all cats. FCGS is a debilitating oral inflammatory disease that can persist for years and lead to euthanasia. FCGS is multifactorial (possibly arising from viral infection, dental disease, and / or allergies) and can affect the tissues of the gums, cheeks, palate, sublingual area, and pharynx. FCGS can be resistant to medical management (immunosuppressive therapy) and surgical management (full mouth dental extraction).

[0010] The pain associated with inflammatory dysfunction of the oral mucosa is typically considered a deep pain that requires intervention, which is typically a systemic treatment or a direct local treatment or an invasive or surgical treatment directed at the pain site. Such treatments include local solutions (applied directly to the gums and teeth for toothache), local injections (into the gums or trigger points for toothache), various systemic analgesics (aspirin, acetaminophen, non-steroidal anti-inflammatory drugs, and narcotics), various other systemic drugs (steroids, diphenylhydantoin, carbamazepine, calcium channel blockers, β-blockers, and tricyclic antidepressants), and surgical procedures (such as tooth extraction). Some treatments are available for the pain associated with inflammatory dysfunction of the oral mucosa, but they are not always effective. Furthermore, 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), but there are none that can treat the underlying neurogenic inflammation. Therefore, there is a need in the art for improved treatments for 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.

Prior Art Documents

Patent Documents

[0011] [Patent Document 1] U.S. Patent No. 4,939,194 [Patent Document 2] U.S. Patent No. 5,021,450 [Patent Document 3] U.S. Patent No. 5,232,684 [Patent Document 4] U.S. Patent No. 5,296,225 [Patent Document 5] U.S. Patent Application Publication No. 2015 / 0051271 [Non-Patent Document]

[0012] [Non-Patent Document 1] Szallasi et al. (1999) Brit. J. Pharmacol. 128:428-434 [Non-Patent Document 2] Caterina et al. (1997) Nature 389:816-824 [Non-Patent Document 3] Tominaga et al. (1998) Neuron 21:531-543 [Non-Patent Document 4] Szalllasi et al. (1999) Mol. Pharmacol. 56:581-587 [Non-Patent Document 5] Karai et al. (2004) J. of Clin. Invest. 113:1344-1352 [Non-Patent Document 6] Amaya, F. et al. (2003) Brain Res. 963:190-196 [Non-Patent Document 7] Asai, H. et al. (2005) Pain 117:19-29 [Non-Patent Document 8] Shinoda, M. et al. (2008) J Pain 9:687-699 [Non-Patent Document 9] Rashid, M. et al. (2003) J Pharmacol. Exp. Ther. 304:940-948

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Summary of the Invention

Means for Solving the Problems

[0013] Abstract The present disclosure aims to meet this need and / or provide other benefits. Provided herein is a method of topically administering RTX to a subject in need thereof for the treatment of inflammatory dysfunction of the oral mucosa. The present disclosure is based in part on the recognition that oral topical administration of RTX for the treatment of inflammatory dysfunction of the oral mucosa can not only provide effective pain relief but also treat the underlying neurogenic inflammation.

[0014] In one aspect, provided herein is a method for treating inflammatory dysfunction of the oral mucosa, the method comprising the step of topically administering a therapeutically effective amount of resiniferatoxin (RTX) to a subject in need of treatment of the inflammatory dysfunction of the oral mucosa.

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

[0016] 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.

[0017] In an embodiment, the neurogenic inflammation is reduced. In an embodiment, the pain is reduced.

[0018] In an embodiment, the pain is orofacial pain. In an embodiment, the pain is caused by alveolar structural disorders, cancer, neuropathic pain, or idiopathic pain. In an embodiment, the pain is caused by alveolar structural disorders. In an embodiment, the pain is caused by cancer. In an embodiment, the pain is caused by neuropathic pain. In an embodiment, the pain is caused by idiopathic pain. In an embodiment, the pain is caused by stomatitis. In an embodiment, the pain is caused by chronic gingivostomatitis (CGS). In an embodiment, the pain is caused by feline chronic gingivostomatitis (FCGS). In an embodiment, the idiopathic pain is caused by burning mouth syndrome.

[0019] In an embodiment, the pain is caused by radiotherapy or chemotherapy. In an embodiment, the pain is caused by radiotherapy. In an embodiment, the pain is caused by chemotherapy. In an embodiment, the pain is caused by radiation-induced mucositis.

[0020] In an embodiment, the pain is caused by alveolar structural disorders. In an embodiment, the pain is caused by toothache or oral mucosal pain. In an embodiment, the pain is caused by toothache. In an embodiment, the pain is caused by oral mucosal pain.

[0021] In an embodiment, the subject is a mammal. In an embodiment, the mammal is a cat, dog, horse, pig, ruminant, cow, sheep, goat, or domesticated mammal. In an embodiment, the mammal is a cat. In an embodiment, the mammal is a dog. In an embodiment, the mammal is a horse. In an embodiment, the mammal is a pig. In an embodiment, the mammal is a ruminant. In an embodiment, the mammal is a cow. In an embodiment, the mammal is a sheep. In an embodiment, the mammal is a goat. In an embodiment, the mammal is a domesticated mammal. In an embodiment, the mammal is a human.

[0022] In an embodiment, the RTX is administered in a pharmaceutical formulation comprising the RTX and 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 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.

[0023] In an embodiment, the pharmaceutically acceptable buffer is a phosphate buffer and / or the pH of the formulation is about 6.0 to 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.

[0024] In an embodiment, the above-mentioned RTX is administered at a dose of about 0.1 μg to about 100 μg. In an embodiment, the concentration of RTX in the above-mentioned pharmaceutical preparation is in the range of 0.02 to 300 μg / ml. In an embodiment, the concentration of RTX in the above-mentioned pharmaceutical preparation is in the range of 0.02 to 0.1 μg / ml, 0.1 to 1 μg / ml, 1 to 5 μg / ml, 5 to 10 μg / ml, 10 to 20 μg / ml, 20 to 50 μg / ml, 50 to 100 μg / ml, 100 to 150 μg / ml, 150 to 200 μg / ml, 200 to 250 μg / ml, or 250 to 300 μg / ml. In an embodiment, the concentration of RTX in the above-mentioned pharmaceutical preparation is in the range of 0.1 to 50 μg / ml.

[0025] In an embodiment, the above-mentioned RTX is topically administered in a volume of 0.5 to 5 ml. In an embodiment, the above-mentioned RTX is topically administered in a volume in the range of 0.5 to 1.0 ml, 1.0 to 1.5 ml, 1.5 to 2 ml, 2 to 3 ml, 3 to 4 ml, or 4 to 5 ml.

[0026] In an embodiment, a general anesthetic or a local anesthetic is administered before the administration of RTX. In an embodiment, an analgesic is administered after the administration of RTX. In an embodiment, the above-mentioned analgesic is an opioid or a non-steroidal anti-inflammatory drug (NSAID). In an embodiment, the above-mentioned analgesic is an opioid. In an embodiment, the above-mentioned analgesic is a non-steroidal anti-inflammatory drug (NSAID). In an embodiment, the above-mentioned RTX is administered to a plurality of sites.

[0027] In one aspect, there is provided herein a method for treating neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa, the method comprising the step of topically administering a therapeutically effective amount of resiniferatoxin (RTX) to a subject in need of treatment of neurogenic inflammation.

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

Brief Description of the Drawings

[0029]

Figure 1

[0030] Figure 1B shows the feed consumption of each cat as a % ration consumed over an 8-day test (data collection was not done on day 2).

[0031]

Figure 2-1

Figure 2-2

[0032]

Figure 3

[0033] The graph of Figure 3B % Maximum Possible Efficacy (%MPE) shows the % change in SDAI from Day 0 (before treatment) to Day 28 for each cat. This shows the effectiveness (semi - quantitative evaluation) of 6.25 μg, 12.5 μg, and 25 μg RTX treatments.

[0034] Figure 3C shows the baseline SDAI scores for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX).

