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

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority and benefit of U.S. Provisional Application No. 63 / 354,215, filed on June 21, 2022, the content of which is incorporated herein by reference in its entirety. Background of the Invention

[0003] 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 syndrome, post - traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and depression.

[0004] Post - acute sequelae of SARS - CoV - 2 infection (PASC) (commonly known as "long COVID" or "long haulers") is a term used to describe a range of symptoms experienced by people with a probable or confirmed history of SARS - CoV - 2 infection, typically starting 3 months after the onset of COVID - 19 infection and lasting at least two months, and cannot be explained by alternative diagnoses. PASC symptoms span multiple organ systems and can occur within symptom clusters (i.e., neurological, non - neurological, and systemic symptom clusters), or 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 the exact epidemiology, incidence, and the impact of this condition on long - term disability. A conservative estimate based on data collected from many countries is that on average 30% of people with COVID - 19 will experience PASC (Nalbandian et al., Nat Med. 2021; 27(4): 601 - 15).

[0005] PASC is a multifaceted condition that affects multiple body systems. The symptoms of PASC may be new onset after initial recovery from an acute or even mild COVID-19 episode (e.g., new onset of pain), or persistent since the initial illness. Although the symptoms of PASC vary, pain, fatigue, and sleep disturbances have been found to be the main symptoms, which 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 is currently no FDA-approved treatment for PASC. Therefore, there is an unmet need to relieve pain and other symptoms associated with PASC in this population. People with PASC are typically treated with medications that target peripheral pain, including opioids. However, the central sensitization (or nociceptive plasticity) characteristics of multi-site pain in PASC suggest a possible lack of response to these treatments. Cyclobenzaprine hydrochloride is a non-opioid centrally acting analgesic that may provide treatment for this unmet need to relieve pain and other symptoms in people with PASC. Summary of the Invention

[0006] Some embodiments of the present disclosure are:

[0007] 1. A method of treating post-acute sequelae (PASC) of severe acute respiratory syndrome (SARS)-CoV-2 infection or one or more symptoms associated with said PASC, the method comprising administering to a subject in need 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.

[0008] 2. The method according to embodiment 1, wherein the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition is cyclobenzaprine hydrochloride.

[0009] 3. The method according to embodiment 2, wherein the cyclobenzaprine hydrochloride is hydrochloric acid cyclobenzaprine.

[0010] 4. The method according to any one of embodiments 1 - 3, wherein cyclobenzaprine or a pharmaceutically acceptable salt thereof is in the form of a eutectic mixture.

[0011] 5. The method according to embodiment 4, wherein the eutectic mixture is a mannitol eutectic mixture.

[0012] 6. The method according to embodiment 5, wherein the mannitol eutectic mixture is selected from a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β-mannitol eutectic mixture, a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture, a mixture of a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β-mannitol eutectic mixture and a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture, and granules comprising an outer layer of a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture and an inner layer of β-mannitol.

[0013] 7. The method according to any one of embodiments 1-6, wherein the pharmaceutical composition comprising a pharmaceutically acceptable salt of cyclobenzaprine or its eutectic mixture further comprises a basifying agent.

[0014] 8. The method according to embodiment 7, wherein the basifying agent is selected from 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.

[0015] 9. The method according to embodiment 8, wherein the basifying agent is dipotassium hydrogen phosphate.

[0016] 10. The method according to any one of embodiments 1-9, wherein the pharmaceutical composition comprises 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0017] 11. The method according to embodiment 10, wherein the pharmaceutical composition comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0018] 12. The method according to any one of embodiments 1-11, wherein the pharmaceutical composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0019] 13. The method according to embodiment 12, wherein the pharmaceutical composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0020] 14. The method according to embodiment 12, wherein the pharmaceutical composition comprises about 5.6 mg of cyclobenzaprine hydrochloride.

[0021] 15. The method according to embodiment 12 or 13, wherein the pharmaceutical composition comprises about 2.8 mg of cyclobenzaprine hydrochloride.

[0022] 16. The method according to embodiment 12, wherein the pharmaceutical composition comprises from about 2.8 mg to about 5.6 mg of cyclobenzaprine hydrochloride.

[0023] 17. The method according to embodiment 14, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, and wherein the combined amount of cyclobenzaprine hydrochloride in the two dosage units is about 5.6 mg.

[0024] 18. The method according to embodiment 15, wherein the pharmaceutical composition is administered simultaneously in two dosage units, and wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine hydrochloride.

[0025] 19. The method according to any one of embodiments 1-18, wherein the pharmaceutical composition is administered daily.

[0026] 20. The method according to embodiment 19, wherein the pharmaceutical composition is administered once daily.

[0027] 21. The method according to embodiment 19 or 20, wherein the pharmaceutical composition is administered at bedtime.

[0028] 22. The method according to any one of embodiments 1-21, wherein the pharmaceutical composition is formulated for sublingual, buccal mucosal, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalation, transdermal, rectal, vaginal, parenteral or palatal administration.

[0029] 23. The method according to embodiment 22, wherein the pharmaceutical composition is formulated as a tablet, film or suppository.

[0030] 24. The method according to embodiment 22, wherein the pharmaceutical composition is formulated for sublingual administration.

[0031] 25. The method according to any one of embodiments 1-24, wherein the pharmaceutical composition is administered for at least 14 weeks.

[0032] 26. The method according to any one of embodiments 1-25, wherein the subject has tested positive for SARS-CoV-2 infection for at least three months prior to administration of the pharmaceutical composition.

[0033] 27. The method according to embodiment 1, wherein the one or more symptoms associated with PASC are neurological, non-neurological, systemic symptoms or a combination thereof.

[0034] 28. The method according to embodiment 1, wherein the 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 dysfunction, respiratory symptoms, cardiovascular abnormalities, hair loss, olfactory abnormalities, psychosocial symptoms, and abdominal symptoms.

[0035] 29. The method according to embodiment 28, wherein the respiratory symptoms are independently selected from the group consisting of: shortness of breath, chest pain, cough, expectoration, pharyngolaryngitis, sore throat, abnormal breathing, and shortness of breath.

[0036] 30. The method according to embodiment 28, wherein the cognitive dysfunction is characterized by brain fog.

[0037] 31. The method according to embodiment 30, wherein the brain fog is one or more of the following: memory problems, attention problems, lack of mental clarity, or inability to concentrate.

