Cyclobenzaprine treatment for post - acute sequelae of SARS - CoV - 2 infection (PASC)

Abstract

The present disclosure provides a method for treating post-acute sequelae of severe acute respiratory syndrome (SARS)-CoV-2 infection (PASC) or one or more symptoms associated with said PASC, said method comprising administering to a subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present disclosure provides, in some embodiments, a method and a pharmaceutical composition for treating post-acute sequelae of (SARS)-CoV-2 infection (PASC) or one or more symptoms associated therewith in a subject in need thereof or at risk thereof, wherein said pharmaceutical composition comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 354,215, filed on June 21, 2022, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Background Cyclobenzaprine, or 3-(5H - dibenzo[a,d]cyclohepten - 5 - yliden)-N,N - dimethyl - 1 - propanamine, was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasm of local origin (Katz and Dube. Clin Ther. 1988;10(2):216 - 28). Subsequent studies have shown that cyclobenzaprine is also effective in the treatment of fibromyalgia, post - traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and depression.

[0003] Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) (also known colloquially as "long COVID" or "long hauler") is a term used to describe a constellation of symptoms experienced by people who have a history of probable or confirmed SARS-CoV-2 infection and who typically have symptoms lasting at least two months starting three months from the onset of COVID-19 infection and which cannot be explained by an alternative diagnosis. PASC symptoms span multiple organ systems, can occur within symptom clusters (i.e., neurological, non-neurological, and systemic), and can fluctuate or recur over time (Davis et al. EclinicalMedicine. 2021;38:101019, Crook et al. BMJ. 2021; 374:n1648, Bierle et al. J Prim Care Community Health. 2021;12:1-8, WHO 2021). The lack of a standardized definition of PASC makes it difficult to determine accurate epidemiology, incidence, and the impact of the condition on long-term disability. A conservative estimate based on data collected from many countries is that an average of 30% of people who have had COVID-19 will experience PASC (Nalbandian et al. Nat Med. 2021;27(4):601-15). PASC is a multifaceted condition that affects multiple body systems. The symptoms of PASC can be either initial onset (e.g., onset of pain) after the first recovery from an acute or even mild COVID-19 episode, or can persist from the initial illness. The symptoms of PASC are diverse, but pain, fatigue, and sleep disturbances have been found to be the main symptoms that affect quality of life and the ability to return to full-time work (Alonso-Matielo et al. Front Physiol. 2021;594 (7862):259-64, Davis et al. EclinicalMedicine. 2021;38:101019, Sahin et al. Eur Neurol. 2021;84:450-9). There are currently no FDA-approved treatments for PASC. Therefore, there are unmet needs for reducing pain and other symptoms associated with PASC in this population. People with PASC are generally treated with drugs that target peripheral pain (including opioids), but central sensitization (or pain modulatory) characteristic of multi-site pain in PASC suggests that they may lack response to these treatments. Cyclobenzaprine HCl is a non-opioid central nervous system-acting analgesic that may provide a treatment for this unmet need of reducing pain and other symptoms in people with PASC.