[0035]

Figure 4

Mode for Carrying Out the Invention

[0036] Detailed Description Reference will now be made in detail to certain embodiments of the present invention. Examples thereof are illustrated in the accompanying drawings. While the invention is described in conjunction with the illustrated embodiments, it is to be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the appended claims.

[0037] Before describing the present teachings in detail, it should be understood that the present disclosure is not limited to specific compositions or process steps and can thus vary. As used in this specification and the appended claims, the singular forms "a", "an", and "the" are to be noted as including plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a conjugate" includes plural conjugates, reference to "a cell" includes plural cells, and the like. The use of alternatives herein (e.g., "or") is understood to mean either one or both of the alternatives, or any combination thereof.

[0038] The terms "and" and " / or" as used herein are to be understood to mean, for each of the specifically identified features or components, the specific disclosure with or without the other. For example, as used herein in a phrase such as "A and / or B", the term "and / or" is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following scenarios: 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); as well as C (alone).

[0039] As used herein, the terms "comprising," "including," "having," "containing," and grammatical variations thereof are, when used herein, intended to be non-limiting in that one or more items in a list are not excluded from the list by the item or items recited, and other items may be substituted for or added to the recited items. It is understood that when an aspect is described herein with the term "comprising," other similar aspects that are described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0040] As used herein, the terms "mcg," "μg," and "ug" are interchangeable and refer to micrograms.

[0041] As used herein, the term "about" refers to a value or composition within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, "about" or "approximately" can mean within one standard deviation, or within a standard deviation greater than one, depending on the practice in the art. Alternatively, "about" or "approximately" can mean within up to 10% (i.e., ±10%) or more depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. Further, especially with respect to biological systems or processes, the term can mean within up to one order of magnitude or up to five-fold of a value. When a particular 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 that particular value or composition. In embodiments, "about" encompasses variations within 10%, 5%, 2%, 1%, or 0.5% of the stated value.

[0042] Numerical ranges include both ends of the numbers defining the range. It is understood that measured values and measurable values are approximations, taking into account the significant figures and errors associated with that measurement. Also, all ranges should be interpreted as including their endpoints unless there is an explicit exclusion such as "excluding the endpoints"; thus, for example, the "range from 1 to 10" includes the values 1 and 10, as well as all numbers greater than 1 and less than 10 and (where appropriate) non-integer values.

[0043] The use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" is not intended to be limiting. It should be understood that both the foregoing general description and the detailed description are exemplary and explanatory only and do not limit the present teachings. Unless specifically noted otherwise in the above specification, embodiments in this specification that describe various components as "including" are also contemplated as "consisting of" or "consisting essentially of" the recited components; embodiments in this specification that describe various components as "consisting of" are also contemplated as "including" or "consisting essentially of" the recited components; and embodiments in this specification that describe various components as "consisting essentially of" 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).

[0044] The headings of sections used in this specification are for organizational purposes only and are in no way to be construed as limiting the desired subject matter. In the event that any incorporated document conflicts with any term defined in this specification, this specification shall control. Although the teachings are described with reference to various embodiments, the teachings are not intended to be limited to such embodiments. On the contrary, the teachings include various alternatives, modifications, and equivalents as will be recognized by those of ordinary skill in the art.

[0045] Definitions As used herein, the term "inflammatory dysfunction of the oral mucosa" refers to the inflammation and pain associated with diseases of the oral mucosa, some of which are immune-mediated (e.g., Behçet's disease, oral lichen planus, pemphigus and pemphigoid, recurrent aphthous stomatitis, Sjogren's syndrome, caudal stomatitis, stomatitis, chronic gingivostomatitis (CGS), feline chronic gingivostomatitis (FCGS), or oral cancer). These diseases tend to be chronic and often have a profound impact on an individual's quality of life. Common causes of inflammatory dysfunction of the oral mucosa include, for example, viral infections, yeast infections, bacterial infections, chemotherapy or radiation therapy treatments for cancer, a weakened or insufficient immune system, and many others. Mammals having an oral mucosal disease can develop painful stomatitis or ulcers in the mucosal inner layer (the "skin" inside the mouth, including the cheeks and lips).

[0046] As used herein, the term "orofacial pain" refers to pain resulting from disorders of the alveolar structures, such as toothache or oral mucosal pain. Oral mucosal pain can be caused by neurogenic inflammation, which can be a result of various oral mucosal diseases. Toothache can be a result of pulp pain, periodontal pain, or gingival pain. As used herein, "orofacial pain" also refers to pain resulting from idiopathic oral pain (e.g., burning mouth syndrome or persistent idiopathic dentoalveolar pain). As used herein, "orofacial pain" can also refer to neuropathic pain or pain resulting from local or systemic inflammation. Further, as used herein, the term "orofacial pain" refers to pain caused by cancer (e.g., oral cancer) or cancer treatment (e.g., radiation therapy). In embodiments, orofacial pain can be caused by radiation therapy or chemotherapy-induced mucositis. In embodiments, orofacial pain can be caused by stomatitis. In embodiments, orofacial pain can be caused by chronic gingivostomatitis.

[0047] As used herein, the term "neuropathic pain" refers to pain resulting from damage or disease that affects sensory neurons.

[0048] A "ruminant" is a mammal that has a ruminant stomach. Examples of ruminants include, but are not limited to, cows, sheep, antelopes, deer, and giraffes.

[0049] The terms "effective amount," "therapeutically effective amount," or "effective dose," or related terms may be used interchangeably and refer to an amount of a therapeutic agent (RTX) that is sufficient to, when administered to a subject, affect a measurable improvement or even complete resolution of pain and neurogenic inflammation associated with inflammatory dysfunction of the oral mucosa. For example, administration of an effective dose is sufficient to inhibit neurogenic inflammation and stop pain in a subject. The therapeutically effective amount of the therapeutic agent (RTX) provided herein will vary depending on the subject being treated and the disease state, the weight of the subject, the severity of the disease state in the subject, etc., which can be readily determined by one of ordinary skill in the art. In one embodiment, the therapeutically effective amount depends on the subject to be treated and the particular aspect of the disorder to be treated and can be ascertained by one of ordinary skill in the art using known techniques. Further, as is known in the art, adjustments regarding weight, general health, time of administration, drug interactions, and disease severity may be necessary.

[0050] The terms "subject" and "patient," as used herein, 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, simian, ape, murine (e.g., mouse and rat), bovine, porcine, equine, canine, feline, caprine, lupine, ranine, or piscine.

[0051] The terms "administering," "administered," and grammatical variations thereof refer to physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Exemplary non-parenteral (i.e., topical) routes of administration of the formulations disclosed herein include, for example, topical, epidermal, or mucosal routes of administration. In one embodiment, the formulation is topically administered to the oral mucosa in the mouth in the form of a solution, suspension, cream, lotion, gel, paste, spray, powder, or ointment. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0052] "Treating" should be understood broadly and includes, at least in part, delaying, slowing, or arresting the worsening of symptoms associated with, for example, an inflammatory dysfunction of the oral mucosa, or treating such symptoms, including any beneficial effect. Treating also includes bringing about any form of improved patient function, as will be discussed in detail below. In embodiments, treating also means prolonging survival as compared to what would be expected in the absence of treatment. The above terms also mean alleviating or abrogating one or more of a disorder, disease, or condition, or symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself. Persons in need of treatment include those who already have the above disease or disorder.

[0053] 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. Examples of pharmaceutically acceptable vehicles are buffered isotonic solutions such as phosphate buffered saline (PBS).

[0054] The terms "or a combination thereof" and "or combinations thereof", as used herein, refer to any and all permutations and combinations of the listed terms preceding those terms. 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 also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB if order is important in a particular context. Continuing with this example, combinations that include repetitions of one or more items or terms such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. are explicitly included. One of ordinary skill in the art will understand that, unless otherwise apparent from the context, typically there is no limit to the number of items or terms in any combination.