[0038] 32. The method according to embodiment 28, wherein the psychosocial symptoms are independently selected from the group consisting of: sleep disorders, depression, anxiety, sense of inferiority, and poor quality of life.

[0039] 33. The method according to embodiment 32, wherein the sleep disorders are independently selected from the group consisting of: insomnia, difficulty falling asleep, vivid or lucid dreams, and non-restorative sleep.

[0040] 34. The method according to embodiment 28, wherein the malaise is post-exertional malaise.

[0041] 35. The method according to embodiment 28, wherein the pain is independently selected from the group consisting of: multi-site pain, diffuse myalgia, joint pain, musculoskeletal pain, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, low back pain with sciatica, lower back pain, and pain in one or more of the limbs, hands, feet, fingers, or toes.

[0042] 36. The method according to embodiment 35, wherein the one or more symptoms associated with PASC is multi-site pain.

[0043] 37. The method according to embodiment 28 or 36, wherein the one or more symptoms associated with PASC are multi-site pain and fatigue.

[0044] 38. The method according to embodiment 33 or 36, wherein the one or more symptoms associated with PASC are multi-site pain and insomnia.

[0045] 39. A method according to any one of embodiments 28, 33, and 36, wherein the one or more symptoms associated with PASC are multi-site pain, fatigue, and insomnia.

[0046] 40. A method according to any one of embodiments 35 - 39, wherein the multi-site pain affects at least 4 regions of the body.

[0047] 41. A method according to embodiment 40, wherein the multi-site pain regions are evaluated using a Michigan Body Map.

[0048] 42. A method according to embodiment 41, wherein the multi-site pain regions are selected from one or more of the regions of the Michigan Human Map, the regions including the left arm, right arm, left leg, right leg, front of the torso, back of the torso, or the head.

[0049] 43. A method according to any one of embodiments 27 - 42, wherein the one or more symptoms associated with PASC are new onset, after initial recovery from acute (SARS)-CoV-2 infection, persistent after (SARS)-CoV-2 infection, or persistent after discharge from inpatient care at a hospital, clinic, or other healthcare facility after hospitalization due to (SARS)-CoV-2 infection.

[0050] 44. A method according to embodiment 43, wherein the one or more symptoms associated with PASC fluctuate or recur over time.

[0051] 45. A method according to embodiment 43 or 44, wherein the one or more symptoms associated with PASC persist after (SARS)-CoV-2 infection.

[0052] 46. A method according to embodiment 45, wherein the one or more symptoms associated with PASC persist for at least 2 months after (SARS)-CoV-2 infection.

[0053] 47. A method according to embodiment 46, wherein the one or more symptoms associated with PASC persist for about 8 - 12 weeks after (SARS)-CoV-2 infection.

[0054] 48. A method according to embodiment 46, wherein the one or more symptoms associated with PASC persist for about 3 - 18 months after (SARS)-CoV-2 infection.

[0055] 49. A method according to embodiment 46, wherein the one or more symptoms associated with PASC persist for about 90 days after (SARS)-CoV-2 infection.

[0056] 50. The method according to embodiment 46 or 48, wherein one or more symptoms associated with PASC persist for up to about 18 months after (SARS)-CoV-2 infection.

[0057] 51. The method according to embodiment 46 or 48, wherein one or more symptoms associated with PASC persist for about 6 months after (SARS)-CoV-2 infection.

[0058] 52. The method according to embodiment 43 or 44, wherein one or more symptoms associated with PASC persist after discharge from inpatient care at a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection.

[0059] 53. The method according to embodiment 52, wherein one or more symptoms associated with PASC persist for about 60 days after discharge from inpatient care at a hospital, clinic, or other medical facility following hospitalization due to (SARS)-CoV-2 infection.

[0060] 54. The method according to any one of embodiments 1 to 53, wherein 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.

[0061] 55. The method according to 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.

[0062] 56. The method according to any one of embodiments 1 to 55, wherein the subject is a human.

[0063] BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 Displays the Michigan Body Map (MBM) for assessing diffuse pain.

[0065] Figure 2 Displays the diagnostic codes for selecting subjects with multi-site pain. Any COVID-19-related diagnostic code (ICD-10-CM) or positive PCR test occurring on or after January 20, 2020 ( ). Patients diagnosed with other specified viral infections (code 879.89) on or after January 20, 2020 are excluded.1 Multisite pain includes: myalgia, myositis, fibromyalgia, pain, or ≥2 other distinct pain diagnosis codes during the target time period. Pain in joints, limbs, hands, feet, fingers, toes, throat, and chest was evaluated using specific children in the parent code. 2 [COVID = Coronavirus disease; LONIC = Logical Observation Identifiers Names and Codes]

[0066] Figure 3A and 3B are tables showing the demographics of subjects with COVID-19 and PASC ( Figure 3A ), as well as PASC and multisite pain ( Figure 3B ).

[0067] Figure 4 is a table showing the prevalence of pain-related diagnoses of multisite pain among subjects with PASC.

[0068] Figure 5 is a graph showing the prevalence of respiratory abnormalities, abdominal symptoms, anxiety / depression, and cognitive symptoms (or "brain fog") among subjects with PASC on days 91 - 180.

[0069] Figure 6 is a graph showing the prevalence of inflammatory markers (e.g., erythrocyte sedimentation rate and C-reactive protein) and tissue damage markers (e.g., alkaline phosphatase and creatine kinase) among subjects with PASC.

[0070] Figure 7 is a graph showing the prevalence of PASC subjects using analgesics, NSAIDs, anti-inflammatory drugs, and sedatives / hypnotics. [NSAID = Nonsteroidal anti-inflammatory drug]

[0071] Figure 8 is a graph showing the prevalence of PASC subjects using benzodiazepine derivative anxiolytics, opioids, and non-opioids.

[0072] DETAILED DESCRIPTION

[0073] 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 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.

[0074] GENERAL

[0075] The term "this application" means the entire application.

[0076] Unless otherwise defined in this application, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In case of conflict, the present specification (including definitions) shall prevail.

[0077] It should be understood that any embodiment described in this application, including embodiments described under different aspects of the present disclosure and different parts of this specification (including embodiments described only in the examples), may be combined with one or more other embodiments of the present disclosure, unless expressly disclaimed or inappropriate, and thus are disclosed as embodiments of the present disclosure. Combinations of embodiments are not limited to those specific combinations described in the multiple dependent claims of the present disclosure.

[0078] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification (including its specific definitions) shall prevail.

