WO2021146371A1

WO2021146371A1 - Method of inducing analgesia using a halogenated alcohol

Info

Publication number: WO2021146371A1
Application number: PCT/US2021/013360
Authority: WO
Inventors: Shane AUSTIN; Mark Holman
Original assignee: Expanesthetics, Inc.
Priority date: 2020-01-17
Filing date: 2021-01-14
Publication date: 2021-07-22

Abstract

A method for of inducing analgesia in a subject afflicted with an epidermolysis bullosa (EB) disorder, by administering to the subject a therapeutically effective amount of a halogenated alcohol compound, administered by any pharmaceutically acceptable route, including but not limited to oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal routes. The halogenated alcohol compound can be either 3,4,4,4-Tetrafluoro-3 - (trifluoromethyl)butan-l-ol (CAS# 90999-87-4) or 3,3-Bis (trifluoromethyl)-4,4,4- trifluorobutan-1-ol (CAS# 14115-49-2). The therapeutically effective amount of either halogenated alcohol compound is effective for relieving, ameliorating or reducing chronic pain or acute pain associated with an EB disorder.

Description

METHOD OF INDUCING ANALGESIA USING A HALOGENATED ALCOHOL

FIELD OF THE INVENTION

[0001] The present invention relates to methods of treating a subject having pain associated with epidermolysis bullosa.

BACKGROUND OF THE INVENTION

[0002] Epidermolysis bullosa (EB) comprises a group of genetic disorders that affect multiple systems and are characterized by cutaneous and/or mucosal fragility resulting in post-traumatic blistering. The four types ofEB include EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindi er Syndrome. Even though EBS, the most prevalent of the EB disorders, is considered to have the “mildest” of symptoms relative to the other classes, it is nonetheless associated with constant and severe pain for the entire lifespan of the patient. Pain conditions vary in prevalence and location among all types of EB, and cars comprise one or more pairs modes, non-limiting examples of which include acute pain, chronic pain, nociceptive pain, inflammatory pain, visceral pain, and neuropathic pain. Often, pain is localized to the sites of blisters, sores, and other abnormalities that can form as a result of the disease itself, but pain can also result from care measures that are implemented on a day-to-day basis, including but not limited to dressing changes, baths, and movement therapies, as well as pain associated with surgical intervention, including acute post-operative pain. Patients can also experience neuropathic pain described as ''‘burning,” '‘pricking,” “electric shocks,” “tingling,” “numbness,” and “itching” (see Brun, T, et al., (2017) Orphanet Journal of Rare Diseases 12:119-126).

[0003] Although the pain associated with each of the four types of EB have been generally well-characterized and assessed in patients, there is scant evidence of drug-based pain control remedies that are specific to EB. With regard to acute or post-operative pain in particular, there have been no controlled trials of pain therapies specific to EB. Instead, leading authorities have largely recommended the same drug regimens and general principles of pain care that are commonly prescribed to non-EB patients, specific to the type, mode, and location of the pain. (see Goldschneider, K.R., et al., (2014) BMC Medicine 12:178-200). Such drug regimens can include, but are not limited to: opioids, non-steroidal anti-inflammatories (NSAIDs), acetaminophen, gabapentinoids, cyclooxygenase-2 inhibitors, A-methyl-D-aspartate (NMDA) receptor agonists, tricyclic antidepressants, anxiolytics, and anesthetics, which can be administered by any pharmaceutically-acceptable route, including but not limited to oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal administration routes. [0004] However, one or more of the remedies and/or administration routes listed above can be and are often unavailable for a particular patient, depending on the patient’s age, history, location and type of pain, and/or the type of injury itself. For example, some patients may not be able to receive medication rectally because they either already have, or are susceptible to, mucosal injury. Similar restrictions may be present orally and/or nasally, based on any sensitivity or injury that the patient may have presently or previously have. Further, in many instances, even though a medication itself may be effective for a non-EB patient, that same medication can have a negligible effect, or no effect at all, on an EB patient. For example, in a study evaluating quality of life of patients with EBS, 50% of the patients reported no efficacy with acetaminophen, and two people (of thirteen respondents who were taking a Grade 2 analgesic) reported no efficacy with an opioid or codeine {see Brun, J., et al., above). Opioids in particular have been effective in reducing pain for many people, but they are rife with several side effects, including but not limited to sedation, dependence, gastric damage and general tolerability problems. However, for some patients with EB, including infants and adults in hospice or end-of-life care, opioids are the only effective pain teatment.