[0055] "Well-tolerated," as used herein, refers to the response of a subject to administration of RTX in which the subject experiences little or no clinically adverse effects (e.g., only mild or moderate adverse effects, or only mild adverse effects). Mild adverse effects (e.g., minor events that do not require specific medical intervention; only asymptomatic laboratory findings; very little clinical relevance); Moderate adverse effects (e.g., only minimal intervention; local intervention; non-invasive intervention; transfusion; elective interventional radiology procedure; or events that require therapeutic endoscopy or surgery). Adverse effects include adverse and unintended signs, symptoms, or diseases associated with the use of RTX. Examples of adverse effects include, but are not limited to, toxicity and distress manifested by, for example, hyperthermia or hypothermia, hypotension, hypertension, hypocapnia, and ventricular arrhythmia, somnolence, responsiveness, anorexia, and / or weight loss.

[0056] Summary In a chronic pain state, the vanilloid (TRPV1) receptor is upregulated in neurons, has a reduced stimulus threshold, and causes an increased perception of pain. TRPV1 agonists (e.g., capsaicin) activate and depolarize the TRPV1 receptor, initially causing a burning sensation from nerve stimulation. After the TRPV1 receptor is fully depolarized, the nociceptive area becomes desensitized and analgesic, particularly for neuropathic pain (Bley, K. (2010) TRPV1 agonist approaches for pain management. In: 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 less potent than RTX) is 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.

[0057] The vanilloid receptor-1 (TRPV1) is a multimodal cation channel that is prominently expressed in nociceptive primary afferent neurons (see, e.g., Caterina et al., (1997) Nature 389:816 - 824; Tominaga et al., (1998) Neuron 21:531 - 543). Activation of the receptor typically occurs at nerve terminals via the application of noxious heat (TRPV1 conveys heat - induced pain) or during inflammation or exposure to vanilloids. Activation of TRPV1 - expressing afferent nerves has been widely reported to cause 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) Antioxid 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). SP (but not CGRP) released at sensory terminals binds to the neurokinin (NK)1 receptor on blood vessels, causing vasodilation and increased vascular permeability, which permits the loss of protein and fluid (plasma leakage) and thus promotes the local accumulation of monocytes and leukocytes that contribute 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).

[0058] Activation of TRPV1 by an agonist (e.g., resiniferatoxin or capsaicin) results in opening of calcium channels and transmission of pain sensation (see, e.g., Szalllasi et al., (1999) Mol. Pharmacol. 56:581-587). After initial activation of TRPV1, the TRPV1 agonist desensitizes TRPV1 to subsequent stimuli. This desensitization phenomenon has been utilized to produce analgesia to subsequent noxious challenges.

[0059] Local administration of resiniferatoxin (RTX), a potent vanilloid receptor agonist, to nerve endings in the skin has been shown to induce long-lasting insensitivity to chemical pain stimuli (e.g., U.S. Publication US20210007998; U.S. Patent No. 5,296,225). However, such topical application is limited to the surface of the skin and only addresses the perception of pain and not the underlying neurogenic inflammation.

[0060] The present disclosure provides a topical formulation of RTX that can be applied to the oral mucosa or oral cavity and treats not only pain associated with inflammatory dysfunction of the oral mucosa but also neurogenic inflammation underlying the pain that affects the gingiva, cheek, palate, sublingual or pharyngeal tissues and causes the pain.

[0061] Compositions for Exemplary Methods and Uses Provided herein is a topical formulation of RTX for application to the oral mucosa or oral cavity for the control or reduction of pain associated with inflammatory dysfunction of the oral mucosa and underlying neurogenic inflammation.

[0062] In one aspect, provided herein is a method for treating inflammatory dysfunction in the oral mucosa, the method comprising topically administering to a subject in need of treatment of the inflammatory dysfunction in the oral mucosa a therapeutically effective amount of RTX.

[0063] A composition comprising RTX for use in a method for treating an inflammatory dysfunction of the oral mucosa, the method comprising topically administering to a subject in need of treatment of the inflammatory dysfunction of the oral mucosa a therapeutically effective amount of the composition, is provided herein.

[0064] In yet another aspect, a method and composition for preventing a neurogenic inflammatory process occurring in the mouth and / or treating a neurogenic inflammation associated with an inflammatory dysfunction of the oral mucosa, the method comprising topically administering to a subject a therapeutically effective amount of RTX, are provided herein.

[0065] In yet another aspect, a method for treating a neurogenic inflammation associated with an inflammatory dysfunction of the oral mucosa, the method comprising topically administering to a subject in need of treatment of the neurogenic inflammation a therapeutically effective amount of RTX, is provided herein.

[0066] In embodiments, the subject has one or more symptoms of an inflammatory dysfunction of the oral mucosa prior to treatment, and the treatment reduces or inhibits one or more symptoms. For example, symptoms of an inflammatory dysfunction of the oral mucosa include oral-facial pain, neurogenic inflammation, idiopathic pain, neuropathic pain, oral ulcers or stomatitis, blisters, or discomfort when eating.

[0067] The compositions and methods described herein are for use in any subject in need of treatment of an inflammatory dysfunction of the oral mucosa, e.g., where RTX is effective to bind to and activate TRPV-1 or a homolog thereof. In embodiments, the subject is a mammal. In embodiments, the mammal is a human. In embodiments, the mammal is a cat. In embodiments, the mammal is a dog. In embodiments, the mammal is a monkey. In embodiments, the mammal is a ruminant. In embodiments, the mammal is a horse, cow, pig, sheep, goat, or a domesticated mammal.

[0068] The compositions and methods described herein are for use in any subject in need of treatment of neurogenic inflammation, e.g., where RTX is effective to bind to and activate TRPV-1 or a homolog thereof.

[0069] Administration and Formulations RTX can be administered topically to the oral mucosa or oral cavity. RTX can be administered topically to one or more sites depending on the number of sites of inflammation within the oral cavity or on the oral mucosa. In embodiments, the RTX is administered topically to a single site. In embodiments, the RTX is administered topically to more than one site. In embodiments, the RTX is administered to multiple sites.

[0070] In an embodiment, the total dose of RTX is topically applied to one site in a single application. In an embodiment, the total dose of RTX is topically applied to one site in more than one application. In an embodiment, the total dose of RTX is topically applied to one site in two applications. In an embodiment, the total dose of RTX is topically applied to one site in three applications. In an embodiment, the total dose of RTX is topically applied to one site in four applications. In an embodiment, the total dose of RTX is topically applied to one site in five applications. In an embodiment, each lesion in the oral cavity received one coat of RTX. In an embodiment, each lesion in the oral cavity received two coats of RTX. In an embodiment, each lesion in the oral cavity received three coats of RTX. In an embodiment, each lesion in the oral cavity received four coats of RTX. In an embodiment, each lesion in the oral cavity received five coats of RTX. In an embodiment, the RTX solution was dropped into the gingival sulcus.

[0071] In an embodiment, the method further includes administering a general anesthetic or a local anesthetic prior to administration of RTX. In an embodiment, the method further includes administering a general anesthetic prior to administration of RTX. In an embodiment, the method further includes administering a local anesthetic prior to administration of RTX.

[0072] In an embodiment, the subject is placed under anesthesia prior to administration of RTX. In an embodiment, the local anesthetic is administered via injection. In an embodiment, the local anesthetic is topically administered.

[0073] In an embodiment, the local anesthetic is an amino-amide anesthetic (e.g., lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine, ropivacaine, or levobupivacaine). In an embodiment, the topical local anesthetic is benzocaine, lidocaine, cocaine, propanocaine, or oxybuprocaine.

[0074] The discomfort after treatment can be managed with analgesics. In embodiments, the method further includes the step of administering an analgesic after administration of RTX. In embodiments, the analgesic is an opioid or a non-steroidal anti-inflammatory drug (NSAID). In embodiments, the analgesic is a non-steroidal anti-inflammatory drug (NSAID). In embodiments, the analgesic is an opioid. In embodiments, the opioid is buprenorphine.

[0075] In embodiments, the analgesic was administered for 5 days or less after administration of RTX. In embodiments, the analgesic was administered for 4 days or less after administration of RTX. In embodiments, the analgesic was administered for 3 days or less after administration of RTX. In embodiments, the analgesic was administered for 2 days or less after administration of RTX. In embodiments, the analgesic was administered for 1 day or less after administration of RTX. In embodiments, no analgesic was administered after administration of RTX.