[0079] Throughout this specification, the word "comprising" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of the stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0080] As used in this application, the term "comprising" means "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. Thus, these terms will be understood to imply the inclusion of the stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0081] As used in this application, the term "about" refers to a value or parameter that includes (and describes) embodiments for that value or parameter itself. For example, a description of "about X" includes a description of "X". As used in this application, the term "about" allows a variation of ±10% within the range of significant figures. A numerical range includes the numbers defining the range.

[0082] Any examples following the terms "such as" or "for example" are not meant to be exhaustive or limiting.

[0083] Unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

[0084] The articles "a", "an", and "the" are used in this application to refer to one or more than one (i.e., at least one) of the grammatical objects of the article.

[0085] Although the numerical ranges and parameters disclosed herein are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors that are necessarily caused by the standard deviation found in their respective test measurements. In addition, it should be understood that all ranges disclosed in this application cover any and all subranges subsumed therein. For example, the stated range "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10 (and including the minimum value of 1 and the maximum value of 10); that is, all subranges starting with a minimum value of 1 or greater (e.g., 1 to 6.1) and ending with a maximum value of 10 or less (e.g., 5.5 to 10).

[0086] In the case of descriptions or embodiments in terms of other groupings according to Markush groups or alternative elements, this application covers not only the entire group listed as a whole, but also each member of the group and all possible subgroups of the main group individually, and also covers the main group in which one or more of the constituent members are absent.

[0087] Exemplary methods and materials are described in this application, although methods and materials similar or equivalent to those described in this application can also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and not restrictive.

[0088] Definitions

[0089] To facilitate a better understanding of the present disclosure, certain terms are first defined. These definitions should be read in light of the remainder of the present disclosure as would be understood by a person of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by a person of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0090] As used in this application, the term "treatment" and its cognates refer to the complete or partial amelioration or modulation of post-acute sequelae of severe acute respiratory syndrome (SARS)-CoV-2 infection (PASC) or at least one distinguishable symptom associated therewith using 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, "treatment" refers to alleviating pain. In some embodiments, "treatment" refers to reducing sleep disturbances. In some embodiments, "treatment" refers to an improvement in sleep quality. In some embodiments, "treatment" refers to alleviating fatigue. In some embodiments, "treatment" refers to an improvement in concentration. In some embodiments, "treatment" refers to "improvement", "great improvement", or "very great improvement" in the context of these and other symptoms associated with PASC.

[0091] In some embodiments, cyclobenzaprine is in the form of the free base or a pharmaceutically acceptable salt of the free base. In some embodiments, cyclobenzaprine is the free base. In some embodiments, cyclobenzaprine is a pharmaceutically acceptable salt. In some embodiments, cyclobenzaprine is an acid salt. In some embodiments, the cyclobenzaprine acid salt is cyclobenzaprine hydrochloride (cyclobenzaprine HCl) (see, e.g., WO2013 / 188847, which is incorporated herein by reference).

[0092] In some embodiments of the present disclosure, cyclobenzaprine or its acid salt is present as a eutectic mixture. In some embodiments, the eutectic mixture includes mannitol. In other embodiments, the mannitol is β-mannitol or δ-mannitol. In some embodiments, cyclobenzaprine hydrochloride is in the form of a eutectic mixture selected from the group consisting of: a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β-mannitol eutectic mixture, a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture, a mixture of a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β-mannitol eutectic mixture and a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture, and a granule comprising an outer layer of a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ-mannitol eutectic mixture and an inner layer of β-mannitol. See, e.g., WO2014 / 145156 and WO2016 / 044796, both of which are incorporated herein by reference. It should be understood that the "cyclobenzaprine hydrochloride" eutectic mixture of the present disclosure refers to any one of these eutectic mixtures or granules.

[0093] As used herein, the term "eutectic mixture" or "in the form of a eutectic mixture" refers to a mixture of compounds or elements that has a single chemical composition that melts at a lower temperature than any other composition composed of the same components. A composition containing a eutectic mixture is called a eutectic composition, and its melting temperature is called the eutectic temperature. Eutectic compositions generally have higher stability and / or dissolution rates than their non-eutectic counterparts. Because eutectic mixtures enhance dissolution, they can be used to increase permeability in solid dispersions and dispersion systems.

[0094] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine or a eutectic mixture of a pharmaceutically acceptable salt of cyclobenzaprine and a basifying agent. In some embodiments, the basifying agent exerts its effect during the time period when the formulation is dispersed in the mucous material (including buccal and sublingual tissues), while a portion of the formulation dissolves in the mucous material and exerts its effect for a period of time after the tablet dissolves in the mucous material.

[0095] As used herein, "alkalizing 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), bicarbonates or carbonates, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugate bases of some organic acids (including bicarbonates), and sulfides. The alkalizing agent that has a particular effect on cyclobenzaprine hydrochloride is dipotassium hydrogen phosphate (K2HPO4). Another alkalizing agent that has a particular effect on cyclobenzaprine hydrochloride is potassium dihydrogen phosphate (KH2PO4). Another alkalizing agent that has a particular effect on cyclobenzaprine hydrochloride is disodium hydrogen phosphate (Na2HPO4). Another alkalizing agent that has a particular effect on cyclobenzaprine hydrochloride is tripotassium citrate. Another alkalizing agent that has a particular effect on cyclobenzaprine hydrochloride is trisodium citrate.

[0096] As used herein, "TNX-102SL" refers to a low-dose sublingual formulation of a cyclobenzaprine hydrochloride-mannitol eutectic mixture and an alkalizing agent, as described in PCT application number WO2013 / 188847, which is incorporated herein by reference. TNX-102SL allows for the mucosal absorption of cyclobenzaprine free base into the bloodstream, and without wishing to be bound by theory, due to its bypassing of first-pass hepatic metabolism, TNX-102SL uniquely reduces the production of the long half-life active metabolite of cyclobenzaprine, norcyclobenzaprine. This allows for a significant improvement in long-term efficacy.

[0097] As used herein, "subject" and "patient" are used interchangeably herein and refer to a mammal, including but not limited to humans and non-human animals. These terms include mammals such as humans and primates (e.g., monkeys, gorillas, apes, and chimpanzees). In some embodiments, the subject is a 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 is in need of treatment for PASC or one or more symptoms associated with PASC.

[0098] 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 Human Body Map. These regions on the Michigan Human 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.