Prior Art Documents

Non-Patent Documents

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Summary of the Invention

Means for Solving the Problems

[0005] Abstract Some embodiments of the present disclosure are as follows: 1. A method for treating post-acute sequelae of SARS-CoV-2 infection (PASC) or one or more symptoms associated with said PASC, the method comprising administering to a subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 2. The method of embodiment 1, wherein the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition is an acid salt of cyclobenzaprine. 3. The method of embodiment 2, wherein the acid salt of cyclobenzaprine is cyclobenzaprine HCl. 4. The method of any one of embodiments 1 to 3, wherein the cyclobenzaprine or a pharmaceutically acceptable salt thereof is in a cocrystal form. 5. The method of embodiment 4, wherein the cocrystal is a mannitol cocrystal. 6. The method of embodiment 5, wherein the mannitol eutectic is selected from the group consisting of a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol eutectic, a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic, a mixture of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol and 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic, and granules comprising an outer layer of 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic and an inner layer of β-mannitol. 7. The method according to any one of embodiments 1 to 6, wherein the pharmaceutical composition comprising a pharmaceutically acceptable salt or eutectic of cyclobenzaprine further comprises a basifying agent. 8. The method of embodiment 7, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, bicarbonate, and sulfide. 9. The method of embodiment 8, wherein the basifying agent is dipotassium hydrogen phosphate. 10. The method according to any one of embodiments 1 to 9, wherein the pharmaceutical composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof between 0.1 mg and 30 mg. 11. The method of embodiment 10, wherein the pharmaceutical composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof between 1 mg and 20 mg. 12. The method according to any one of embodiments 1 to 11, wherein the pharmaceutical composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof less than 10 mg. 13. The method of embodiment 12, wherein the pharmaceutical composition comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof less than 5 mg. 14. The method of embodiment 12, wherein the pharmaceutical composition comprises about 5.6 mg of cyclobenzaprine HCl. 15. The method of embodiment 12 or 13, wherein the pharmaceutical composition comprises about 2.8 mg of cyclobenzaprine HCl. 16. The method of embodiment 12, wherein the pharmaceutical composition comprises cyclobenzaprine HCl between about 2.8 mg and about 5.6 mg. 17. The method of embodiment 14, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, and the total amount of cyclobenzaprine HCl in the two dosage units is about 5.6 mg. 18. The method of embodiment 15, wherein the pharmaceutical composition is administered simultaneously in two dosage units, and each dosage unit comprises about 2.8 mg of cyclobenzaprine HCl. 19. The method of any one of embodiments 1 to 18, wherein the pharmaceutical composition is administered daily. 20. The method of embodiment 19, wherein the pharmaceutical composition is administered once a day. 21. The method of embodiment 19 or 20, wherein the pharmaceutical composition is administered at bedtime. 22. The method of any one of embodiments 1 to 21, wherein the pharmaceutical composition is formulated for sublingual, buccal, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalation, transdermal, rectal, intravaginal, parenteral or palatal administration. 23. The method of embodiment 22, wherein the pharmaceutical composition is formulated as a tablet, film or suppository. 24. The method of embodiment 22, wherein the pharmaceutical composition is formulated for sublingual administration. 25. The method of any one of embodiments 1 to 24, wherein the pharmaceutical composition is administered for at least 14 weeks. 26. The method of any one of embodiments 1 to 25, wherein the subject showed a positive reaction in a SARS-CoV-2 infection test at least 3 months before administration of the pharmaceutical composition. 27. The method of embodiment 1, wherein the one or more symptoms associated with PASC are neurological, non-neurological, systemic, or a combination thereof. 28. The one or more symptoms associated with the PASC are selected from the group consisting of fatigue, malaise, pain, muscle weakness, sweating, chills, limb edema, dizziness, cognitive dysfunction, respiratory symptoms, cardiovascular abnormalities, hair loss, olfactory abnormalities, psychosocial symptoms, and abdominal symptoms, according to the method of Embodiment 1. 29. The respiratory symptoms are independently selected from the group consisting of hyperventilation, chest pain, cough, sputum, sore throat, throat pain, abnormal breathing, and shortness of breath, according to the method of Embodiment 28. 30. The cognitive dysfunction is characterized by brain fog, according to the method of Embodiment 28. 31. The brain fog is one or more of memory impairment, concentration impairment, lack of mental clarity, or inability to concentrate, according to the method of Embodiment 30. 32. The psychosocial symptoms are independently selected from the group consisting of sleep disorders, depression, anxiety, feelings of inferiority, and deterioration of quality of life, according to the method of Embodiment 28. 33. The sleep disorders are independently selected from the group consisting of insomnia, sleep onset disorder, vivid dreams or lucid dreams, and sleep without physical recovery, according to the method of Embodiment 32. 34. The malaise is post-exertional malaise, according to the method of Embodiment 28. 35. The pain is independently selected from the group consisting of pain in multiple sites, diffuse myalgia, joint pain, pain in the musculoskeletal system, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, low back pain associated with sciatica, lower back pain, and pain in one or more of the limbs, hands, toes, or fingertips, according to the method of Embodiment 28. 36. The one or more symptoms associated with the PASC are pain in multiple sites, according to the method of Embodiment 35. 37. The one or more symptoms associated with the PASC are pain in multiple sites and fatigue, according to the method of Embodiment 28 or 36. 38. The one or more symptoms associated with the PASC are pain in multiple sites and insomnia, according to the method of Embodiment 33 or 36. 39. The method according to any one of embodiments 28, 33, and 36, wherein the one or more symptoms associated with the PASC are multiple-site pain, fatigue, and insomnia. 40. The method according to any one of embodiments 35 to 39, wherein the multiple-site pain affects at least four regions of the body. 41. The method according to embodiment 40, wherein the regions of the multiple-site pain are evaluated using a Michigan Body Map. 42. The method according to embodiment 41, wherein the regions of the multiple-site pain are selected from one or more of the regions of the Michigan Body Map, including the left arm, right arm, left leg, right leg, front of the trunk, back of the trunk, or head. 43. The method according to any one of embodiments 27 to 42, wherein the one or more symptoms associated with the PASC are primary, follow the first recovery from acute (SARS)-CoV-2 infection, persist after (SARS)-CoV-2 infection, or persist after discharge from inpatient care in a hospital, clinic, or other medical facility after hospitalization due to (SARS)-CoV-2 infection. 44. The method according to embodiment 43, wherein the one or more symptoms associated with the PASC vary or recur over time. 45. The method according to embodiment 43 or 44, wherein the one or more symptoms associated with the PASC persist after (SARS)-CoV-2 infection. 46. The method according to embodiment 45, wherein the one or more symptoms associated with the PASC persist for at least two months after (SARS)-CoV-2 infection. 47. The method according to embodiment 46, wherein the one or more symptoms associated with the PASC persist for about 8 to 12 weeks after (SARS)-CoV-2 infection. 48. The method according to embodiment 46, wherein the one or more symptoms associated with the PASC persist for about 3 to 18 months after (SARS)-CoV-2 infection. 49. The method according to embodiment 46, wherein the one or more symptoms associated with the PASC persist for about 90 days after (SARS)-CoV-2 infection. 50. The method of embodiment 46 or 48, wherein the one or more symptoms associated with PASC persist for up to about 18 months after (SARS)-CoV-2 infection. 51. The method of embodiment 46 or 48, wherein the one or more symptoms associated with PASC persist for about 6 months after (SARS)-CoV-2 infection. 52. The method of embodiment 43 or 44, wherein the one or more symptoms associated with PASC persist after discharge from inpatient care in a hospital, clinic, or other medical facility after hospitalization due to (SARS)-CoV-2 infection. 53. The method of embodiment 52, wherein the one or more symptoms associated with PASC persist for about 60 days after discharge from inpatient care in a hospital, clinic, or other medical facility after hospitalization due to (SARS)-CoV-2 infection. 54. The method of any one of embodiments 1 - 53, wherein the one or more symptoms associated with PASC are evaluated by a Numerical Rating Scale (NRS), Patient Global Impression of Change (PGI-C), PROMIS scale, Sheehan Disability Scale (SDS), Post-COVID-19 Functional Status (PCFS) scale, Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), or a combination thereof. 55. The method of embodiment 54, wherein the PROMIS scale is selected from the group consisting of the PROMIS - Sleep Disturbance scale, the PROMIS - Fatigue scale, and the PROMIS - Cognitive Function scale. 56. The method of any one of embodiments 1 - 55, wherein the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

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DETAILED DESCRIPTION

[0014] Detailed Description In some embodiments, the present disclosure provides methods and pharmaceutical compositions for treating post-acute sequelae of (SARS)-CoV-2 infection (PASC) or one or more symptoms associated therewith in subjects in need thereof or at risk thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In other embodiments, the present disclosure provides the use of cyclobenzaprine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PASC or one or more symptoms associated therewith. General

[0015] The term "herein" means the entire present application.

[0016] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In case of conflict, this specification, including definitions, shall prevail.

[0017] None of the embodiments described in this specification, including those described under various aspects of the present disclosure and various parts of this specification (including embodiments described only in the examples), are explicitly disclaimed or inappropriate and, if not otherwise disclosed as embodiments of the present disclosure, can be combined with one or more other embodiments of the present disclosure. Combinations of embodiments are not limited to those specific combinations described in a number of dependent embodiments of the present disclosure.

[0018] All publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, this specification, including its specific definitions, will control.

[0019] Throughout this specification, variations such as the phrases "comprise," "comprises," or "comprising" are understood to imply the inclusion of the stated integer (or element) or group of integers (or elements), but not the exclusion of any other integer (or element) or group of integers (or elements).

[0020] As used herein, the term "including" means "including but not limited to." "Including" and "including but not limited to" are used interchangeably. Accordingly, these terms are understood to imply the inclusion of the stated integer (or element) or group of integers (or elements), but not the exclusion of any other integer (or element) or group of integers (or elements).