[0076] In embodiments, for topical administration, RTX can be formulated into solutions, lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Accordingly, one or more thickening agents, humectants, and stabilizers can be included in the formulation. 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.

[0077] In an embodiment, the pharmaceutical formulation provided herein is formulated as a cream for topical administration, which comprises RTX and one or more pharmaceutically acceptable additives or carriers. In one embodiment, the cream provided herein comprises RTX, and one or more additives or carriers 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 cream provided herein comprises RTX, as well as water, octyldodecanol, mineral oil, stearyl alcohol, cocamide DEA, polysorbate 80, myristyl alcohol, sorbitan monostearate, lactic acid, and benzyl alcohol.

[0078] In an embodiment, the pharmaceutical formulation provided herein is formulated as a gel for topical administration, which comprises RTX and one or more pharmaceutically acceptable additives or carriers. In one embodiment, the gel provided herein comprises RTX, and one or more additives or carriers selected from the group consisting of water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide, and doxate sodium. In another embodiment, the gel provided herein comprises RTX, as well as water, isopropyl alcohol, octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium hydroxide, and doxate sodium.

[0079] In an embodiment, the pharmaceutical formulation provided herein is formulated as a solution for topical administration, which comprises RTX and one or more pharmaceutically acceptable additives or carriers.

[0080] In an embodiment, the above RTX is administered together with a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutically acceptable carrier contains water. In an embodiment, the pharmaceutically acceptable carrier contains polysorbate 80. In an embodiment, the pharmaceutically acceptable carrier contains polyethylene glycol. In an embodiment, the pharmaceutically acceptable carrier contains a sugar or a sugar alcohol. In an embodiment, the pharmaceutically acceptable carrier contains mannitol. In an embodiment, the pharmaceutically acceptable carrier contains dextrose. In an embodiment, the pharmaceutically acceptable carrier contains a pharmaceutically acceptable buffer. In an embodiment, the pharmaceutically acceptable carrier contains a phosphate buffer. In an embodiment, the pharmaceutically acceptable carrier contains a pharmaceutically acceptable salt. In an embodiment, the pharmaceutically acceptable carrier contains NaCl. In an embodiment, the pharmaceutically acceptable carrier contains an organic solvent such as ethanol or DMSO, for example, as a trace or residual component used to assist in the dissolution of RTX, mainly before dilution in an aqueous composition.

[0081] The concentration of RTX in the above formulation can be any suitable value for the delivery of the intended dose. In embodiments, the concentration of RTX in the pharmaceutical formulation is in the range of 0.02 to 300 μg / ml. In embodiments, the concentration of RTX in the pharmaceutical formulation is in the range of 0.02 to 0.1 μg / ml, 0.1 to 1 μg / ml, 1 to 5 μg / ml, 5 to 10 μg / ml, 10 to 20 μg / ml, 20 to 50 μg / ml, 50 to 100 μg / ml, 100 to 150 μg / ml, 150 to 200 μg / ml, 200 to 250 μg / ml, or 250 to 300 μg / ml. In embodiments, the concentration of RTX in the pharmaceutical formulation is from 0.5 μg / ml to 0.6 μg / ml, 0.6 μg / ml to 0.7 μg / ml, 0.7 μg / ml to 0.8 μg / ml, 0.8 μg / ml to 0.9 μg / ml, 0.9 μg / ml to 1.0 μg / ml, 1.0 μg / ml to 1.1 μg / ml, 1.1 μg / ml to 1.2 μg / ml, 1.2 μg / ml to 1.3 μg / ml, 1.3 μg / ml to 1.4 μg / ml, 1.4 μg / ml to 1.5 μg / ml, 1.5 μg / ml to 2 μg / ml, 2 μg / ml to 3 μg / ml, 3 μg / ml to 4 μg / ml, 4 μg / ml to 5 μg / ml, 5 μg / ml to 6 μg / ml, 6 μg / ml to 7 mcg / ml, 7 μg / ml to 8 μg / ml, 8 μg / ml to 9 μg / ml, 9 μg / ml to 10 μg / ml, 10 μg / ml to 11 μg / ml, 11 μg / ml to 12 μg / ml, 12 μg / ml to 13 μg / ml, 13 μg / ml to 14 μg / ml, or 14 μg / ml to 15 μg / ml. In embodiments, the concentration of RTX in the pharmaceutical formulation is in the range of 0.1 to 50 μg / ml, 1 to 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 (for example, 0.1 to 50 μg / ml or 1 to 25 μg / ml), or about 0.1 μg / ml, 0.2 μg / ml, 0.5 μg / ml, 1 μg / ml, 1.5 μg / ml, 2 μg / ml, 3 μg / ml, 4 μg / ml, 5 μg / ml, 6 μg / ml, 7 μg / ml, 8 μg / ml, 9 μg / ml, 10 μg / ml, 11 μg / ml, 12 μg / ml, 13 μg / ml, 14 μg / ml, 15 μg / ml, 20 μg / ml, 25 μg / ml, 30 μg / ml, 40 μg / ml, or 50 μg / ml.

[0082] In an embodiment, the above RTX is delivered in a composition having a volume of 0.1 ml to 1 ml, 1 ml to 10 ml, 10 ml to 20 ml, 20 ml to 30 ml, 30 ml to 40 ml, 40 ml to 50 ml, 50 ml to 60 ml, 60 ml to 70 ml, 70 ml to 80 ml, 80 ml to 90 ml, or 90 ml to 100 ml. In an embodiment, the above RTX is delivered in a composition having a volume of 0.5 ml to 5 ml. In an embodiment, the above RTX is delivered in a composition having a volume in the range of 0.5 to 1.0 ml, 1.0 to 1.5 ml, 1.5 to 2 ml, 2 to 3 ml, 3 to 4 ml, or 4 to 5 ml.

[0083] Starting from the concentrated stock solution, the formulation of RTX for delivery to a subject can be prepared by dilution in a suitable diluent (for example, a saline solution).

[0084] The above formulation can have any pH suitable for topical administration. In an embodiment, the pharmaceutical formulation containing RTX and a pharmaceutically acceptable carrier has a pH in the range of 6.0 to 7.6. In an embodiment, the pharmaceutical formulation containing RTX and a pharmaceutically acceptable carrier has a pH 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 pharmaceutical formulation containing RTX and a pharmaceutically acceptable carrier has a pH of about 6.5 or about 7.2.

[0085] In an embodiment, the formulation contains 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 formulation may further contain a buffer solution, for example, a phosphate buffer solution (for example, sodium phosphate buffer solution). In an embodiment, the concentration of the phosphate buffer solution is 10 - 50 mM. In an embodiment, the concentration of the phosphate buffer solution is 10 - 30 mM. In an embodiment, the concentration of the phosphate buffer solution is 10 mM. In an embodiment, the concentration of the phosphate buffer solution is 30 mM. The formulation may have a pH in the range of 7 - 7.5 (for example, about 7.2). In an embodiment, in any of the aforementioned formulations, the concentration of RTX may be 1 - 30 μg / ml (for example, 3.12 μg / ml or 12.5 μg / ml). In an embodiment, the formulation further contains a phosphate buffer solution at the concentration and pH shown for the phosphate buffer solution in Table 1, for example. In an embodiment, the formulation further contains NaCl at the concentration shown for NaCl in Table 1, for example. When both are present, the phosphate buffer solution and NaCl may be present (but not necessarily) in the combination of the concentrations and phosphate buffer solution pH shown for the individual formulations.

[0086] Exemplary formulations of RTX are shown in the following table.

[0087] Table: Exemplary RTX Solution Formulations

Table 5-1

Table 5-2

[0088] In an embodiment, the formulation in Table 1 contains 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.

[0089] In an embodiment, the formulation in Table 1 contains 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.

[0090] In an embodiment, the above dextrose or mannitol is omitted from the formulation shown in Table 1.