[0099] Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

[0100] (Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), commonly known as "Long COVID" or "Long Haulers") occur in individuals with a history of probable or confirmed SARS-CoV-2 infection, typically starting three months after the onset of SARS-CoV-2 infection, with symptoms persisting for at least two months, usually longer, and not explained by alternative diagnoses. PASC can be broadly described as the presence of one or more symptoms (persistent or relapsing / remitting; new or the same symptoms as acute COVID-19) in individuals infected with SARS-CoV-2 even after the clinical phase of acute illness has clinically resolved. One or more symptoms associated with PASC include fatigue, muscle weakness, sweating, myalgia, arthralgia, chills, limb edema, dizziness, post-exertional malaise, cognitive dysfunction, respiratory symptoms (shortness of breath, chest pain, cough, sputum production, pharyngitis), cardiovascular abnormalities, hair loss, olfactory abnormalities, neurocognitive difficulties (including memory and attention problems), psychological symptoms (such as difficulty sleeping, depression, anxiety, feelings of inferiority), and generally poor quality of life.

[0101] Pain, fatigue, and sleep disturbances have been found to be the main symptoms associated with PASC that affect quality of life. Fatigue occurs in approximately 40% to 80% of PASC patients, on average 4 to 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). Persistent pain lasting up to 8 to 12 weeks after the resolution of acute viral infection is also reported in approximately 20% to 64% of patients (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 widespread "body pain". In many cases, multiple pain sites are reported. Various sleep disturbances have also been reported in PASC, with nearly 80% of PASC patients experiencing insomnia, difficulty falling asleep, vivid / lucid dreams, or non-restorative sleep (Davis et al., EClinicalMedicine. 2021;38:101019).

[0102] Treatment Methods

[0103] In one aspect, the present disclosure relates to a method of 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 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.

[0104] In some embodiments, the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition used in the methods of the present disclosure is cyclobenzaprine hydrochloride. In some embodiments, the cyclobenzaprine hydrochloride used in the methods of the present disclosure is cyclobenzaprine hydrochloride.

[0105] In some embodiments, cyclobenzaprine or a pharmaceutically acceptable salt thereof used in the methods of the present disclosure is in the form of a eutectic mixture. In some embodiments, the pharmaceutically acceptable salt of cyclobenzaprine used in the present disclosure is in the form of a eutectic mixture. In some embodiments, the eutectic mixture used in the methods of the present disclosure is a mannitol eutectic mixture. In some embodiments, the mannitol eutectic mixture used in the methods of the present disclosure is selected from the group consisting of: a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol eutectic mixture, a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture, a mixture of a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol and a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture, and a granule comprising an outer layer of a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture and an inner layer of β - mannitol. In some embodiments, the mannitol eutectic mixture used in the methods of the present disclosure is a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol eutectic mixture. In some embodiments, the mannitol eutectic mixture used in the methods of the present disclosure is a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture. In some embodiments, the mannitol eutectic mixture used in the methods of the present disclosure is a mixture of a 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol and a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture. In some embodiments, the mannitol eutectic mixture used in the methods of the present disclosure is a granule comprising an outer layer of a 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture and an inner layer of β - mannitol.

[0106] In another aspect, the present disclosure relates to a method of 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 methods of the present disclosure is in the form of a eutectic mixture and is administered together with a basifying agent. In some embodiments, the basifying agent used in the methods 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, and trisodium citrate. In some embodiments, the basifying agent used in the methods of the present disclosure is potassium dihydrogen phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is dipotassium hydrogen phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is tripotassium phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is sodium carbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is sodium bicarbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is calcium carbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is calcium bicarbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is TRIS buffer. In some embodiments, the basifying agent used in the methods of the present disclosure is sodium dihydrogen phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is disodium hydrogen phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is trisodium phosphate. In some embodiments, the basifying agent used in the methods of the present disclosure is potassium carbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is potassium bicarbonate. In some embodiments, the basifying agent used in the methods of the present disclosure is potassium acetate. In some embodiments, the basifying agent used in the methods of the present disclosure is sodium acetate. In some embodiments, the basifying agent used in the methods of the present disclosure is dipotassium citrate. In some embodiments, the basifying agent used in the methods of the present disclosure is tripotassium citrate. In some embodiments, the basifying agent used in the methods of the present disclosure is disodium citrate. In some embodiments, the basifying agent used in the methods of the present disclosure is trisodium citrate.

[0107] In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises from 0.1 milligram to 30 milligrams of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises from 1 milligram to 20 milligrams of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises less than 10 milligrams of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises less than 5 milligrams of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises about 5.6 milligrams of cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises 5.6 milligrams of cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises about 2.8 milligrams of cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises 2.8 milligrams of cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises from about 2.8 milligrams to about 5.6 milligrams of cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition used in the methods of the present disclosure comprises from 2.8 milligrams to 5.6 milligrams of cyclobenzaprine hydrochloride.

[0108] 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 thereof and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, and the combined amount of cyclobenzaprine hydrochloride 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 thereof and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, and the combined amount of cyclobenzaprine hydrochloride 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 hydrochloride. 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 hydrochloride. 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 hydrochloride. 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 hydrochloride. 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.

[0109] In some embodiments, the pharmaceutical composition or eutectic mixture thereof used in the methods of the present disclosure is formulated for sublingual, buccal mucosa, intranasal, oral, intravenous, intramuscular, subcutaneous, inhaled, transdermal, rectal, vaginal, 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 mucosa 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 inhaled 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 vaginal 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.

[0110] In some embodiments, the pharmaceutical composition used in the methods of the present disclosure is formulated as a tablet, 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 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 film for sublingual administration.

[0111] In some embodiments, the subject has tested positive for SARS-CoV-2 infection at least three months prior to administration of the pharmaceutical composition used in the methods of the present disclosure.

[0112] In some embodiments, one or more symptoms associated with PASC are neurological, non-neurological, systemic symptoms, or a combination thereof. In some embodiments, one or more symptoms associated with PASC are neurological symptoms. In some embodiments, one or more symptoms associated with PASC are non-neurological symptoms. In some embodiments, one or more symptoms associated with PASC are systemic symptoms. 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 dysfunction, 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: shortness of breath, chest pain, cough, sputum production, pharyngolaryngitis, sore throat, abnormal breathing, and shortness of breath. In some embodiments, the cognitive dysfunction is characterized by brain fog. In some embodiments, the brain fog is one or more of the following: memory problems, attention problems, 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 poor 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 non-restorative sleep. In some embodiments, the malaise is post-exertional malaise. In some embodiments, the pain is independently selected from the group consisting of: multi-site pain, diffuse myalgia, joint pain, musculoskeletal pain, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, low back pain with sciatica, lower back pain, and pain in the limbs, hands, feet, fingers, or toes.