[0021] As used herein, the term "about" refers to and encompasses (and describes) values or parameters that include embodiments related to the value or parameter itself. For example, a recitation of "about X" encompasses a recitation of "X". As used herein, the term "about" allows for a variation of ±10% within the range of its significant digits. Numerical ranges include both ends of the numbers that define the range.

[0022] Any examples following the terms "e.g." or "for example" are not meant to be exhaustive or limiting.

[0023] Unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular.

[0024] The articles "a", "an", and "the" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article.

[0025] Notwithstanding that the numerical ranges and parameters disclosed are approximate values, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors that necessarily result from the standard deviation found in their respective test measurements. Further, it should be understood that all ranges disclosed herein encompass any and all subranges subsumed therein. For example, the recited range of "1 to 10" includes any and all subranges between the minimum value 1 and the maximum value 10 (and including both ends); that is, all subranges starting with a minimum value of 1 or greater than 1 (e.g., 1 to 6.1) and ending with a maximum value of 10 or less than 10 (e.g., 5.5 to 10) should be considered to be encompassed.

[0026] When aspects and embodiments are described in terms of a Markush group or other grouping of alternatives, this application is intended to cover not only the entire listed group as a whole, but also each member of that group, each and every conceivable subgroup of the main group, and the main group minus one or more of its group members.

[0027] Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0028] Definitions For a better understanding of the present disclosure, certain terms are first defined. These definitions should be read and understood in light of the remainder of the present disclosure, as would be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Further definitions are set forth throughout the detailed description.

[0029] As used herein, the term "treating" and its cognates refer to the complete or partial amelioration or modulation of post-acute sequelae of SARS-CoV-2 infection (PASC) or at least one recognized symptom associated therewith in a composition comprising cyclobenzaprine, a pharmaceutically acceptable salt of cyclobenzaprine, or a composition comprising cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine and a pharmaceutically acceptable carrier. In some embodiments, "treating" refers to reducing pain. In some embodiments, "treating" refers to reducing sleep disturbances. In some embodiments, "treating" refers to improving the quality of sleep. In some embodiments, "treating" refers to reducing fatigue. In some embodiments, "treating" refers to improving concentration. In some embodiments, "treating" refers to "improvement", "much improved" or "very much improved" in the context of these and other symptoms associated with PASC.

[0030] In some embodiments, cyclobenzaprine is in the form of a free base or a pharmaceutically acceptable salt of said free base. In some embodiments, cyclobenzaprine is a free base. In some embodiments, cyclobenzaprine is a pharmaceutically acceptable salt. In some embodiments, cyclobenzaprine is an acid salt. In some embodiments, the acid salt of cyclobenzaprine is cyclobenzaprine hydrochloride (cyclobenzaprine HCl) (see, for example, WO2013 / 188847, incorporated herein by reference).

[0031] In some embodiments of the present disclosure, cyclobenzaprine or its acid salts are present in a eutectic. In some embodiments, the eutectic comprises mannitol. In other embodiments, the mannitol is β-mannitol or δ-mannitol. In some embodiments, the cyclobenzaprine HCl is in a eutectic form selected from the group consisting of a eutectic of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol, a eutectic of 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol, a mixture of a eutectic of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol and a eutectic of 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol, and granules comprising an outer layer of a eutectic of 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol and an inner layer of β-mannitol. See, for example, WO2014 / 145156 and WO2016 / 044796, both of which are incorporated herein by reference. It should be understood that reference to the "cyclobenzaprine HCl" eutectic of the present disclosure refers to any of these eutectics or granules.

[0032] As used herein, the terms "eutectic" or "in eutectic form" refer to a mixture of compounds or elements having a single chemical composition that melts at a lower temperature than any other composition composed of the same components. Compositions containing a eutectic are known as eutectic compositions, and their melting temperature is known as the eutectic temperature. Eutectic compositions often have higher stability and / or dissolution rates than their non-eutectic counterparts. Since eutectics enhance dissolution, they can be used to increase permeability in solid dispersions and dispersive systems.

[0033] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine or a co-crystal of a pharmaceutically acceptable salt of cyclobenzaprine and a basifying agent. In some embodiments, the basifying agent exerts its effect during the time the formulation is dispersed in a mucoid material (including oral and sublingual tissues), and a portion of the formulation dissolves in the mucoid material and remains dissolved for a period of time after the tablet has dissolved in the mucoid material.

[0034] As used herein, "basifying agent" is selected from the group consisting of potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaH2PO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, Na2HPO4), trisodium phosphate (Na3PO4), bicarbonate or carbonate, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of some organic acids (including bicarbonate), and sulfide. The basifying agent having a specific effect on cyclobenzaprine HCl is dipotassium hydrogen phosphate (K2HPO4). Another basifying agent having a specific effect on cyclobenzaprine HCl is potassium dihydrogen phosphate (KH2PO4). Another basifying agent having a specific effect on cyclobenzaprine HCl is disodium hydrogen phosphate (Na2HPO4). Another basifying agent having a specific effect on cyclobenzaprine HCl is tripotassium citrate. Another basifying agent having a specific effect on cyclobenzaprine HCl is trisodium citrate.

[0035] As used herein, "TNX-102 SL" refers to a sublingual formulation of cyclobenzaprine HCl-mannitol eutectic and a basic agent, as described in PCT application number WO2013 / 188847, which is incorporated herein by reference. TNX-102 SL enables the transmucosal absorption of cyclobenzaprine free base into the blood and, although not wishing to be bound by theory, uniquely reduces the formation of norcyclobenzaprine, a long-lived active metabolite of cyclobenzaprine, due to its bypass of first-pass liver metabolism. This allows for greatly improved long-term efficacy.

[0036] As used herein, the terms "subject" and "patient" are used interchangeably herein and refer to mammals, including but not limited to humans and non-human animals. These terms include mammals such as humans, as well as primates (e.g., monkeys, gorillas, anthropoids, and chimpanzees). In some embodiments, the subject is human. Thus, the term "subject" or "patient", as used herein, means any mammalian patient or subject to whom the compositions of the present disclosure can be administered. In some embodiments, the subject has a need for treatment of PASC or one or more symptoms associated with PASC.

[0037] As used herein, "multi-site pain" or "multi-site pain associated with PASC" refers to persistent pain in 4 or more regions on the Michigan Body Map. These regions on the Michigan Body Map include one or more of the left arm, right arm, left leg, right leg, front of the torso, back of the torso, or head.