[0091] In an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to any of the RTX concentrations or concentration ranges disclosed herein. For example, in an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to 0.3 to 200 mcg / ml. In an embodiment, the concentration of RTX in the formulation shown in Table 1 is 200 mcg / ml. In an embodiment, the concentration of RTX in the formulation shown in Table 1 is 0.3 to 100 mcg / ml. In an embodiment, the concentration of RTX in the formulation shown in Table 1 is 100 mcg / ml. In an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to 0.3 to 50 mcg / ml. In an embodiment, the concentration of RTX in the formulation shown in Table 1 is 25 mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to 0.3 to 15 mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to 0.5 to 10 mcg / ml. As another example, in an embodiment, the concentration of RTX in the formulation shown in Table 1 is adjusted to 0.6 to 1.5 mcg / ml. The above dextrose or mannitol is omitted from any such formulation having an adjusted RTX concentration.

[0092] The formulations in Table 1 can be prepared according to the following exemplary methods. These are provided for Formulations 3 and 5, but can be adapted by those skilled in the art to other formulations. Formulation 3 can be made by adding 46 mg of sodium dihydrogen phosphate monohydrate, 94.7 mg of disodium hydrogen phosphate anhydrous, and 860 mg of NaCl to a 100 ml volumetric flask. 50 ml of water is added to dissolve the components in the flask, followed by the addition of 1.0 g of polysorbate 80 to form the aqueous components. 20 mg of RTX is added to the aqueous components in the volumetric flask and the pH is adjusted to 7.2 with hydrochloric acid / sodium hydroxide. Then, 30 mL of PEG 300 is added and the solution is sonicated to dissolve the solids. It should be noted that RTX initially sometimes precipitates at the interface of the aqueous solution and PEG, but returns into the solution upon sonication. The total mixture in the flask is diluted to volume (100.00 ml) with water and this is mixed by an inversion process. The entire formulation is filtered through a 0.2 μm polytetrafluoroethylene (PTFE) filter.

[0093] Formulation 5 can be made by adding 138 mg of sodium dihydrogen phosphate monohydrate, 284.1 mg of disodium hydrogen phosphate anhydrous, and 540 mg of NaCl to a 100 ml volumetric flask. 50 ml of water is added to dissolve the components in the flask, followed by the addition of 3.0 g of polysorbate 80 and 800 mg of dextrose to form the aqueous components. 20 mg of RTX is added to the aqueous components in the volumetric flask and the pH is adjusted to 7.2 with hydrochloric acid / sodium hydroxide. Then, the solution is sonicated to dissolve all the solids (alternatively, the RTX can first be dissolved in a small volume of ethanol or DMSO and then this solution can be added to the aqueous components). The total mixture in the flask is diluted to volume (100.00 ml) with water and this is mixed by an inversion process. The entire formulation is filtered through a 0.2 μm PTFE filter.

[0094] Prepare the formulation according to Formulation 11 to 1 mL using 200 mcg RTX, 300 mcg polysorbate 80 (using commercially available polysorbate 80); 5.4 mg sodium chloride, 500 mcg dextrose, 1.38 mg sodium dihydrogen phosphate monohydrate, 2.84 mg disodium hydrogen phosphate anhydrous, and water, and then adjust the pH to 7.2 with hydrochloric acid / sodium hydroxide. As noted above, the dextrose may be omitted.

[0095] Prepare the formulation according to Formulation 13 to 1 mL using 25 mcg RTX, 30 mg polysorbate 80 (using commercially available polysorbate 80); 5.4 mg sodium chloride, 50 mg dextrose, 1.38 mg sodium dihydrogen phosphate monohydrate, 2.84 mg disodium hydrogen phosphate anhydrous, water, and then adjust the pH to 7.2 with hydrochloric acid / sodium hydroxide. As noted above, the dextrose may be omitted.

[0096] Further details of the techniques relating to formulations and administration can be found in Gennaro, A., ed., Remington’s Pharmaceutical Sciences, 18th Edition (1990) (Mack Publishing Co., Easton, Pa.).

[0097] Dosage The methods described herein are for use in a subject in which RTX is effective, e.g., capable of binding to and activating TRPV1 or its homologs, and in which there is a need for treatment of inflammatory dysfunction and / or neurogenic inflammation of the oral mucosa. In embodiments, the RTX is administered at a dose of 0.1 to 150 μg. In embodiments, the dose of RTX ranges from 0.1 to 0.5 μg, 0.5 to 1 μg, 1 to 2 μg, 2 to 5 μg, 5 to 10 μg, 10 to 20 μg, 20 to 30 μg, 30 to 40 μg, 40 to 50 μg, 50 to 60 μg, 60 to 70 μg, 70 to 80 μg, 80 to 90 μg, 90 to 100 μg, 100 to 110 μg, 110 to 120 μg, 120 to 130 μg, 130 to 140 μg, or 140 to 150 μg.

[0098] In embodiments, the RTX is administered in a single dose. In embodiments, the RTX is administered in repeated doses. In embodiments, the RTX is administered in 1, 2, 3, 4, or 5 doses.

[0099] In embodiments, the RTX is administered daily. In embodiments, the RTX is administered every other day. In embodiments, the RTX is administered weekly.

[0100] Neurogenic Inflammation and Pain Inflammatory dysfunction of the oral mucosa is associated with neurogenic inflammation and pain. In embodiments, inflammatory dysfunction of the oral mucosa is associated with neurogenic inflammation. In embodiments, inflammatory dysfunction of the oral mucosa is associated with pain.

[0101] In embodiments, the pain can be reduced using the compositions and methods described herein. In embodiments, the pain can be suppressed using the compositions and methods described herein. In embodiments, the pain is orofacial pain.

[0102] In an embodiment, the pain is caused by alveolar structure disorders, cancer, neuropathic pain, or idiopathic pain. In an embodiment, the pain is caused by alveolar structure disorders. In an embodiment, the pain is caused by cancer. In an embodiment, the pain is caused by neuropathic pain. In an embodiment, the pain is caused by idiopathic pain. In an embodiment, the pain is caused by stomatitis. In an embodiment, the pain is caused by caudal stomatitis. In an embodiment, the pain is caused by chronic gingivostomatitis (CGS). In an embodiment, the pain is caused by feline chronic gingivostomatitis (FCGS). In an embodiment, the pain is caused by radiotherapy. In an embodiment, the pain is caused by toothache or oral mucosal pain. In an embodiment, the pain is caused by toothache. In an embodiment, the pain is caused by oral mucosal pain. In an embodiment, the pain is caused by inflammation of the oral mucosa.

[0103] In an embodiment, the cancer is treated with radiotherapy. In an embodiment, the pain is caused by radiotherapy or chemotherapy-induced mucositis.

[0104] In an embodiment, the idiopathic pain is caused by burning mouth syndrome.

Example

[0105] 1. Preliminary safety study of oral topical application of resiniferatoxin (RTX) for the control of pain associated with feline chronic gingivostomatitis (FCGS) This example provides safety data related to the oral topical application of RTX. The main objective of this study was to determine the initial tolerance of RTX when it is topically administered under anesthesia to the oral cavity of cats as a single treatment.

[0106] Four cats were enrolled in this study. Each cat presented with mild to moderate gingival inflammation. The cats were assigned to two treatment groups according to the severity of gingival inflammation. Cats in Group 1 (cats with mild case of gingivitis) were administered a diluted RTX solution (12.5 μg / mL) topically to the maxillary and mandibular gingival tissues (buccal and palatal / lingual gingiva) on Day 0 of the study. Cats in Group 2 (cats with a current or recent history of moderate gingivitis) received the same treatment regimen on Day 0 of the study, with the addition of application to the palatal and sublingual tissues.

[0107] The total dose of RTX tested per cat (diluted with sterile saline solution to a total volume of 2 mL) was as follows: 17.5 μg (cats in Group 1), 23.75 μg (cats in Group 1), or 25 μg (cats in Group 2) of 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 application of RTX was applied topically inside the mouth of each cat. The above RTX was applied to the entire mouth.