[0113] In some embodiments, the one or more symptoms associated with PASC are selected from the group consisting of multi-site pain, fatigue, and insomnia. In some embodiments, the one or more symptoms associated with PASC are multi-site pain. In some embodiments, the one or more symptoms associated with PASC are multi-site pain, but not insomnia or fatigue. In some embodiments, the one or more symptoms associated with PASC are multi-site pain and fatigue. In some embodiments, the one or more symptoms associated with PASC are multi-site pain and fatigue, but not insomnia. In some embodiments, the one or more symptoms associated with PASC are multi-site pain and insomnia. In some embodiments, the one or more symptoms associated with PASC are multi-site pain and insomnia, but not fatigue. In some embodiments, the one or more symptoms associated with PASC are multi-site pain, fatigue, and insomnia. In some embodiments, multi-site pain affects at least 4 regions of the body. In some embodiments, the multi-site pain regions are evaluated using a Michigan human body diagram. In some embodiments, the multi-site pain regions are selected from one or more regions of the Michigan human body diagram, including the left arm, right arm, left leg, right leg, front of the torso, back of the torso, or head. In some embodiments, the multi-site pain region is the left arm. In some embodiments, the multi-site pain region is the right arm. In some embodiments, the multi-site pain region is the left leg. In some embodiments, the multi-site pain region is the right leg. In some embodiments, the multi-site pain region is the front of the torso. In some embodiments, the multi-site pain region is the back of the torso. In some embodiments, the multi-site pain region is the head.

[0114] In some embodiments, one or more of the symptoms associated with PASC are newly onset, persist after initial recovery from acute (SARS)-CoV-2 infection, persist after (SARS)-CoV-2 infection, or persist after discharge from inpatient care at a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC are newly onset. In some embodiments, one or more of the symptoms associated with PASC occur after initial recovery from acute (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for at least 2 months after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for about 8 - 12 weeks after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for about 3 - 18 months after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for about 90 days after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for up to about 18 months after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for about 6 months after (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist after discharge from inpatient care at a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC persist for about 60 days after discharge from inpatient care at a hospital, clinic, or other healthcare facility following hospitalization due to (SARS)-CoV-2 infection. In some embodiments, one or more of the symptoms associated with PASC fluctuate or recur over time.

[0115] In some embodiments, 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. In some embodiments, one or more symptoms associated with PASC are evaluated by a Numerical Rating Scale (NRS). In some embodiments, one or more symptoms associated with PASC are evaluated by a Patient Global Impression of Change (PGI-C). In some embodiments, one or more symptoms associated with PASC are evaluated by a PROMIS scale. In some embodiments, one or more symptoms associated with PASC are evaluated by a Sheehan Disability Scale (SDS). In some embodiments, one or more symptoms associated with PASC are evaluated by a Post-COVID-19 Functional Status (PCFS) scale. In some embodiments, one or more symptoms associated with PASC are evaluated by an Insomnia Severity Index (ISI). In some embodiments, one or more symptoms associated with PASC are evaluated by an Epworth Sleepiness Scale (ESS). In some embodiments, 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. In some embodiments, the PROMIS scale is the PROMIS - Sleep Disturbance scale. In some embodiments, the PROMIS scale is the PROMIS - Fatigue scale. In some embodiments, the PROMIS scale is the PROMIS Cognitive Function scale.

[0116] Michigan Body Map (MBM)

[0117] The Michigan Body Map (MBM), based on the 2011 Fibromyalgia (FM) Survey Criteria, is a tool for assessing the presence of multi-site pain in fibromyalgia. The 2011 FM Survey Criteria include using the Widespread Pain Index (WPI) to assess pain in 19 specific body regions. The regions 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 graphical human body model onto which the 19 regions from the WPI are superimposed at anatomically relevant locations. The MBM also contains 16 additional regions 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 divides the 35 regions into 7 body regions is used to assess the diffuseness of pain in subjects with PASC, with multi-site pain defined as pain in at least 4 of the 7 regions for at least 3 months ( Figure 1 ).

[0118] Sheehan Disability Scale (SDS)

[0119] The Sheehan Disability Scale (SDS) is a brief self-report tool that assesses the degree of impairment of symptoms on work / school, social life, and home life or family responsibilities on a 10-point visual analog scale (Williams et al., Handbook of Psychiatric Measures. 2000). These 3 items can also be summed into a single-dimensional measure of overall functional impairment ranging from 0 (unimpaired) to 30 (highly impaired).

[0120] Daily 24-hour pain recall using an 11-point Numerical Rating Scale (NRS)

[0121] The Numerical Rating Scale (NRS) is a numerical assessment of the severity of the most severe pain, the worst sleep quality, the severity of the most severe fatigue, and the severity of the most severe memory / attention problems within a 24-hour recall using an 11-point scale ranging from 0 (no pain) to 10 (the most severe possible pain).

[0122] Patient-Reported Outcome Measurement Information System (PROMIS) scale

[0123] The Patient-Reported Outcomes Measurement Information System (PROMIS) is a National Institutes of Health (NIH)-funded initiative to develop tools for use in chronic conditions (www.nihpromis.org). Three PROMIS scales include the PROMIS - Sleep Disturbance Scale, the PROMIS - Fatigue Scale, and the PROMIS - Cognitive Function Scale. These scales provide 5-point scales ranging from 1 (not at all) to 5 (very much) to assess questions regarding sleep quality, fatigue severity, and cognitive function ability over the past 7 days, respectively.

[0124] Patient Global Impression of Change (PGI-C)

[0125] The Patient Global Impression of Change (PGI-C) is a validated tool for measuring a subject's assessment of change in their condition (Guy. Dhew Pub No. ADM 76 - 338 (1976), Dworkin et al., J Pain. 2008; 94:149 - 58). The PGI-C form provides a question:

[0126] Overall, my PASC since the start of the study has been:

[0127] 1 = Very much improved

[0128] 2 = Much improved

[0129] 3 = Minimally improved

[0130] 4 = No change

[0131] 5 = Slightly worse

[0132] 6 = Much worse

[0133] 7 = Very much worse.