[0038] Post-Acute Sequelae of Severe Acute Respiratory Syndrome (SARS)-CoV-2 Infection (PASC) Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) (also known colloquially as "long COVID" or "long hauler") occurs in individuals who have a history of almost certain or confirmed SARS-CoV-2 infection and who typically have symptoms that last at least two months and often longer, starting three months from the onset of SARS-CoV-2 infection, and that cannot be explained by an alternative diagnosis. PASC can be broadly described as the presence of one or more symptoms (continuous or relapsing / remitting; new or the same symptoms as acute COVID-19) in individuals infected with SARS-CoV-2 even after the clinical period of recovery from the acute illness. One or more symptoms associated with PASC include fatigue, reduced muscle strength, sweating, muscle pain, joint pain, chills, limb swelling, dizziness, post-exertional malaise, cognitive dysfunction, respiratory symptoms (dyspnea, chest pain, cough, sputum, sore throat), cardiovascular abnormalities, hair loss, olfactory abnormalities, neurocognitive difficulties including memory and concentration impairment, psychological symptoms (e.g., sleep difficulties, depression, anxiety, feelings of inferiority), and generally a worsening of quality of life.

[0039] Pain, fatigue, and sleep disturbances have been found to be major symptoms associated with PASC that affect quality of life. Fatigue occurred in approximately 40% - 80% of PASC patients, on average, 4 - 8 weeks after infection (Crook et al. BMJ. 2021; 374:n1648, Davis et al. EClinicalMedicine. 2021;38:101019, Lambert et al. medRxiv. 2021, Lopez - Leon et al. medRxiv. 2021, Bierle et al. J Prim Care Community Health. 2021;12:1 - 8). Approximately 20% - 64% of patients also reported persistent pain up to 8 - 12 weeks after resolution of acute viral infection (Moreno - Perez et al. J Infect. 2021; 82(3):378 - 83, Lambert et al. medRxiv. 2021). Types of pain reported in PASC include diffuse myalgia, arthralgia, musculoskeletal pain, headache, chest pain, abdominal pain, and general "body pain". In many cases, pain in multiple sites was reported. Various sleep disturbances have also been reported in PASC, and nearly 80% of PASC patients experience insomnia, sleep onset disorder, vivid / lucid dreams, or non - restorative sleep (Davis et al. EClinicalMedicine. 2021;38:101019).

[0040] Treatment method In one aspect, the present disclosure relates to a method for treating post - acute sequelae of severe acute respiratory syndrome (SARS) - CoV - 2 infection (PASC) or one or more symptoms associated with said PASC, said method comprising administering to a subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine and a pharmaceutically acceptable carrier.

[0041] In some embodiments, the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition used in the methods of the present disclosure is an acid salt of cyclobenzaprine. In some embodiments, the acid salt of cyclobenzaprine used in the methods of the present disclosure is cyclobenzaprine HCl.

[0042] In some embodiments, the cyclobenzaprine or a pharmaceutically acceptable salt thereof used in the methods of the present disclosure is in the form of a cocrystal. In some embodiments, the pharmaceutically acceptable salt of cyclobenzaprine used in the present disclosure is in the form of a cocrystal. In some embodiments, the cocrystal used in the methods of the present disclosure is a mannitol cocrystal. In some embodiments, the mannitol cocrystal used in the methods of the present disclosure is selected from the group consisting of a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol cocrystal, a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal, a mixture of a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol cocrystal and a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal, and granules comprising an outer layer of a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal and an inner layer of β-mannitol. In some embodiments, the mannitol cocrystal used in the methods of the present disclosure is a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol cocrystal. In some embodiments, the mannitol cocrystal used in the methods of the present disclosure is a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal. In some embodiments, the mannitol cocrystal used in the methods of the present disclosure is a mixture of a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol cocrystal and a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal. In some embodiments, the mannitol cocrystal used in the methods of the present disclosure is granules comprising an outer layer of a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol cocrystal and an inner layer of β-mannitol.

[0043] In another aspect, the present disclosure relates to a method for treating PASC or one or more symptoms associated with the PASC, the method comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable acid salt of cyclobenzaprine and a basifying agent. In some embodiments, the pharmaceutical composition comprising a pharmaceutically acceptable salt of cyclobenzaprine used in the method of the present disclosure is in the form of a co-crystal and is administered together with a basifying agent. In some embodiments, the basifying agent used in the method of the present disclosure is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, bicarbonate, and sulfide. In some embodiments, the basifying agent used in the method of the present disclosure is potassium dihydrogen phosphate. In some embodiments, the basifying agent used in the method of the present disclosure is dipotassium hydrogen phosphate. In some embodiments, the basifying agent used in the method of the present disclosure is tripotassium phosphate. In some embodiments, the basifying agent used in the method of the present disclosure is sodium carbonate. In some embodiments, the basifying agent used in the method of the present disclosure is sodium bicarbonate. In some embodiments, the basifying agent used in the method of the present disclosure is calcium carbonate. In some embodiments, the basifying agent used in the method of the present disclosure is calcium bicarbonate. In some embodiments, the basifying agent used in the method of the present disclosure is TRIS buffer. In some embodiments, the basifying agent used in the method of the present disclosure is sodium dihydrogen phosphate. In some embodiments, the basifying agent used in the method of the present disclosure is disodium hydrogen phosphate.In some embodiments, the basifying agent used in the method of the present disclosure is trisodium phosphate. In some embodiments, the basifying agent used in the method of the present disclosure is potassium carbonate. In some embodiments, the basifying agent used in the method of the present disclosure is potassium bicarbonate. In some embodiments, the basifying agent used in the method of the present disclosure is potassium acetate. In some embodiments, the basifying agent used in the method of the present disclosure is sodium acetate. In some embodiments, the basifying agent used in the method of the present disclosure is dipotassium citrate. In some embodiments, the basifying agent used in the method of the present disclosure is tripotassium citrate. In some embodiments, the basifying agent used in the method of the present disclosure is disodium citrate. In some embodiments, the basifying agent used in the method of the present disclosure is trisodium citrate.

[0044] In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof between 0.1 mg and 30 mg. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof between 1 mg and 20 mg. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof less than 10 mg. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine or a pharmaceutically acceptable salt thereof less than 5 mg. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises about 5.6 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises 5.6 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine HCl between about 2.8 mg and about 5.6 mg. In some embodiments, the pharmaceutical composition used in the method of the present disclosure comprises cyclobenzaprine HCl between 2.8 mg and 5.6 mg.