[0108] The cats were anesthetized during and for 30 minutes after treatment administration. Diphenhydramine (2 mg / kg, IM) was given as a preanesthetic pretreatment for at least 30 minutes before administration. Then, induction was performed using a combination of medetomidine 0.03 mg / kg, ketamine 5 mg / kg, and butorphanol 0.2 mg / kg; dose volume 0.1 mL / kg, IM. After application of lidocaine hydrochloride spray to the larynx, intubation was performed and anesthesia was maintained using an isoflurane-oxygen mixture. Standard anesthetic monitoring of vital signs was performed approximately every 5 - 10 minutes after administration, and care was taken to avoid hypothermia throughout the above procedure. For further monitoring, the cats remained under anesthesia for 30 minutes after administration. When waking up from anesthesia, the reversal drug atipamezole (0.2 mg / kg, IM) was administered.

[0109] To evaluate RTX tolerance, adverse event monitoring was performed using the following parameters: measurement of vital signs during anesthesia; physical examinations were performed both in the morning (AM) and in the afternoon (PM) after recovery from anesthesia (i.e., removal of the endotracheal tube), at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 3 hours and 4 hours, and on the day, 3 days and 7 days after administration; clinical observations twice a day; measurement of daily feed consumption.

[0110] After RTX application, intermittent lip smacking and lip licking were noted in both groups (Pudding and Clank, group 1; Bianca and Forbes, group 2), and salivation was also noted (Pudding and Clank, group 1; Bianca, group 2). The onset of these observations ranged from 15 minutes to 2 hours after recovery from anesthesia and all resolved by the day after administration. As further findings, a slight increase in the severity of gingivitis (Pudding, group 1; Forbes, group 2), and a moderate increase in severity from one cat (Bianca) in group 2 (this cat also presented with lip erythema) were noted in one cat from each treatment group. The observation of changes in the severity of gingivitis was noted between 15 minutes after recovery from anesthesia and 1 day after administration. In both cases of slight changes, they resolved by 3 days after administration without intervention. The cat (Bianca) showing a moderate increase in gingival inflammation (moderate and marked scores compared to mild at baseline) returned to a moderate classification, which continued until the end of the study.

[0111] The above cats were followed for 8 days after RTX administration to evaluate RTX tolerance and safety. The feed consumption of the cats over 8 days after RTX administration is shown in Figure 1B. Although there appears to be a transient decrease in feed consumption, the feed consumption of the cats returned to normal by day 7. The body weight of the cats was determined before RTX administration and 8 days after RTX administration. Figure 1A shows that although there was a transient decrease in feed consumption, the body weight returned to normal (i.e., the weight before RTX administration) by day 8.

[0112] This trial clearly showed that RTX was well tolerated with very mild and transient adverse events as follows: transient lip licking / erythema of the lips, transient salivation (15 minutes to 2 hours after administration), a slight increase in the severity of gingivitis (up to 24 hours), and a transient decrease in feed consumption.

[0113] 2. Efficacy and safety of oral topical application of resiniferatoxin (RTX) for the control of pain associated with feline chronic gingivostomatitis (FCGS) This example provides efficacy and safety data related to the oral topical application of RTX for the control of FCGS in cats. The effect of RTX treatment on the inflammation causing feline chronic gingivostomatitis was also observed.

[0114] Primary objective: To show the effect of RTX in controlling oral pain associated with feline chronic gingivostomatitis (FCGS) in client-owned cats on day 28 using the Veterinarian Specific Outcome Measure (VSOM) and the Stomatitis Disease Activity Index (SDAI). To characterize the required dose of RTX for topical application to the oral mucosa for the control of pain associated with feline chronic gingivostomatitis (FCGS).

[0115] Selection criteria: - The cat had a recorded diagnosis of FCGS. - The cat had experienced FCGS clinical signs related to oral pain for at least 3 months after the diagnosis of FCGS. - Oral pain had a negative impact on the quality of life. - Except for corticosteroids (see exclusion criteria), drug therapies commonly used for the treatment of pain were acceptable, provided that they had been administered for at least 2 weeks before enrollment in the trial and no change in the regimen was expected during the time the cat was in the trial. - The cats had a composite Veterinary Specific Outcome Measure (VSOM) of 10 or higher (see paragraphs

[0094] and

[0095] below) for three activities selected by the principal investigator of the clinical trial, and each question had a score of at least 3.

[0116] Exclusion criteria: - Cats less than 12 months of age. - Cats weighing less than 2 kg. - Cats with a low likelihood of surviving a 30-minute anesthesia or sedation procedure. - Cats that had a low likelihood of surviving 4 weeks due to health problems other than oral pain. - Cats that were not available throughout the study period or were considered inappropriate by the principal investigator of the clinical trial for other reasons. - Cats that were participating in another study. - Cats that were pregnant or lactating. - Cats that had an oral surgical procedure within 30 days before screening. - Cats that received a cannabinoid agonist (e.g., cannabidiol (CBD) or anandamide) within 28 days of the start of the study. - Cats that received an oral corticosteroid within 1 week of the start of the study or an injectable corticosteroid within 6 weeks of the start of the study, and / or required drug therapy or supplements during the study that could have interfered with the purpose of the study.

[0117] Twenty-eight cats (each weighing more than 2 kg and older than 12 months of age) were enrolled in this study. There was no obvious trend in the age of the cats enrolled in the study. A physical examination of the enrolled cats was performed (recording their physical examination findings such as general overview, ears / eyes / mouth, abdomen / gastrointestinal system, musculoskeletal system, neurological urogenital system, lymphatic system, etc.). Their weights and vital signs were also recorded.

[0118] Efficacy variables Veterinarian-specific outcome scale(VSOM) - A qualitative assessment of the general stomatitis signalment was performed before treatment initiation and on days 7, 14, and 28 (at the end of treatment). Cats were evaluated for salivation, pain during eating, pain and swelling during manipulation of oral tissues. Each clinical sign was graded on a scale of 1 - 5 (1 = no problem; 5 = impossible). The results are shown in Figures 2 - 4.

[0119] Treatment success was defined as "at least a 2 - point reduction in the total VSOM score on day 28 compared to the VSOM score on day 0". A decrease of less than 2, no change, or an increase in the total score was defined as treatment failure. Cats showing an increase in any individual VSOM were considered treatment failures regardless of the total VSOM score. Based on this definition, the success rate on day 28 was 90.0% for cohort 1 (6.25 μg RTX), 80.0% for cohort 2 (12.5 μg RTX), and 88.9% for cohort 3 (25 μg RTX). The results for each cohort were not statistically compared; only descriptive statistics were created due to the small number of cats per cohort and the lack of randomization. However, there was no evidence of a relationship between treatment success and dose.

[0120] Figure 2A shows the VSOM scores obtained on day 0 (before treatment initiation), days 7, 14, and 28. The graph shows the effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatments. Figure 2B shows the same VSOM scores organized by treatment group (6.25 μg, 12.5 μg, or 25 μg RTX). This shows that similar changes were observed on day 28 in all groups. Finally, Figure 2C shows the % change in VSOM scores from day 0 (before treatment) to day 28. This graph shows the % maximum possible effect (%MPE). This shows that the MPE on day 28 ranges from 68% to 80%.

[0121] Oral inflammation disease activity index(SDAI) - This semi - quantitative assessment of oral inflammation was performed before treatment initiation (day 0) and on day 28 (at the end of treatment). The cats were evaluated by the owner regarding the cat's interest in and ability to eat cat food, perceived comfort, grooming behavior, and activity level. Each evaluation was graded on a scale of 0 - 3 (0 = no problem; 3 = severe problem). The details of the evaluation are shown in Table 1 below.