[0005] Effective safe pain control for all people, including EB patients and non-EB patients alike, is regarded worldwide as a high priority clinical need. However, the majority of developments in this field have failed to deliver high-efficacy products free of undesirable side effects and safety issues that can be brought on by opioids US Patents 9,381,185, 9,757,353, and 10,010,525, as well as US Application Publications US2014/0018414 and US2019/0000793, the disclosures of which are incorporated by reference in their entireties, discloses the identification of certain halogenated compounds, including halogenated alcohol compounds, for inducing anesthesia, and includes a method of inducing anesthesia by administering to a subject the halogenated compound via the respiratory system. However, none of these compounds, or any other compound, has been identified to specifically treat pain associated with EB disorders. [0006] Consequently, there exists a need to develop new and improved analgesics, particularly for patients with an EB disorder, and for which Grade 1 analgesics are ineffective and opioids are the only pain mangement option.

SUMMARY OF THE INVENTION

[0007] In one aspect, the invention provides a method of inducing analgesia in a subject, particularly a subject afflicted with an EB disorder, comprising the step of administering to the subject a therapeutically effective amount of a halogenated alcohol compound, via any pharamacetucally acceptable route, including but not limited to oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal routes.

[0008] According to the present invention, the halogenated alcohol compound can be 3, 4, 4, 4- Tetrafluoro-3-(trifluoromethyl)butan-l-ol (CAS# 90999-87-4).

[0009] According to the present invention, the halogenated alcohol compound can be 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol (CAS# 14115-49-2).

[0010] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the therapeutically effective amount of the administered halogenated alcohol compound can deliver a therapeutically effective blood concentration of the halogenated alcohol compound. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the therapeutically effective amount of the administered halogenated alcohol compound can increase the pain threshold of a subject, particularly a subject afflicted with an EB disorder, relative to the subject’s baseline pain threshold. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the therapeutically effective amount of the administered halogenated alcohol compound can increase the pain threshold of a subject afflicted with an EB disorder in a dose-dependent manner. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the therapeutically effective amount of the administered halogenated alcohol compound can increase the pain threshold of a subject afflicted with an EB disorder to a pain threshold similar or equivalent to a control subject who is not afflicted with an EB disorder. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the therapeutically effective amount of the administered halogenated alcohol compound can increase the pain threshold of a subject afflicted with an EB disorder without increasing it beyond the pain threshold of a control subject who is not afflicted with an EB disorder.

[0011] In another aspect, the invention provides a use of a halogenated alcohol compound for the treatment of pain, particularly pain associated with an EB disorder. According the present invention, and useful in combination with any one or more of the above aspects and embodiments, the halogenated alcohol compound can be 3,4,4,4-Tetrafluoro-3- (trifluoromethyl)butan-l-ol. According the present invention, and useful in combination with any one or more of the above aspects and embodiments, the halogenated alcohol compound can be 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol.

[Q012] In another aspect, the invention provides a method of treating pain associated with an EB disorder, in a subject in need of such treatment, the method comprising the step of administering to said subject, via any pharmaceutally acceptable route, particularly a route selected from the group consisting of oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal, a therapeutically effective amount of any of the halogenated alcohol compounds described above. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the subject is an infant. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the subject is a child. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the subject is an adult According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the halogenated alcohol compound can be given to a subject in conjunction with an end-of-Hfe care plan.