[0134] Post-COVID-19 Functional Status (PCFS) Scale

[0135] The Post-COVID-19 Functional Status (PCFS) Scale is an ordinal scale used to assess 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. 2021; 19:40).

[0136] This scale rates the functional status of the subject as:

[0137] 0 = No functional limitations

[0138] 1 = Negligible functional limitations

[0139] 2 = Mild functional limitation

[0140] 3 = Moderate functional limitation

[0141] 4 = Severe functional limitation

[0142] D = Death.

[0143] Insomnia Severity Index (ISI)

[0144] The Insomnia Severity Index (ISI) is a 7-item self-report questionnaire (Spielman et al., Sleep. 1987; 10(1):45 - 56, Morin et al., Sleep. 2011; 34(5):601 - 8) that assesses the nature, severity, and impact of insomnia. The usual recall period is "the last month", and the dimensions evaluated are the severity of sleep onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, others' attention to the sleep problem, and distress caused by sleep difficulties. The scores range from 0 (no problem) to 4 (very severe problem), and the resulting total scores range from 0 to 28, which are interpreted as:

[0145] 0 - 7 = No insomnia

[0146] 8 - 14 = Subthreshold insomnia

[0147] 15 - 21 = Moderate insomnia

[0148] 22 - 28 = Severe insomnia.

[0149] Epworth Sleepiness Scale (ESS)

[0150] The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire with 8 questions (Johns. Sleep. 1991; 14(6):540 - 5). Subjects rate their usual chance of dozing or falling asleep on a scale of 0 to 3 while engaged in 8 different activities. The total score can range from 0 to 24, and higher scores indicate a higher average sleep propensity in daily life.

[0151] To more fully understand the present application, the following examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present application in any way. The implementation of the present application is illustrated by the following non-limiting examples. Examples

[0152] Example 1. Study design of a retrospective electronic health record review of the clinical characteristics of subjects with PASC

[0153] Subject selection

[0154] 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 haulers). These clinical characteristics included (1) the incidence of multi-site pain symptoms with or without fatigue and insomnia-related symptoms, (2) the correlation with somatic and central nervous system symptoms, and (3) medication use. The source of the EHR was the TriNetX Dataworks USA network, which contains data on 75.2 million subjects. Subjects with PASC were selected based on a previously developed identification algorithm (Taquet et al., PLoS Med. 2021;18(9):e10003773) who had the following clinical characteristics 90 days after infection: chest / throat pain, abnormal breathing, abdominal symptoms, fatigue / malaise, anxiety / depression, pain, headache, cognitive dysfunction, and myalgia, and had at least 1 healthcare encounter ≥180 days after the first COVID-19 indication in the database (Table 1).

[0155] Diagnostic codes were used to capture subjects with complex pain, i.e., those who may have a central-mediated component of nociceptive plasticity. The selection of the target population was limited by the use of existing diagnostic codes( Figure 2 ). Subjects with diagnoses related to diffuse pain or >2 anatomically distinct pain sources (i.e., multi-site pain) were selected by the algorithm( Figure 2 ).

[0156] Table 1. Subject selection

[0157]

[0158] Initial study population

[0159] The initial study population of adults with SARS-CoV-2 infection with at least 6 months of follow-up included 260,082 records, of which 52,322 met the PASC criteria (Table 1). The data were divided into 5 subgroups: (1) subjects without multi-site pain, (2) subjects with multi-site pain but without insomnia or fatigue, (3) subjects with multi-site pain and fatigue (but without insomnia), (4) subjects with multi-site pain and insomnia (but without fatigue), and (5) subjects with multi-site pain, fatigue, and insomnia (Table 2).

[0160] Table 2. Subject population

[0161]

[0162] Analysis showed that PASC symptoms were mainly present in the female population( Figure 3A)。The multi-site pain in PASC follows a similar trajectory, with a female predominance( Figure 3A )。African Americans account for 20.3% of the PASC population( Figure 3B )。The proportion of African Americans among PASC subjects is higher than that in the general population and increases in the multi-site pain group, except in the pain, fatigue, and insomnia triad( Figure 3B )。Given the under-treatment and misdiagnosis of African Americans presenting with pain symptoms, this inconsistency may have implications for public health.

[0163] Analysis of somatic and central nervous system symptoms in subjects with PASC

[0164] Somatic symptoms associated with PASC, such as respiratory and abdominal abnormalities, occur with approximately equal frequency in subjects with and without multi-site pain( Figure 5 )。The presence of insomnia and fatigue increases the prevalence of these symptoms and those associated with pain diagnosis( Figure 4 and 5 )。

[0165] Anxiety and depression are very common in most of the PASC population, reaching nearly 70% in the study population( Figure 5 )。Subjects with multi-site pain reported significantly lower symptoms of depression and anxiety, which may be a manifestation of somatization (nociceptive plasticity), where the central processing of pain signals may be differently interpreted as depression / anxiety or pain in different subjects (Fitzcharles et al., Lancet. 2021; 397: 2098-110). PASC subjects also experienced cognitive symptoms (e.g., "brain fog"); however, due to limitations in available diagnostic codes, it was difficult to capture them in the current database. In patients with multi-site pain, cognitive symptoms showed a pattern similar to that of depression and anxiety( Figure 5 )。Like depression and anxiety, this may reflect different processing of central pain signals.

[0166] Inflammation of tissue damage markers in subjects with PASC

[0167] A high proportion of subjects with PASC showed inflammatory markers (e.g., erythrocyte sedimentation rate and C-reactive protein)( Figure 6 )。Overall laboratory findings did not indicate that inflammation or tissue damage was the main mechanism leading to multi-site pain in PASC( Figure 6 ), supporting the central sensitization / nociceptive plasticity mechanism underlying multi-site pain.

[0168] Analgesic use in subjects with PASC

[0169] Analgesics, anti-inflammatory drugs, and benzodiazepines The use of anxiolytics increased with the occurrence of fatigue or insomnia, while the use of non-steroidal anti-inflammatory drugs (NSAIDs) was consistent across all groups ( Figure 7 ). The use of opioids was relatively high, approximately 19%, among PASC patients without multi-site pain ( Figure 8 ). However, the use of opioids almost doubled among patients with multi-site pain ( Figure 8 ). The occurrence of fatigue or insomnia was associated with even more opioid use, and insomnia was a particularly strong factor, contributing to >50% of opioid use ( Figure 8 ).