[0122] Table 1. Questions for Owner Evaluation

Table 1

Table 6

Table 7

[0123] Table 2. Stomatitis Disease Activity Index - SDAI

Table 2

[0124] Figure 3A shows the change in SDAI scores for each cat obtained before treatment initiation (day 0) and on day 28. Figure 3A shows the effectiveness of 6.25 μg, 12.5 μg, and 25 μg RTX treatment (even at the lowest dose used, 6.25 μg). Figure 3B shows the % change in SDAI scores from day 0 (before treatment) to day 28. This graph shows the % maximum possible effect (%MPE). This indicates that the MPE on day 28 ranges from 30% to 85% (most cats experience an improvement of approximately 60%). Figure 3C shows the baseline SDAI scores (day 0) for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX). Figure 4 shows the baseline SDAI scores (day 0) for each cat in the three treatment groups (6.25 μg, 12.5 μg, and 25 μg RTX), as well as the SDAI scores on day 28. Figure 4 shows that the tendency for improvement is less at higher doses of RTX (25 μg) and greatest at 12.5 μg.

[0125] Regarding the SDAI scores (Figures 3A - 3B and 4), it was observed that at higher doses, the tendency for improvement was less. Figure 3C incidentally shows that the group treated with the highest dose (25 μg RTX) had the highest SDAI score (before treatment). Thus, the severity of inflammation before treatment may condition the overall response to treatment. Treatment is most effective for moderate disease.

[0126] The success of treatment using the SDAI measurement criteria was retrospectively defined as a 20% reduction in SDAI on day 28 compared to day 0. Based on this definition, the percentage of success was 100.0%, 80.0%, and 44.4% for cohorts 1, 2, and 3, respectively. The discrepancy in the success rate of cohort 3 using the above two measurement criteria may be due to the higher baseline SDAI scores. However, these results confirmed that the increase in inflammation as measured by SDAI is not correlated with the success of treatment using behavioral measurement criteria such as VSOM.

[0127] Safety variables Death - Regardless of whether it was due to natural death or euthanasia, death did not occur during the test.

[0128] Adverse events and serious adverse events -

[0129] Define an adverse event (AE) as any undesirable event that occurs in a test animal during the test, regardless of whether the event is considered causally related to the test treatment and whether it was predicted or not. Adverse events were reported during the test at the scheduled time from day 0 to the last day of the test. One specific adverse event (defined as a serious adverse event) was reported in a prompt manner to allow for possible modification of the test protocol. Define a serious adverse event (SAE) as any medical occurrence that results in hospitalization for more than 24 hours, or causes significant disability or a pathological condition, or threatens life, or results in death.

[0130] One SAE occurred during the course of this test and was determined by the principal investigator of the clinical trial to be medically significant. On day 14 of the test, NIE-08 (cohort 2; local resiniferatoxin dose of 6.25 ug / mL at 12.5 ug) was reported to be extremely painful. This was determined by the principal investigator of the clinical trial as possibly related to stress from movement or oral manipulation. The cat had an increased episode of crying and screaming and was unable to eat non-pureed food. The event was considered by the principal investigator of the clinical trial to be serious on day 14 of the test and was noted to have improved on day 17 of the test, when the patient permanently left the test. However, this cat was included in the efficacy analysis as a treatment failure. HAM-01 (cohort 1; local resiniferatoxin dose of 6.25 ug / mL at 3.12 ug) developed respiratory signs not related to RTX application by day 9 and left the test on day 9. WEX-09 (cohort 3; local resiniferatoxin dose of 25 ug at 12.5 ug / mL) left the test due to progressive pain recorded as an SAE and was included in the efficacy analysis as a treatment failure.

[0131] The treating physician described the adverse events according to the following explanations: - Mild; asymptomatic or mild symptoms; only clinical signs or diagnostic observations; no intervention indicated. - Moderate; minimal, outpatient or non-invasive intervention indicated; moderate limitation of activities of daily living (ADL). - Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; significant limitation of ADL.

[0132] Clinical signs that were not considered to be related to RTX administration and were not determinatively related to the progression of pain were not regarded as adverse events. Patients who experienced adverse events received appropriate medical treatment as determined by the treating physician.

[0133] The severity, causality, and outcome of adverse events were recorded. Causality is a determination of whether there was a reasonable possibility that the above drug could have caused or contributed to the AE. This relationship was described as "unlikely", "possible", "probable", "definite", or "unknown".

[0134] Blood (4 - 5 mL) was collected at the start of the study for a complete blood count (CBC) and a serum chemistry panel.

[0135] Most of the AEs were classified as mild. There was no clear consistent trend between AEs and dose, severity, or causality. There was an increase in the incidence of AEs on days 7 and 14 of the study. This corresponded to study visits but decreased on day 28 of the study.

[0136] Sedation and anesthesia The cats that were starved were pretreated with an antihistamine drug at least 30 - 45 minutes before RTX treatment (the antihistamine drug was used to counteract possible allergic reactions that cats and dogs may have to polysorbate 80). The registered cats were anesthetized using standard cat sedation / anesthesia based on a mixture of analgesics / sedatives / anesthetics. The 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 blood pressure machine (e.g., tail cuff and / or limbs). Body temperature (98 - 99° F) was maintained using a heated water blanket or equivalent thermal barrier (e.g., Vetko). An equilibration IV solution was used to maintain appropriate hydration (approximately 2 mL / kg / h intravenous (IV) infusion) and / or infusion bolus (2 - 5 mL / kg IV) if required. After the cats reached an appropriate anesthesia level, the RTX solution was applied. A copy of the anesthesia record was included in the test file.

[0137] Prior to treatment with RTX, the location of oral lesions was recorded and photographs of the oral cavity were taken to record the oral lesions before treatment and on day 28.

[0138] RTX Preparation and Application RTX was provided as a 25 μg / mL (2.4 mL) solution in a 2R glass vial. The IVP was maintained in its original sterile glass container (vial) until use. The IVP was brought to room temperature before administration and gently swirled before use, but not shaken. The dosage and preparation instructions are described in Table 3.

[0139] Each animal was randomly assigned to one of three groups. Ten cats (Group 1) were treated with 6.25 μg RTX (total) diluted in sterile saline solution to a total volume of 2 mL. Nine cats (Group 2) were treated with 12.5 μg RTX (total) diluted in sterile saline solution to a total volume of 2 mL. Nine cats (Group 3) were treated with 25 μg RTX (total) diluted in sterile saline solution to a total volume of 2 mL.

[0140] Table 3. Animal Treatment - Topical Oral Application

Table 3

[0141] The RTX solution was applied directly to visible lesions and adjacent tissues using a clean cotton tip applicator. The non-target administration area (caudal mouth / pharynx) was protected using 4×4 gauze. Any targeted area was dried with sterile gauze or using an air-water syringe system. The saturated cotton swab was gently pressed along the targeted area for 10 seconds. Two to three coats per lesion were applied using the same cotton swab. The area was dried for several seconds before moving on to the next lesion by exposing the area to air or gently using the air-water syringe system. If possible and if there was no active bleeding due to the procedure, the RTX solution was dripped into the gingival sulcus. If the targeted area was actively bleeding, an attempt was made to reduce or stop the bleeding prior to RTX application.

[0142] After treatment of all lesions, any remaining RTX solution was applied to the tissue adjacent to the most affected area. Once all applied RTX had been dried for at least 20 minutes, the treated area was gently cleaned with 4×4 gauze moistened with saline solution.

[0143] After local oral application of RTX, cats were kept under general anesthesia for at least 10 minutes (with a total anesthesia time of at least 30 minutes).

[0144] When used, the reversal agent (e.g., atipamezole) was discontinued for at least 1 hour after application of the RTX solution. If acute reactions (e.g., involuntary motor movements or respiratory efforts, exacerbated cardiovascular changes, nociceptive responses) occurred during administration, cats received a short-acting analgesic (e.g., but not limited to fentanyl (1 - 2 μg / kg IV) or sufentanil, and / or propofol (0.5 mg / kg IV)) to control motor movement if necessary. The characteristics and magnitude of these reactions were reported as adverse events (AEs).

[0145] If anaphylaxis-like reactions (e.g., facial swelling, auricular swelling, excessive airway secretions, tachycardia, hypotension, urticaria, vomiting / regurgitation, diarrhea, erythema and / or hyperthermia) were observed during treatment or recovery, and the cat was unstable and in a life-threatening condition, 0.2 - 0.4 mg / kg of sodium dexamethasone phosphate was administered IV over 1 minute. The continuation of the test for any cat that received corticosteroids under the above conditions was re-evaluated due to their potent anti-inflammatory effects. All drugs used to treat adverse events after administration of RTX were reported.