[0013] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the halogenated alcohol compounds described above can also be useful and effective for treating chronic pain states associated with an EB disorder. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the halogenated alcohol compounds described above can also be useful and effective for treating acute pain states associated with an EB disorder. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, non-limiting examples of specific conditions associated with an EB disorder and in which pain may be relieved, ameliorated or modulated include, but are not limited to: post-operative and/or injury-associated pain; skin and wound pain, including resulting from bathing and/or dressing changes; upper and lower gastrointestinal tract pain; musculoskeletal pain, including joint pain, bone pain, back pain, arthritis, and eye pain, neuropathic pain; cancer pain; trigeminal neuralgia; and stroke, including combinations thereof. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the halogenated alcohol compounds described above can be used to treat existing pain in a subject who has an EB disorder, and can also be used when prophylactic treatment is considered medically necessary, for instance, in advance of a surgical procedure, bath, and/or dressing change.

[0014] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the halogenated alcohol compounds described above can be used as an analgesic in the form of a monotherapy (i.e., use of a halogenated alcohol compound alone) for treatment of an EB disorder. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the halogenated alcohol compound can be 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol (CAS# 90999-87-4). According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the halogenated alcohol compound can be 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol (CAS# 14115-49-2).

[0015] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the halogenated alcohol compounds described above can be given to a subject afflicted with an EB disorder as a co-therapy with one or more analgesic drug treatments. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the one or more other analgesic drug treatments can be selected from the group consisting of an opioid, NSAID, acetaminophen, gabapentinoid, cyclooxygenase-2 inhibitor, NMDA receptor agonist, tricyclic antidepressant, anxiolytic, and an anesthetic, including combinations thereof. According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, the one or more analgesic drug compounds can be administered by any pharmaceutally acceptable route, particularly a route selected from the group consisting of oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal route.

[0016] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of halogeiiated alcohol compounds described above can be used, either alone as a monotherapy or as a co-therapy, with one or more conventional analgesics, to treat pain, particularly pain associated with an EB disorder. Without being limited by a particular theory, such mono and co-therapies may be used to reduce, diminish, or limit, or avoid altogether, the common, familiar and sometimes undesireable side effects, for example chemical dependence, associated with the use of certain conventional analgesic compounds. In an embodiment, the haiogenated alcohol compounds described above can be used as a co- therapy with one or more conventional non-opiod analgesic compounds. In another embodiment, according to the present invention and useful in combination with any one or more of the above aspects and embodiments, any of the haiogenated alcohol compounds described above can be administered to a patient that has an EB disorder as a co-therapy with an opioid, in order to reduce the amount and/or frequency of the dose of an opioid, while achieving the desired analgesic effect.

[0017] According to the present invention, and useful in combination with any one or more of the above aspects and embodiments, any of the medicaments described above can take a number of different forms depending, in particular, on the manner in which the haiogenated alcohol compound is to be used. Thus, as a non-limiting example and according to the present invention, the medicament can comprise a haiogenated alcohol compound in the form of a powder and incorporated in a tablet, capsule, liquid, gel, or any other suitable form. In another non-limiting example and according to the present invention, the haiogenated alcohol compound may also be dissolved in a suitable solvent (which can include water) to form a liquid medicament. In another non-limiting example and according to the present invention, the haiogenated alcohol compound may also be incorporated within a slow_' ^· or delayed release device or enteric coating.

BRIEF DESCRIPTION OF THE INVENTION

[0018] Figure 1 shows the results of a study to determine the dose-dependent analgesic effect of 3,4,4,· 4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol, in response to a mechanical stimulus. [0019] Figure 2 shows the results of a study to determine the dose-dependent analgesic effect of 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol, in response to a mechanical stimulus.

[0020] Figure 3 shows the results of a study to determine the dose-dependent analgesic effect of 3,4,4, 4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol, in response to a thermal stimulus.

[0021] Figure 4 shows the results of a study to determine the dose-dependent analgesic effect of 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol, in response to a thermal stimulus.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The invention encompasses methods for treating pain in patients afflicted with an epidermolysis bullosa (EB) disorder, particularly in subjects for which Grade 1 analgesics such as acetaminophen and ibuprofen have a reduced effectiveness or have no effect, using a halogenated alcohol compound, or a pharmaceutical composition comprising a halogenated alcohol compound, to induce analgesia. As used herein, the terms, “composition” or "pharmaceutical composition," refer to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier, in order to facilitate administration of the halogenated alcohol compound to a subject, particularly a subject with an EB disorder.