[0045] In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, wherein the total amount of cyclobenzaprine HCl in the two dosage units is about 5.6 mg. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt of cyclobenzaprine and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, wherein the total amount of cyclobenzaprine HCl in the two dosage units is 5.6 mg. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered simultaneously in two dosage units, wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered simultaneously in two dosage units, wherein each dosage unit comprises 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered in a single dosage unit comprising about 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered in a single dosage unit comprising 2.8 mg of cyclobenzaprine HCl. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered daily. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered once daily. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered at bedtime. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is administered for at least 14 weeks.

[0046] In some embodiments, the pharmaceutical composition or its co-crystal used in the methods of the present disclosure is formulated for sublingual, buccal, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalation, transdermal, rectal, intravaginal, parenteral or palatal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for sublingual administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for buccal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for intranasal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for oral administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for intravenous administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for intramuscular administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for inhalation administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for transdermal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for rectal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for intravaginal administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for parenteral administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated for palatal administration.

[0047] In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a tablet, thin film, or suppository. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a tablet. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a thin film. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a suppository. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a tablet for sublingual administration. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a thin film for sublingual administration.

[0048] In some embodiments, the subject tested positive for SARS-CoV-2 infection for at least three months prior to administration of the pharmaceutical composition used in the methods of the present disclosure.

[0049] In some embodiments, one or more symptoms associated with PASC are neurological, non-neurological, systemic, or a combination thereof. In some embodiments, one or more symptoms associated with the above PASC are neurological. In some embodiments, one or more symptoms associated with the above PASC are non-neurological. In some embodiments, one or more symptoms associated with the above PASC are systemic. In some embodiments, one or more symptoms associated with PASC are selected from the group consisting of fatigue, malaise, pain, muscle weakness, sweating, chills, limb edema, dizziness, cognitive impairment, respiratory symptoms, cardiovascular abnormalities, hair loss, olfactory abnormalities, psychosocial symptoms, and abdominal symptoms. In some embodiments, the respiratory symptoms are independently selected from the group consisting of tachypnea, chest pain, cough, sputum, sore throat, throat pain, abnormal breathing, and shortness of breath. In some embodiments, the cognitive impairment is characterized by brain fog. In some embodiments, the brain fog is one or more of memory impairment, impaired concentration, lack of mental clarity, or inability to concentrate. In some embodiments, the psychosocial symptoms are independently selected from the group consisting of sleep disorders, depression, anxiety, feelings of inferiority, and worsening of quality of life. In some embodiments, the sleep disorders are independently selected from the group consisting of insomnia, difficulty falling asleep, vivid or lucid dreams, and sleep without perceived restoration of physical strength. In some embodiments, the malaise is post-exertional malaise. In some embodiments, the pain is independently selected from the group consisting of pain in multiple sites, diffuse myalgia, joint pain, musculoskeletal pain, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, low back pain associated with sciatica, lower back pain, and pain in the limbs, hands, toes, and fingertips.

[0050] In some embodiments, one or more symptoms associated with the above PASC are selected from the group consisting of pain in multiple sites, fatigue, and insomnia. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites, but there is no insomnia or fatigue. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites and fatigue. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites and fatigue, but not insomnia. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites and insomnia. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites and insomnia, but not fatigue. In some embodiments, one or more symptoms associated with the above PASC are pain in multiple sites, fatigue, and insomnia. In some embodiments, the above pain in multiple sites affects at least four regions of the body. In some embodiments, the regions of the above pain in multiple sites are evaluated using the Michigan Body Map. In some embodiments, the regions of the above pain in multiple sites are selected from one or more of the regions of the Michigan Body Map including the left arm, right arm, left leg, right leg, front of the trunk, back of the trunk, or head. In some embodiments, the region of the above pain in multiple sites is the left arm. In some embodiments, the region of the above pain in multiple sites is the right arm. In some embodiments, the region of the above pain in multiple sites is the left leg. In some embodiments, the region of the above pain in multiple sites is the right leg. In some embodiments, the region of the above pain in multiple sites is the front of the trunk. In some embodiments, the region of the above pain in multiple sites is the back of the trunk. In some embodiments, the region of the above pain in multiple sites is the head.

[0051] In some embodiments, one or more symptoms associated with PASC are new onset, follow the initial recovery from acute (SARS)-CoV-2 infection, persist after (SARS)-CoV-2 infection, or persist after discharge from inpatient care in a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with the above PASC are new onset. In some embodiments, one or more symptoms associated with the above PASC follow the initial recovery from acute (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for at least two months after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for about 8 to 12 weeks after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for about 3 to 18 months after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for about 90 days after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for up to about 18 months after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for about 6 months after (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist after discharge from inpatient care in a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with PASC persist for about 60 days after discharge from inpatient care in a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more symptoms associated with the above PASC vary or recur over time.

[0052] In some embodiments, one or more symptoms associated with PASC are evaluated by a Numerical Rating Scale (NRS), a Patient Global Impression of Change (PGI-C), a PROMIS scale, a Sheehan Disability Scale (SDS), a Post-COVID-19 Functional Status (PCFS) scale, an Insomnia Severity Index (ISI), an Epworth Sleepiness Scale (ESS), or a combination thereof. In some embodiments, one or more symptoms associated with the above PASC are evaluated by a Numerical Rating Scale (NRS). In some embodiments, one or more symptoms associated with the above PASC are evaluated by a Patient Global Impression of Change (PGI-C). In some embodiments, one or more symptoms associated with the above PASC are evaluated by a PROMIS scale. In some embodiments, one or more symptoms associated with the above PASC are evaluated by a Sheehan Disability Scale (SDS). In some embodiments, one or more symptoms associated with the above PASC are evaluated by a Post-COVID-19 Functional Status (PCFS) scale. In some embodiments, one or more symptoms associated with the above PASC are evaluated by an Insomnia Severity Index (ISI). In some embodiments, one or more symptoms associated with the above PASC are evaluated by an Epworth Sleepiness Scale (ESS). In some embodiments, the above PROMIS scale is selected from the group consisting of a PROMIS - Sleep Disturbance scale, a PROMIS - Fatigue scale, and a PROMIS - Cognitive Function scale. In some embodiments, the above PROMIS scale is a PROMIS - Sleep Disturbance scale. In some embodiments, the above PROMIS scale is a PROMIS - Fatigue scale. In some embodiments, the above PROMIS scale is a PROMIS - Cognitive Function scale.