[0170] Example 2. Study Design for Evaluating TNX-102SL, Cyclobenzaprine Hydrochloride, and PASC

[0171] A Phase 2, randomized, multi-center, parallel-group, double-blind, placebo-controlled, 14-week study was conducted to evaluate the efficacy and safety of once-daily administration of TNX-102SL 5.6 mg (usually administered as two 2.8 mg doses) at bedtime for managing or treating multi-site pain associated with PASC.

[0172] Approximately 470 subjects aged 18 - 65 years were enrolled in this study. Subjects must have had a history of SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) within the past 3 months prior to enrollment and met the criteria for multi-site pain as defined by the Michigan Human Map following SARS-CoV-2 infection, i.e., multi-site pain (defined as pain in at least 4 regions), with symptoms present at a similar level for at least 6 weeks but no longer than 12 months, and new onset of pain or significant worsening of pain consistent with a previous COVID-19 infection. Subjects were randomized in a 1:1 ratio, i.e., 235 subjects in each of the TNX-102SL arm and the placebo arm.

[0173] The study consisted of the following: a screening visit (Visit 1), a washout and screening period of at least 7 days (for subjects who did not require washout) and no more than 35 days, including a 7-day baseline data collection phase immediately preceding the baseline visit. Eligible subjects who provided written informed consent were evaluated in the study at screening and discontinued all excluded medications during the washout period, which had to be completed so that subjects were drug-free for at least 14 days prior to randomization. Following the screening period were the baseline and randomization visit (Visit 2), and 4 treatment visits (Visits 3, 4, 5, and 6) at Weeks 2, 6, 10, and 14 for efficacy and safety assessments, as well as assessments of study drug compliance and tolerance. There was an additional safety follow-up call at Week 16 (Visit 7). The total study duration for each individual was 20 weeks. The maximum treatment duration was 14 weeks.

[0174] During the screening visit (Visit 1), subjects were trained in the use of the diary system. Every evening, when the subject used the diary, the system prompted the subject to reflect on the past 24 hours and record their worst pain severity, worst memory / attention problems, worst fatigue, sleep quality assessment from the previous night, and study drug administration from the previous night (after randomization).

[0175] During the washout and screening period immediately preceding the baseline visit, the down-titration and discontinuation of the exclusion medication were completed. Seven days after discontinuation of the exclusion medication, subjects began a 7-day lead-in period during which key baseline daily diary efficacy data were collected. Subjects were required to record their worst daily pain severity, worst daily memory / attention problems, worst daily fatigue using a 24-hour recall on an 11-point (0 - 10) NRS scale and provide a sleep quality assessment from the previous night, also using an 11-point NRS scale. The mean of the 7 days immediately preceding Visit 2 (baseline / randomization visit; Day 1) was used as the pre-treatment baseline score.

[0176] After completing any required washout of the exclusion therapy and recording baseline diary scores for at least 7 days, subjects returned to the study site for baseline assessment and randomization (Day 1, Visit 2), and they were randomly assigned in a 1:1 ratio to receive TNX-102SL or matching placebo sublingual tablets.

[0177] Subjects took 1 randomly assigned study drug (TNX-102SL 2.8 mg or placebo) sublingually at bedtime once daily on Days 1 - 14. After efficacy and safety assessments and study drug adherence assessment at Week 2 (Visit 3), the daily dose of TNX-102SL was increased to 5.6 mg (2 x 2.8 mg tablets) or 2 placebo tablets, taken sublingually at bedtime daily and simultaneously. Subjects continued to record their worst daily pain, worst daily memory / attention problems, worst daily fatigue, and provide a sleep quality assessment from the previous night for the next 10 weeks.

[0178] Subjects returned to the clinic at Weeks 6, 10, and 14 (Visits 4, 5, and 6 respectively) for efficacy and safety assessments, study drug adherence assessment, and dose tolerance assessment of the 5.6 mg dose. In the event that TNX-102SL 5.6 mg (or 2 placebo tablets) was considered intolerable due to adverse events or would otherwise lead to study termination, the daily dose was reduced to 1 tablet per night (TNX-102SL 2.8 mg or 1 placebo tablet). If / when the investigator deemed it clinically necessary, a re-challenge with 2 TNX-102SL 2.8 mg tablets (i.e., 5.6 mg dose) or placebo could be attempted at a later date, or the subject could remain on the lower dose for the remainder of the study.

[0179] The primary, secondary, and exploratory efficacy endpoints and safety endpoints are described in Table 3.

[0180] The potential genetic determinants of treatment response were examined by evaluating genetic variants associated with treatment outcomes. Blood samples were obtained from subjects who had signed a separate informed consent for pharmacogenomic analysis at any visit after screening. Exome sequencing and analysis of allelic polymorphisms associated with the treatment response to TNX-102SL were performed.

[0181] Table 3. Evaluation Criteria

[0182]

[0183]

[0184]

Claims

1. A method for treating post - acute sequelae of SARS - CoV - 2 infection (PASC) or one or more symptoms associated with PASC, the method comprising administering to a subject in need 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 according to claim 1, wherein the pharmaceutically acceptable salt of cyclobenzaprine in the pharmaceutical composition is cyclobenzaprine acid salt.

3. The method according to claim 2, wherein the cyclobenzaprine acid salt is cyclobenzaprine hydrochloride.

4. The method according to any one of claims 1 - 3, wherein the cyclobenzaprine or its pharmaceutically acceptable salt is in the form of a eutectic mixture.

5. The method according to claim 4, wherein the eutectic mixture is a mannitol eutectic mixture.

6. The method according to claim 5, wherein the mannitol eutectic mixture is selected from the mixture of 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol eutectic mixture, 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture, the mixture of 75% ± 2% cyclobenzaprine hydrochloride and 25% ± 2% β - mannitol eutectic mixture and 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture, and particles comprising an outer layer of 65% ± 2% cyclobenzaprine hydrochloride and 35% ± 2% δ - mannitol eutectic mixture and an inner layer of β - mannitol.

7. The method according to any one of claims 1 - 6, wherein the pharmaceutical composition comprising the pharmaceutically acceptable salt of cyclobenzaprine or its eutectic mixture further comprises a basifying agent.

8. The method according to claim 7, wherein the basifying agent is selected from 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.