[0023] In an embodiment of the invention, the halogenated alcohol compound can be selected from the group consisting of 3,4,4, 4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol (CAS# 90999-87- 4) and 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol (CAS# 14115-49-2). In another embodiment, the halogenated alcohol compound is 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan- l-ol. In another embodiment, the halogenated alcohol compound is 3,3-Bis (trifluoromethyl)- 4,4,4-trifluorobutan-l-ol. The analgesic activity of 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan- l-ol and 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol in a subject afflicted with an EB disorder is described in the Examples, below.

[0024] In another embodiment, the relative amount of the active halogenated alcohol compound and any additional ingredients in a pharmaceutical composition can be varied, depending upon the identity, size, and condition of the subject treated. By way of example, the composition may comprise between 0.1% and 100% (w/w) of the halogenated alcohol compound. In another embodiment, a composition comprising any of the halogenatied alcohol compounds, particularly either or both of 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol and 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol, can further comprise one or more additional analgesic compounds, non-limiting examples of which can include opioids, non-steroidal anti-inflammatories (NSAIDs), acetaminophen, gabapentinoids, cyclooxygenase-2 inhibitors, N- methyl-D-aspartate (NMDA) receptor agonists, tricyclic antidepressants, anxiolytics, and anesthetics. Without being limited by a particular theory, it is believed that such combinations may lead to synergistic effects that can reduce the dose required of one or more of the compounds to achieve a desired analgesic effect. In particular, such combibations in the presence of an opioid may reduce the dose required of the opioid to achieve a desired analgesic effect. For example, U.S. Patent 8,034,801, herein incorporated by reference in its entirety, describes a synergistic combination of acetaminophen, ibuprofen, and codeine achieving an analgesic effect on neuropathic pain in a rat model. In another example, U.S. Patent 8,268,821, herein incorporated by reference in its entirety, describes the use of a flupirtine, which had been developed in the 1970’s to treat acute pain, as a treatment for neuropathic cancer pain in combination with morphine, and which enabled morphine to be administered at ten times fewer than its ECso value.

[0025] In another embodiment, the halogenated alcohol compound can be formulated for delivery as either a monotherapy or as a co-therapy with any of the analgesic compounds listed above, by any acceptable administration route. Non-limiting examples of suitable administration routes include oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal routes.

[0026] In another embodiment, a formulation of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. Both 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol and (trifluoromethyl)-4,4,4- trifluorobutan-l-ol are commercially available from several manufacturers, including by Synquest Laboratories. Once the halogenated alcohol compound is obtained, a formulation can generally be prepared by including a step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-unit or multi-unit dose. As used herein, a unit dose is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0027] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects having an EB disorder to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals including, as non-limiting examples, agricultural mammals (e.g., cattle, pigs, horses, sheep), domesticated mammals (e.g, cats, and dogs), and laboratory mammals (e.g, rats, mice, rabbits, hamsters). As used herein, the term, “subject,” can be used synonymously with the terms “patient,” or “individual,” without limitation.

[0028] In another embodiment, a halogenated alcohol compound can be administered at a dose sufficient to achieve a desired analgesia or analgesic effect. In another embodiment, the desired analgesia or analgesic effect can comprise a reduction of the pain experienced by the subject, as a result of receiving an effective dose of the compound. In another embodiment, the desired analgesia or analgesic effect can include the complete removal of the pain experienced by the subject. In another embodiment, the desired analgesia increases the pain threshold of a subject with an EB disorder, relative to the subject’s baseline pain threshold level. In another embodiment, the desired analgesia increases a subject’s pain threshold to a level associated with a control subject, including but not limited to a subject that does not have an EB disorder. In another embodiment, the pain threshold of the subject increases in a dose-dependent manner. Without being limited by a particular theory, and in another embodiment, it is believed that administration of a halogenated alcohol compound to a subject with an EB disorder can be accomplished without increasing their pain threshold beyond that of a healthy subject, an effect that is commonly observed when opiates are administered. As used here, the term, “administer,” with respect to a dose provided to a subject with an EB disorder, can refer to actions taken by a medical professional ( e.g ., a physician), or a person controlling medical care of a subject, that control and/or permit the administration of the agent(s)/compound(s) at issue to the subject. Causing to be administered can involve diagnosis and/or determination of an appropriate therapeutic or prophylactic regimen, and/or prescribing particular agent(s)/compounds for a subject. Such prescribing can include, for example, drafting a prescription form, annotating a medical record, and the like.