[0053] Michigan Body Map(MBM) The Michigan Body Map (MBM) is based on the 2011 Fibromyalgia (FM) criteria and is a tool used to assess the presence of pain in multiple sites in fibromyalgia. The 2011 FM criteria include the assessment of pain in 19 specific body regions using the widespread pain index (WPI). Areas from the WPI are then combined with the symptom severity scale to assess the presence and severity of FM (Wolfe et al. Arthritis Care Res. 2010;62(5):600-10, Wolfe et al. J Rheumatol. 2011;38(6)1113-22). The MBM is a graphic mannequin that overlays the 19 areas from the WPI onto anatomically related positions. The MBM also contains 16 additional areas for more general use and has been validated in patients with chronic pain (Brummett et al. Pain. 2016;157(6):1205-12, Hassett et al. Reg Anesth Pain Med. 2019;rapm-2019-101084). A version of the MBM that groups the 35 areas into 7 body regions is used to assess the extent of pain in subjects with PASC, and multiple site pain is defined as pain persisting for at least 3 months in at least 4 of the 7 regions (Figure 1).

[0054] Sheehan Disability Scale (SDS) The Sheehan Disability Scale (SDS) is a brief self-report tool that rates on a 10-point visual analog scale the extent to which work / school, social life, and home life or domestic responsibilities are impaired by symptoms (Williams et al. Handbook of Psychiatric Measures. 2000). Its three items can also be combined into a single-dimensional scale of overall functional impairment ranging from 0 (not impaired) to 30 (severely impaired).

[0055] Daily 24-hour pain recall using an 11-point numerical rating scale (NRS) The Numerical Rating Scale (NRS) is a numerical assessment of the worst pain severity, worst sleep quality, worst fatigue severity, and worst memory / concentration impairment over 24 hours of recall, using an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain).

[0056] Patient-Reported Outcome Measurement Information System (PROMIS) scale The Patient-Reported Outcome Measurement Information System (PROMIS) is a new concept funded by the National Institutes of Health (NIH) to develop means for use over chronic conditions (www.nihpromis.org). Three PROMIS scales include the PROMIS - Sleep Disturbance Scale, the PROMIS - Fatigue Scale, and the PROMIS - Cognitive Function Scale. The scales provide questions to evaluate the quality of sleep, severity of fatigue, and ability of cognitive function respectively over the past 7 days using a 5-point scale ranging from 1 (not at all) to 5 (very much).

[0057] Patient Global Impression of Change (PGI-C) The Patient Global Impression of Change (PGI-C) is a validated means used to measure the evaluation of the subject's state change (Guy. DHEW Pub No. ADM76 - 338 (1976), Dworkin et al J Pain. 2008;94:149 - 58). The PGI-C form provides a single question: Since the start of the trial, my PASC overall has been: 1 = Very improved 2 = Much improved 3 = Slightly improved 4 = No change 5 = Slightly worse 6 = Much worse 7 = Very worse.

[0058] Post - COVID - 19 Functional Status (PCFS) scale The Post-COVID-19 Functional Status (PCFS) scale is an ordinal scale for assessing patient-related functional limitations over time after COVID-19 infection (Klok et al. Eur Respir J. 2020;56(1):2001494, Machado et al. Health Qual Life Outcomes. 2021;19:40). The scale scores the functional status of the subject as follows: 0 = No functional limitations 1 = Negligible functional limitations 2 = Slight functional limitations 3 = Moderate functional limitations 4 = Severe functional limitations D = Death.

[0059] Insomnia Severity Index (ISI) The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire for assessing the nature, severity, and impact of insomnia (Spielman et al. Sleep. 1987; 10(1):45-56, Morin et al. Sleep. 2011;34(5):601-8). The usual recall period is "the past month", and the dimensions evaluated are problems with falling asleep, maintaining sleep, and early morning awakening, dissatisfaction with sleep, interference with daytime functioning due to sleep difficulties, ease of being noticed by others about sleep problems, and severity of distress caused by sleep difficulties. Its score ranges from 0 (no problem) to 4 (very severe problem), and a total score ranging from 0 to 28 is obtained, which is interpreted as follows: 0 - 7 = No insomnia 8 - 14 = Subthreshold insomnia 15 - 21 = Moderate insomnia 22 - 28 = Severe insomnia.

[0060] Epworth Sleepiness Scale (ESS) The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire with eight questions (Johns. Sleep. 1991;14(6):540-5). Subjects rate their usual chance of dozing off or falling asleep on a scale of 0 to 3 while engaged in eight different activities. The total score can range from 0 to 24, with higher scores indicating a higher average sleep tendency in daily life.

[0061] To understand this application more fully, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of this application in any way. The practice of this application is illustrated by the following non-limiting examples.

Example

[0062] Example Example 1. Study Design of a Retrospective Electronic Health Record Review of Clinical Characteristics of Subjects with PASC Subject Selection A retrospective observational electronic health record (EHR) review was conducted to evaluate the clinical characteristics of complex multi-site pain, fatigue, and insomnia in subjects with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID or long hauler. These clinical characteristics included (1) the incidence of multi-site pain symptoms with and without associated symptoms of fatigue and insomnia, (2) the association with physical and CNS symptoms, and (3) the use of pharmacotherapy. The EHR data source was the TriNetX Dataworks USA Network, which contains data on 75.2 million subjects. Subjects with PASC were selected at 90 days post-infection based on the following clinical characteristics using a previously developed identification algorithm (Taquet et al. PLoS Med. 2021; 18(9): e10003773): chest pain / sore throat, abnormal breathing, abdominal symptoms, fatigue / malaise, anxiety / depression, pain, headache, cognitive impairment, and myalgia, and at least one medical visit more than 180 days after the first signs of COVID-19 from the database (Table 1).

[0063] Subjects with complex pain, i.e., those that may have a centrally mediated, pain-modulatory component, were captured using diagnostic codes. The selection of the population of interest was restricted by the use of existing diagnostic codes (Figure 2). Subjects with a diagnosis associated with diffuse pain or >2 anatomically distinct sources of pain (i.e., pain in multiple sites) were selected by an algorithm (Figure 2). Table 1. Subject Selection [Table 1]

[0064] First test cohort The first test cohort of adults with SARS-CoV-2 infection followed for at least 6 months included 260,082 records, of which 52,322 met the criteria for PASC (Table 1). The data were divided into five subgroups: (1) subjects without pain in multiple sites, (2) subjects with pain in multiple sites but without insomnia or fatigue, (3) subjects with pain in multiple sites and fatigue (but without insomnia), (4) subjects with pain in multiple sites and insomnia (but without fatigue), and (5) subjects with pain in multiple sites, fatigue, and insomnia (Table 2). Table 2. Subject Populations [Table 2-1] [Table 2-2]

[0065] Analysis showed that PASC symptoms were predominantly present in the female population (Figure 3A). Multiple-site pain in PASC followed a similar course and was highly prevalent in women (Figure 3A). African Americans comprised 20.3% of the PASC population (Figure 3B). The proportion of African Americans among PASC subjects was higher than that in the general population and increased in the multiple-site pain group, except for in the three main symptoms of pain, fatigue, and insomnia (Figure 3B). This imbalance may impact public health considering the under-treatment and misdiagnosis of African Americans presenting with pain symptoms.