9. The method according to claim 8, wherein the basifying agent is dipotassium hydrogen phosphate.

10. The method according to any one of claims 1 - 9, wherein the pharmaceutical composition comprises 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10, wherein the pharmaceutical composition comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 - 11, wherein the pharmaceutical composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, wherein the pharmaceutical composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

14. The method according to claim 12, wherein the pharmaceutical composition comprises about 5.6 mg of cyclobenzaprine hydrochloride.

15. The method according to claim 12 or 13, wherein the pharmaceutical composition comprises about 2.8 mg of cyclobenzaprine hydrochloride.

16. The method according to claim 12, wherein the pharmaceutical composition comprises from about 2.8 mg to about 5.6 mg of cyclobenzaprine hydrochloride.

17. The method according to claim 14, wherein the pharmaceutical composition is administered simultaneously or sequentially in two dosage units, and wherein the combined amount of cyclobenzaprine hydrochloride in the two dosage units is about 5.6 mg.

18. The method according to claim 15, wherein the pharmaceutical composition is administered simultaneously in two dosage units, and wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine hydrochloride.

19. The method according to any one of claims 1-18, wherein the pharmaceutical composition is administered daily.

20. The method according to claim 19, wherein the pharmaceutical composition is administered once daily.

21. The method according to claim 19 or 20, wherein the pharmaceutical composition is administered at bedtime.

22. The method according to any one of claims 1-21, wherein the pharmaceutical composition is formulated for sublingual, buccal mucosa, intranasal, oral, intravenous, intramuscular, subcutaneous, inhalation, transdermal, rectal, vaginal, parenteral or palatal administration.

23. The method according to claim 22, wherein the pharmaceutical composition is formulated as a tablet, film or suppository.

24. The method according to claim 22, wherein the pharmaceutical composition is formulated for sublingual administration.

25. The method according to any one of claims 1-24, wherein the pharmaceutical composition is administered for at least 14 weeks.

26. The method according to any one of claims 1-25, wherein the subject has tested positive for SARS-CoV-2 infection at least three months prior to administration of the pharmaceutical composition.

27. The method according to claim 1, wherein the one or more symptoms associated with PASC are neurological, non-neurological, systemic symptoms or a combination thereof.

28. The method according to claim 1, wherein the 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 dysfunction, respiratory symptoms, cardiovascular abnormalities, hair loss, olfactory abnormalities, psychosocial symptoms and abdominal symptoms.

29. The method according to claim 28, wherein the respiratory symptoms are independently selected from the group consisting of shortness of breath, chest pain, cough, expectoration, pharyngolaryngitis, sore throat, abnormal breathing and shortness of breath.

30. The method according to claim 28, wherein the cognitive dysfunction is characterized by brain fog.

31. The method according to claim 30, wherein the brain fog is one or more of the following: memory problems, attention problems, lack of mental clarity or inability to concentrate.

32. The method according to claim 28, wherein the psychosocial symptoms are independently selected from the group consisting of sleep disorders, depression, anxiety, feelings of inferiority and poor quality of life.

33. The method according to claim 32, wherein the sleep disorder is independently selected from the group consisting of insomnia, difficulty falling asleep, vivid or lucid dreams, and non-restorative sleep.

34. The method according to claim 28, wherein the discomfort is post-exertional malaise.

35. The method according to claim 28, wherein the pain is independently selected from the group consisting of multi-site pain, diffuse myalgia, joint pain, musculoskeletal pain, headache, facial pain, chest pain, abdominal pain, back pain, joint pain, body pain, low back pain with sciatica, lower back pain, and pain in one or more of the limbs, hands, feet, fingers, or toes.

36. The method according to claim 35, wherein one or more of the symptoms associated with PASC is multi-site pain.

37. The method according to claim 28 or 36, wherein one or more of the symptoms associated with PASC is multi-site pain and fatigue.

38. The method according to claim 33 or 36, wherein one or more of the symptoms associated with PASC is multi-site pain and insomnia.

39. The method according to any one of claims 28, 33, and 36, wherein one or more of the symptoms associated with PASC is multi-site pain, fatigue, and insomnia.

40. The method according to any one of claims 35-39, wherein the multi-site pain affects at least 4 regions of the body.

41. The method according to claim 40, wherein a Michigan Human Figure is used to evaluate the multi-site pain regions.

42. The method according to claim 41, wherein the multi-site pain regions are selected from one or more of the regions of the Michigan Human Figure, the regions including the left arm, right arm, left leg, right leg, front of the torso, back of the torso, or head.

43. The method according to any one of claims 27-42, wherein one or more of the symptoms associated with PASC are new-onset, after initial recovery from acute (SARS)-CoV-2 infection, persistent after (SARS)-CoV-2 infection, or persistent after discharge from inpatient care at a hospital, clinic, or other healthcare facility after hospitalization due to (SARS)-CoV-2 infection.

44. The method according to claim 43, wherein one or more of the symptoms associated with PASC fluctuate or recur over time.

45. The method according to claim 43 or 44, wherein one or more of the symptoms associated with PASC persist after (SARS)-CoV-2 infection.

46. The method according to claim 45, wherein one or more of the symptoms associated with PASC persist for at least 2 months after (SARS)-CoV-2 infection.

47. The method according to claim 46, wherein one or more of the symptoms associated with PASC persist for about 8-12 weeks after (SARS)-CoV-2 infection.

48. The method according to claim 46, wherein one or more symptoms associated with PASC persist for about 3 - 18 months after (SARS)-CoV-2 infection.

49. The method according to claim 46, wherein one or more symptoms associated with PASC persist for about 90 days after (SARS)-CoV-2 infection.

50. The method according to claim 46 or 48, wherein one or more symptoms associated with PASC persist for up to about 18 months after (SARS)-CoV-2 infection.

51. The method according to claim 46 or 48, wherein one or more symptoms associated with PASC persist for about 6 months after (SARS)-CoV-2 infection.

52. The method according to claim 43 or 44, wherein one or more symptoms associated with PASC persist after discharge from inpatient care at a hospital, clinic, or other medical facility following hospitalization for (SARS)-CoV-2 infection.

53. The method according to claim 52, wherein one or more symptoms associated with PASC persist for about 60 days after discharge from inpatient care at a hospital, clinic, or other medical facility following hospitalization for (SARS)-CoV-2 infection.

54. The method according to any one of claims 1 to 53, wherein 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 according to claim 54, wherein the PROMIS scale is selected from the PROMIS Sleep Disturbance scale, the PROMIS Fatigue scale, and the PROMIS Cognitive Function scale.

56. The method according to any one of claims 1 to 55, wherein the subject is a human.

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