[0029] In another embodiment, the appropriate dosage of analgesic agents will vary according to several factors, including the formulation of the composition, patient response, the severity of the condition, the subject’s weight, and the judgment of the prescribing physician. The dosage can be increased or decreased over time, as required by an individual patient. Usually, a patient initially is given a low dose, which is then increased to an efficacious dosage tolerable to the patient.

[0030] The ability to determine an effective dose, based in-part on the factors described above, as well as others, is well -understood by those having ordinary skill in the art. Generally, an efficacious or effective amount of a combination of one or more such analgesic compounds is determined by first administering a low dose or small amount of the analgesic, and then incrementally increasing the administered dose or dosages, adding a second or third medication as needed, until a desired effect is observed in the treated subject with minimal or no toxic side effects. As used herein, the term "effective amount", as well as the terms, “therapeutically effective amount” or "pharmaceutically effective amount," can refer to the amount and/or dosage, and/or dosage regime of one or more compounds necessary to bring about the desired result e.g., an amount sufficient to provide an analgesic effect to a subject.

[0031] Applicable methods for determining an appropriate dose and dosing schedule for administration of anesthetics, including analgesics, are described, for example, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition, 2010, supra ; in a Physicians’ Desk Reference (PDR), supra, in Remington: The Science and Practice of Pharmacy (Remington: The Science & Practice of Pharmacy), 21st Edition, 2011, Pharmaceutical Press, and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al., eds., 9th Edition, 2010, Lippincott Williams & Wilkins; and in Martindale: The Complete Drug Reference , Sweetman, 2005, London: Pharmaceutical Press., and in Martindale, Martindale: The Extra Pharmacopoeia , 31st Edition., 1996, Amer Pharmaceutical Assn, each of which are hereby incorporated herein by reference.

[0032] Dosage amount and interval can be adjusted individually to provide plasma levels of the active compounds which are sufficient to maintain a desired therapeutic effect. Preferably, therapeutically effective serum levels will be achieved by administering a single dose, but efficacious multiple dose schedules are included in the invention. In cases of local administration or selective uptake, the effective local concentration of the compound may not be related to plasma concentration. One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0033] In another embodiment, a dose of any of the halogenated alcohols described above can be provided as a composition with one or more pharmaceutically acceptable carriers. As used herein, the term, “pharmaceutically acceptable carrier," can include any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of any the halogenated alcohol compounds described above, and which are physiologically acceptable to the subject. In another embodiment, a carrier that is compatible does not abrogate the biological activity or properties of the halogenated alcohol compound, and can be relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0034] In another embodiment, pharmaceutically acceptable carriers can be selected from the group consisting of: liquid or solid filler materials, stabilizers, dispersing agents, suspending agents, diluents, excipients, thickening agents, solvents, or encapsulating materials, including combinations thereoef, that can be utilized to carry or transport an active compound, including any of the halogenated alcohols described above, to the subject such to provide an analgesic effect.. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the subject. Non-limiting examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0035] Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington: The Science and Practice of Pharmacy (Remington: The Science & Practice of Pharmacy), 21^st Edition, 2011, Pharmaceutical Press, and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al ., eds., 9^th Edition, 2010, Lippincott Williams & Wilkins, which are incorporated herein by reference.

[0036] While particular embodiments of the invention have been described, the invention can be further modified within the scope of this disclosure. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. As such, such equivalents are considered to be within the scope of the invention, and this application is therefore intended to cover any variations, uses or adaptations of the invention using its general principles. Further, the invention is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the appended claims.