[0146] Post-treatment clinical observations After completion of treatment, a short-acting analgesic (e.g., but not limited to buprenorphine) for up to 3 days was prescribed for pain control related to treatment if needed. Administration of buprenorphine decreased the number of adverse events. Cats in cohort 1 were not treated with buprenorphine after administration of RTX. Cats in cohorts 2 and 3 were treated with buprenorphine after administration of RTX.

[0147] On day 0, once RTX had been applied to all oral lesions (time 0), clinical observations were made by the veterinarian at 10 minutes, 30 minutes, 45 minutes, 60 minutes (±5 minutes), as well as at 2 hours (±10 minutes) and 4 hours (±15 minutes) after treatment administration. Cats were observed for up to 4 hours after treatment administration if needed or until abnormal observations resolved.

[0148] Clinical signs (such as, but not limited to, panting, hypersalivation, tachycardia, restlessness) have been reported as side effects after administration of RTX in cats. These signs resolved within approximately 3 hours after treatment without the need for medical intervention.

[0149] Summary of results Veterinary specific outcome measurement (VSOM) results - On day 7, cohorts 2 and 3 had a higher percentage of success than cohort 1. This could be influenced by the use of buprenorphine after treatment in these two cohorts. However, the percentage of success in cohort 1 continued to increase until day 28, and this cohort had the highest percentage of success. On day 14, all cats in cohort 2 were successful, but 2 of them failed by day 28. Treatment success (as defined above in the section on the variable of effectiveness - VSOM) on day 28 was 90.0% for cohort 1 (6.25 μg RTX), 80.0% for cohort 2 (12.5 μg RTX), and 88.9% for cohort 3 (25 μg RTX).

[0150] 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 correlation was observed between dose and percentage of success, with the highest success in cohort 1 (6.25 μg RTX) and the lowest success in cohort 3 (25 μg RTX). Treatment success was 100.0%, 80.0% and 44.4% for cohorts 1, 2, and 3, respectively.

[0151] However, as can be seen in Table 4, the mean total SDAI score on day 0 varied across the treatment cohorts, with the baseline SDAI being highest in cohort 3. Since the cats were not randomized to the cohorts, variability in the baseline SDAI score should be considered when interpreting the success and failure percentages based on a ≥20% decrease in the SDAI score between day 0 and day 28.

[0152] Table 4. SDAI scores: mean cohort total score on day 0

Table 4

[0153] Comparison of VSOM and SDAI efficacy assessments: Due to the higher baseline SDAI, there was a substantial discrepancy in the percentage of success using the VSOM vs SDAI measurement criteria in cohort 3. However, this discrepancy confirmed that the degree of inflammation does not always correlate with a positive response to treatment (which was behaviorally evaluated in the VSOM assessment). Since the primary purpose of RTX application is to provide oral pain relief, encourage eating, and improve quality of life rather than reduce inflammation, VSOM was determined to be an excellent measurement criterion in this trial.

[0154] The cats were weighed on day 0, day 7, day 14, and day 28. Normal weights were reported for 24 out of 28 cats. Two cats (1 in cohort 1 and 1 in cohort 3) had abnormal (low) weights on day 0 but had normal weights by day 28. One cat (cohort 1) showed weight loss on day 28 compared to day 0. One cat (cohort 2) showed weight loss on day 14.

[0155] The eating ability of the cats was evaluated on day 0, day 7, day 14, and day 28. Most of the cats' eating ability improved throughout the test. On day 28, no difference in eating ability was detected among the cohorts. Overall, most of the cats in all cohorts that completed the test had an improvement in eating ability, but only one cat (in cohort 2) deteriorated.

[0156] Conclusion Even low-dose RTX (6.25 μg) is effective in controlling pain and inflammation for 28 days.

[0157] The application of RTX to inflamed and fragile oral mucosa seems to be safe as the cats did not show signs of systemic RTX exposure.

[0158] The test showed that buprenorphine administration up to 72 hours after treatment improved the tolerance of RTX treatment.

[0159] Adverse events are mostly related to post-treatment discomfort. This is manageable with standard pain treatment (buprenorphine administered once a day for 3 days). Most common AEs were weight loss, decreased appetite, increased salivation, decreased eating ability, and painful / oral pain.

[0160] Body weight was not adversely affected by RTX treatment in most cats. No information was obtained regarding the maintenance of a safe heat sensation.

[0161] The test showed a high success rate in all cohorts using the VSOM measurement criteria and confirmed that behavioral measurement criteria such as VSOM are superior to the SDAI, which also measures inflammation. The safety profile of this administration route was acceptable because most of the AEs were considered mild in severity and the cats did not show signs of systemic exposure to RTX.

[0162] The complete disclosure of all publications cited herein is hereby incorporated by reference in their entirety as if each were individually set forth and incorporated without omission.

[0163] Various modifications and changes to the embodiments disclosed herein will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. The exemplary embodiments and examples are provided by way of illustration only and are not intended to limit the scope of the present invention.

Claims

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

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

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

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

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

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

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

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

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

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

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

12. The method includes the step of administering a pharmaceutical preparation containing the RTX and a pharmaceutically acceptable carrier, and is a composition for the method or use according to any one of the preceding claims.

13. The pharmaceutically acceptable carrier contains water, and is a composition for the method or use according to claim 12.

14. The pharmaceutically acceptable carrier contains polysorbate 80, and is a composition for the method or use according to claim 12 or 13.

15. The pharmaceutically acceptable carrier contains polyethylene glycol, and is a composition for the method or use according to any one of claims 12 to 14.

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

17. The pharmaceutically acceptable carrier contains mannitol, and is a composition for the method or use according to any one of claims 12 to 16.

18. The pharmaceutically acceptable carrier contains dextrose, and is a composition for the method or use according to any one of claims 12 to 17.

19. The pharmaceutically acceptable carrier contains a pharmaceutically acceptable buffer, and optionally, the pharmaceutically acceptable buffer is a phosphate buffer here, and / or the pH of the preparation is about 6.0 to 7.6 or about 7.2, and is a composition for the method or use according to any one of claims 12 to 18.

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

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

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

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

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

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

26. The method further includes a step of administering a general anesthetic or a local anesthetic before the administration of RTX, a composition for the method or use according to any one of the preceding claims.

27. The method further includes a step of administering an analgesic after the administration of RTX, a composition for the method or use according to any one of the preceding claims.

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

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

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

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

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

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

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

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

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

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

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

39. The composition for the method or use according to claim 38, wherein the pain is caused by toothache or oral mucosal pain.

40. The composition for the method or use according to any one of the preceding claims, wherein the pain is caused by radiation therapy-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 of the neurogenic inflammation a therapeutically effective amount of resiniferatoxin (RTX).

42. A composition comprising resiniferatoxin (RTX) for use in 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 of the neurogenic inflammation a therapeutically effective amount of the composition.

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

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

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

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

47. The composition for the method or use according to claim 44, wherein the pain is caused by alveolar structure disorder, cancer, neuropathic pain, or idiopathic pain.

48. The composition for the method or use according to claim 47, wherein the pain is caused by neuropathic pain.

49. The composition for the method or use according to claim 47, wherein the pain is caused by idiopathic pain.

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

51. The composition for the method or use according to claim 44, wherein the pain is caused by stomatitis.

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

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

54. The composition for the method or use according to claim 44, wherein the pain is caused by cancer.

55. The composition for the method or use according to claim 44, wherein the pain is caused by a disorder of the alveolar structure.

56. The composition for the method or use according to claim 55, wherein the pain is caused by toothache or oral mucosal pain.

57. The composition for the method or use according to claim 44, wherein the pain is caused by radiation therapy-induced mucositis.

58. The composition for the method or use according to any one of the preceding claims, wherein the RTX is administered to a plurality of sites.

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