[0066] Analysis of physical and CNS symptoms in subjects with PASC Physical symptoms associated with PASC (e.g., respiratory and abdominal abnormalities) occurred at approximately equal frequencies in subjects, with or without multiple-site pain (Figure 5). The presence of insomnia and fatigue increased the prevalence of these symptoms and symptoms associated with pain diagnoses (Figures 4 and 5).

[0067] Anxiety and depression had a high prevalence in most of the PASC population and reached nearly 70% in the present study population (Figure 5). Subjects with multiple-site pain reported significantly lower symptoms of depression and anxiety. This could be an expression of somatization (pain modulation) that may be interpreted differently as either depression / anxiety in subjects with different central processing of pain signals or pain in different subjects (Fitzcharles et al. Lancet. 2021; 397:2098-110). Cognitive symptoms (e.g., "brain fog") were also experienced by PASC subjects; however, they were difficult to capture in the current database due to limitations in available diagnostic codes. Cognitive symptoms showed a pattern similar to depression and anxiety in subjects with multiple-site pain (Figure 5). Similar to depression and anxiety, this could reflect differential processing of central pain signals.

[0068] Inflammation of tissue damage markers in subjects with PASC Subjects with a high percentage of PASC showed markers of inflammation (e.g., erythrocyte sedimentation rate and C-reactive protein) (Figure 6). Overall examination findings did not suggest that inflammation or tissue damage is the main mechanism contributing to multiple-site pain in PASC (Figure 6). This supports a central sensitization / pain-modulatory mechanism underlying multiple-site pain.

[0069] Analgesic use in subjects with PASC The use of analgesics, anti-inflammatory drugs, and benzodiazepine anxiolytics increased with the occurrence of either fatigue or insomnia, but the use of non-steroidal anti-inflammatory drugs (NSAIDs) was consistent across all groups (Figure 7). Opioid use in PASC patients without multiple-site pain was relatively high at approximately 19% (Figure 8). However, opioid use was nearly twice as high in patients with multiple-site pain (Figure 8). The occurrence of fatigue or insomnia was associated with even more opioid use, and insomnia was a particularly strong factor, resulting in >50% opioid use (Figure 8).

[0070] Example 2. Study design for evaluating TNX-102 SL, cyclobenzaprine HCl, and PASC A 14-week, phase 2, randomized, multi-site, parallel-group, double-blind, placebo-controlled trial is conducted to evaluate the efficacy and safety of once-daily intake of 5.6 mg of TNX-102 SL at bedtime (typically, two 2.8 mg doses simultaneously) for the management or treatment of multiple-site pain associated with PASC.

[0071] Approximately 470 subjects between 18 and 65 years of age are enrolled in this trial. Subjects must have a history of polymerase chain reaction (PCR)-positive SARS-CoV-2 infection confirmed in the past 3 months prior to enrollment, have pain in multiple sites as defined by the Michigan Body Map immediately following SARS-CoV-2 infection, i.e., meet the criteria for pain in multiple sites (defined as pain in at least 4 regions), and have the onset or significant worsening of pain consistent with a previous COVID-19 infection, with symptoms present at a similar level for at least 6 weeks (but within 12 months). Subjects are randomized in a 1:1 ratio (i.e., 235 subjects in each of the TNX-102 SL arm and the placebo arm).

[0072] The trial consists of a screening visit (Visit 1), at least 7 days (for subjects not requiring a washout) and a washout and screening period within 35 days (including a 7-day baseline data collection phase immediately prior to the baseline visit). Eligible subjects who provide written informed consent are evaluated at screening and discontinue any medications being discontinued during the washout period. This must be achieved such that the above subjects have not been on medication for at least 14 days prior to randomization. After the screening period, there are baseline and randomization visits (Visit 2), as well as 4 treatment visits (Visits 3, 4, 5, and 6) at 2, 6, 10, and 14 weeks for efficacy and safety evaluations, and continued assessment of trial drug compliance and tolerability. There is a further safety follow-up call at 16 weeks (Visit 7). The overall duration of the trial for each individual is 20 weeks. The maximum treatment duration is 14 weeks.

[0073] During the screening visit (Visit 1), the subject is trained regarding the use of the diary system. Every night when the subject uses the diary, the system prompts the subject to review the past 24 hours and record their worst pain severity, worst memory / concentration impairment, worst fatigue, an assessment of the quality of sleep since last night, and the administration of the investigational drug the night before (after randomization).

[0074] Achieve the down-titration and discontinuation of the excluded drug therapy during the washout and screening period immediately prior to the baseline visit. After a 7-day break from the excluded drug therapy, the subject starts a 7-day pre-observation phase. During this time, highly important baseline daily diary efficacy data are collected. Request the subject to record their worst daily pain severity, worst daily memory / concentration impairment, worst daily fatigue using an 11-point (0 - 10) NRS scale using 24-hour recall, and provide an assessment of the quality of sleep last night, also using an 11-point NRS scale. The average of the above 7 days immediately prior to Visit 2 (baseline / randomization visit; Day 1) serves as the baseline treatment pre-score.

[0075] After completing any required washout of the excluded treatment and recording baseline diary scores over at least 7 days, the subject returns to the clinical trial site for baseline assessment and randomization (Day 1, Visit 2) and is randomly assigned in a 1:1 ratio to receive TNX-102 SL or the corresponding placebo sublingual tablets.

[0076] Subjects take one randomly assigned tablet of the test drug (TNX-102 SL 2.8 mg or placebo) sublingually once daily at bedtime for 1 to 14 days. After the efficacy and safety evaluations and evaluation of test drug compliance at Week 2 (Clinic Visit 3), the daily dose of TNX-102 SL is increased to 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets and taken sublingually simultaneously at bedtime daily. Subjects continue to record their worst daily pain, worst daily memory / concentration impairment, and worst daily fatigue and provide an evaluation of the quality of sleep from the previous night for the next 10 weeks.