[0037] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements. [0038] The contents of all references, patents, and patent applications mentioned in this specification are hereby incorporated by reference, and shall not be construed as an admission that such reference is available as prior art to the present invention. All of the incorporated publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains, and are incorporated to the same extent as if each individual publication or patent application was specifically indicated and individually indicated by reference.

EXAMPLES

[0039] The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1: Von Frey Assay for Determining Dose-dependent Analgesic Effects of Selected

Halogenated Alcohol Compounds

[0040] A study was conducted in accordance with embodiments of the present disclosure to determine the analgesic effect of two halogenated alcohol compounds, 3,4,4,4-Tetrafluoro-3- (trifluoromethyl)butan-l-ol (CAS# 90999-87-4) and 3,3-Bis (trifluoromethyl)-4,4,4- trifluorobutan-l-ol (CAS# 14115-49-2) of mice afflicted with an EB disorder, using the von Frey assay, which generally utilizes a filament, fiber, or hair to test a rodent’s sensitivity to a mechanical stimulus ( see Carter, M. and Shieh, J.C. (2010). "Nociception". Guide to Research Techniques in Neuroscience . Burlington, MA: Academic Press. 51-52. ISBN 978-0-12-374849- 2). In the following study description, 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol is herein referred to as “Compound A,” and 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol is referred to as “Compound B.” [0041] In the present study, the pain threshold of sex-matched EB Ki/+ and wild-type mice from a mechanical stimulis was compared in a blinded fashion. A series of nylon monofilaments calibrated at a range of forces from 0.0763-5.7620 g were applied to the plantar surface of each hind paw to determine mechanical allodynia, with the threshold force required to elicit withdrawal of the paw determined using the up-down method across a series of trials. To study the effects of intraperitoneal (IP) injection of the select halogenated alcohol compound, EB Ki/+ and wild-type mice were divided into four treatment groups and one control group (n = 6 per group) with each treatment group corresponding to one of the following doses of Compound A: 0, 40, 100 and 160 pg/kg, or one of the following doses of Compound B: 0, 160, 500, 1,600 pg/kg. Animals were assessed at five time points: pre- administration of drug to provide a baseline measurement (t = 0) and at 15, 30, 45, and 60 minutes post-administration.

[0042] As illustrated in Figure 1 (Compound A) and Figure 2 (Compound B), both tested halogenated alcohol compounds exhibited a dose-dependent analgesic response to the mechanical stimulus. With respect to Compound A in particular, the 160 pg/kg dose raised the subjects’ pain threshold to an amount that was identical to wild-type mice within 15 minutes, and which remained at least 15 additional minutes (t = 30) before gradually diminishing and ultimately returning to baseline at t = 60. On the other hand, while Compound B also exhibits a dose-dependent response over a similar time course, it does so at higher dose levels than Compound A, indicating that Compound A is a more potent analgesic, and may be more effective at treating mechanical nociceptive pain, relative to Compound B.

Example 2: Hargreaves Assay for Determining Dose-dependent Analgesic Effects of Selected Halogenated Alcohol Compounds

[0043] A study was conducted in accordance with embodiments of the present disclosure to determine the analgesic effect of two halogenated alcohol compounds, 3,4,4,4-Tetrafluoro-3- (trifluoromethyl)butan-l-ol (CAS# 90999-87-4) (Compound A, above) and 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol (CAS# 14115-49-2) (Compound B, above) of mice afflicted with an EB disorder, using the Hargreaves assay, which generally tests a rodent’s sensitivity to a thermal stimulus (see Carter, M. and Shieh, J.C., above).

[0044] In the present study, the pain threshold of sex-matched EB Ki/+ and wild-type mice from a thermal stimulis was compared in a blinded fashion. A high-intensity light beam was directed at the hind paw, and the average latency time it takes for the mouse to withdraw its hind paw across a series of trials was recorded using a maximal cut-off latency of 30 seconds. As in Example 1, above, the effects of intraperitoneal (IP) injection of the compounds on EB Ki/+ and wild-type mice were determined across four treatment groups (n = 6 per group) with each group corresponding to one of the following doses of Compound A: 0, 40, 100 and 160 pg/kg, or one of the following doses of Compound B: 0, 160, 500, 1,600 pg/kg. Animals were assessed at five time points: pre- administration of drug to provide a baseline measurement (t = 0) and at 15, 30, 45, and 60 minutes post-administration.

[0045] As illustrated in Figure 3 (Compound A) and Figure 4 (Compound B), both tested halogenated alcohol compounds exhibited a dose-dependent analgesic response to the thermal stimulus. As in Example 1, the maximum raise in the pain threshold as a result of administering Compound A was observed at the t = 15 min timepoint, with a gradual decrease in the threshold to the baseline by t = 60 min. Also similar to Example 1, Compound A is generally more potent than Compound B, requiring a lower dose to achieve the same maximum analgesic effect. Surpisingly, though, the raise in the pain threshold as a result of administering Compound B occurs over a longer period of time relative to Compound A, with a maximum pain threshold at the t = 30 min timepoint rather than the t = 15 min time point for Compound A.

Claims

What is claimed is:

1. A method of treating pain associated with an epidermolysis bullosa (EB) disorder, comprising the step of administering to a subject afflicted with the EB disorder, by a route sufficient to achieve an analgesic effect, a therapeutically effective amount of a halogenated alcohol compound, wherein the halogenated alcohol compound is selected from the group consisting of 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol (CAS# 90999-87-4) and 3,3-Bis (trifluorornethyl)-4,4,4-trifluorobutan-l-ol (CAS# 14115-49-2).

2. The method according to Claim 1, wherein the therapeutically effective amount of the administered halogenated alcohol compound delivers a therapeutically effective blood concentration of the halogenated alcohol compound.

3. The method according to any of Claims 1-2, wherein the halogenated alcohol compound is 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol.

4. The method according to any of Claims 1-2, wherein the halogenated alcohol compound is 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol.

5. The method according to any of Claims 1-4, wherein the therapeutically effective amount of the halogenated alcohol compound is effective for relieving, ameliorating or reducing chronic pain or acute pain associated with an EB disorder.

6. The method according to any of Claims 1-5, wherein the halogenated alcohol compound is administered via an adminstration route selected from the group consisting of oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal.

7. The method according to any of Claims 1-6, wherein the therapeutically effective amount of the halogenated alcohol compound is administered as a co-therapy with a compound selected from the group consisting of an opioid, non-steroidal anti-inflammatory (NSAID) compound, acetaminophen, gabapentinoid, cyclooxygenase-2 inhibitor, A-methyl-D-aspartate (NMDA) receptor agonist, tricyclic antidepressant, anxiolytic, and an anesthetic, including combinations thereof.

8. A use of a haiogenated alcohol compound in the manufacture of a medicament for the treatment of pain associated with an EB disorder, wherein the haiogenated alcohol compound is selected from the group consisting of 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol and 3 , 3 -Bi s (trifluoromethyl)-4,4,4-trifluorobutan- 1 -ol .

9. The use of the haiogenated alcohol compound according to Claim 8, wherein the haiogenated alcohol compound is 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butan-l-ol.

10. The use of the haiogenated alcohol compound according to Claim 8, wherein the haiogenated alcohol compound is 3,3-Bis (trifluoromethyl)-4,4,4-trifluorobutan-l-ol.

11. The use of the haiogenated alcohol compound according to any of Claims 8-10, wherein the medicament is formulated to be administered via an adminstration route selected from the group consisting of oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastrical, topical, and oropharyngeal.

12. The use of the haiogenated alcohol compound according to any of Claims 8-11, wherein the medicament is formulated to be administered as a co-therapy with a compound selected from the group consisting of an opioid, NSAID, acetaminophen, gabapentinoid, cyclooxygenase-2 inhibitor, NMDA receptor agonist, tricyclic antidepressant, anxiolytic, and an anesthetic, including combinations thereof.