[0077] Subjects return to the clinic at Weeks 6, 10, and 14 (Clinic Visits 4, 5, and 6, respectively) for efficacy and safety evaluations, evaluation of test drug compliance, and evaluation of dose tolerance at the 5.6 mg dose. If TNX-102 SL 5.6 mg (or two placebo tablets) is considered intolerable due to one or more adverse events and leads to discontinuation of the study otherwise, the daily dose is decreased to one tablet nightly (TNX-102 SL 2.8 mg or one placebo tablet). A rechallenge with two TNX-102 SL 2.8 mg (i.e., 5.6 mg dose) or placebo may be attempted at a later date if the principal investigator of the study deems it clinically appropriate and the subject may remain on the lower dose for the remainder of the study.

[0078] The primary endpoint, secondary endpoints, and exploratory efficacy and safety endpoints are described in Table 3.

[0079] Potential genetic determinants of treatment response are investigated by evaluation of genetic variants in relation to treatment outcome. Blood samples are obtained from subjects who sign a separate informed consent form for pharmacogenomic analysis at any clinic visit after screening. Exome sequencing and analysis are performed for allelic polymorphisms associated with treatment response to TNX-102 SL. Table 3. Criteria for Evaluation

Table 3-1

Table 3-2

Table 3-3

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for treating in a subject in need of treatment one or more symptoms of severe acute respiratory syndrome (SARS)-CoV-2 infection or associated with said PASC.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition is cyclobenzaprine HCl.

3. The pharmaceutical composition according to claim 2, wherein the cyclobenzaprine HCl is in the form of a mannitol eutectic.

4. The pharmaceutical composition according to claim 3, wherein the mannitol eutectic is selected from the group consisting of a 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol eutectic, a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic, a mixture of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol and a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic, and granules comprising an outer layer of a 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic and an inner layer of β-mannitol.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprising cyclobenzaprine HCl or the eutectic thereof further comprises a basicizing agent.

6. The pharmaceutical composition according to claim 5, wherein the basicizing agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate.

7. The pharmaceutical composition according to claim 6, wherein the basicizing agent is dipotassium hydrogen phosphate.

8. The aforementioned pharmaceutical composition, (i) Cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount between 0.1 mg and 30 mg, (ii) Cyclobenzaprine or a pharmaceutically acceptable salt thereof in an amount between 1 mg and 20 mg, (iii) Less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof, (iv) Less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof A pharmaceutical composition according to claim 1, comprising:

9. The aforementioned pharmaceutical composition, (i) Approximately 5.6 mg of cyclobenzaprine HCl, or (ii) Approximately 2.8 mg of cyclobenzaprine HCl A pharmaceutical composition according to any one of claims 2 to 7, comprising:

10. The aforementioned pharmaceutical composition is characterized by being administered simultaneously or sequentially in two dose units. (i) The total amount of cyclobenzaprine HCl in the two dose units is approximately 5.6 mg, or (ii) Each dose contains approximately 2.8 mg of cyclobenzaprine HCl. The pharmaceutical composition according to claim 9.

11. The pharmaceutical composition according to claim 1, characterized in that it is administered daily.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for sublingual, oral, nasal, oral, intravenous, intramuscular, subcutaneous, inhalation, transdermal, rectal, vaginal, or palatal administration.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is formulated as a tablet, a thin film, or a suppository.

14. The pharmaceutical composition according to claim 1, characterized in that it is administered over a period of at least 14 weeks.

15. The pharmaceutical composition according to claim 1, wherein the subject has been tested positive for SARS-CoV-2 infection at least three months prior to administration of the pharmaceutical composition.

16. The pharmaceutical composition according to claim 1, wherein the 1 or more symptoms associated with the PASC are neurological, non-neurological, systemic, or a combination thereof.

17. The pharmaceutical composition according to claim 1, wherein the 1 or more symptoms associated with the PASC are selected from the group consisting of fatigue, malaise, pain, muscle weakness, sweating, chills, edema of the limbs, dizziness, cognitive impairment, respiratory symptoms, cardiovascular abnormalities, hair loss, olfactory abnormalities, psychosocial symptoms, and abdominal symptoms.

18. (i) The respiratory symptoms are independently selected from the group consisting of tachypnea, chest pain, cough, sputum, sore throat, sore throat, abnormal breathing, and shortness of breath. (ii) The cognitive impairment is characterized by one or more of the following, as characterized by brain fog: memory impairment, difficulty concentrating, lack of intellectual clarity, or inability to concentrate. (iii) The psychosocial symptoms are independently selected from the group consisting of sleep disorders, depression, anxiety, feelings of inferiority, and deterioration of quality of life, and the sleep disorders are independently selected from the group consisting of insomnia, difficulty falling asleep, vivid dreams or lucid dreams, and sleep that does not allow for physical recovery. (iv) The fatigue is post-exertional fatigue, or (v) The pain is independently selected from the group consisting of pain in multiple sites, diffuse muscle pain, joint pain, musculoskeletal pain, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, lumbar pain associated with sciatica, lower back pain, and pain in one or more of the limbs, hands, fingers, or toes. The pharmaceutical composition according to claim 17.

19. (i) The one or more symptoms associated with the PASC are multi-site pain, (ii) The one or more symptoms associated with the PASC are multiple site pain and fatigue. (iii) The above 1 or more symptoms associated with PASC are multiple site pain and insomnia, or (iv) The one or more symptoms associated with the PASC are multiple site pain, fatigue, and insomnia. The pharmaceutical composition according to claim 18.

20. (i) Multiple site pain affects at least four areas of the body, (ii) The areas of pain in multiple sites are evaluated using the Michigan Body Map. (iii) The area of ​​pain in multiple locations is selected from one or more of the areas of the Michigan Body Map, including the left arm, right arm, left leg, right leg, front of the trunk, back of the trunk, or head. The pharmaceutical composition according to claim 19.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the 1 or more symptoms associated with the PASC are initial, follow the first recovery from acute (SARS)-CoV-2 infection, persist after (SARS)-CoV-2 infection, or persist after release from inpatient care in a hospital, clinic or other medical facility following hospitalization for (SARS)-CoV-2 infection.

22. The pharmaceutical composition according to claim 21, wherein the one or more symptoms associated with the PASC are variable or recurring over time.

23. The pharmaceutical composition according to claim 1, wherein the 1 or more symptoms associated with the PASC are evaluated by a numerical rating scale (NRS), patient's general condition change (PGI-C), PROMIS scale, Sheehan's disorder scale (SDS), post-COVID-19 functional status (PCFS) scale, insomnia severity questionnaire (ISI), Epworth sleepiness scale (ESS), or a combination thereof.

24. The pharmaceutical composition according to claim 1, wherein the subject is a human.

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