Cyclobenzaprine treatment for fibromyalgia

Abstract

A method for treating fibromyalgia and one or more of its associated symptoms of pain, sleep disorders, and / or fatigue, comprising administering to a subject in need thereof 5.6 mg cyclobenzaprine HCl per day by transmucosal administration in one or more dosage units, wherein the cyclobenzaprine HCl is in the form of a eutectic, and the one or more dosage units further comprise a basifying agent.

Description

Background Art

[0001] Background Cyclobenzaprine, or 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, was first approved by the US Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin (Katz and Dube, 1988).

[0002] An estimated 6 to 12 million adults in the United States have fibromyalgia, 90% of whom are women. Fibromyalgia is considered a central nervous system disorder and symptoms include chronic widespread pain, nonrestorative sleep, fatigue, impaired cognition, and mood disorders. These symptoms are thought to result from inappropriate pain signaling in the central nervous system in the absence of peripheral injury. Fibromyalgia causes significant impairment in all areas of life, with patients presenting with low levels of health-related quality of life (e.g., reduced daily function and work impairment (e.g., reduced productivity and disability)). Since less than half of fibromyalgia patients currently receive complete relief from the three FDA-approved drugs, there remains an unmet need to treat fibromyalgia. Furthermore, there is substantial off-label use of narcotic analgesics and prescription sleep aids. More than one-third of those diagnosed use prescription opioids as a means of treatment. Cyclobenzaprine HCl, as described in various embodiments of the present disclosure, meets this unmet need and improves pain, sleep quality, and fatigue in subjects suffering from fibromyalgia.

Summary of the Invention

Means for Solving the Problems

[0003] Summary of the Present Disclosure One aspect of the present disclosure provides a method for treating fibromyalgia and one or more of its associated symptoms, particularly pain, sleep disturbances and / or fatigue, the method comprising the step of administering to a subject in need thereto 5.6 mg of cyclobenzaprine HCl per day in one or more dose units by transmucosal administration, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprising a basicizing agent.

[0004] Another aspect of the present disclosure provides a method for treating fibromyalgia and its associated symptoms of pain, sleep disturbance and / or fatigue, the method comprising the step of administering to a subject in need thereto 5.6 mg of cyclobenzaprine HCl per day in one or more dose units by transmucosal administration, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprises a basicizing agent.

[0005] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic may instead be selected from the group consisting of a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic, a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol with a 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. It should be understood that the “cyclobenzaprine HCl eutectic” in the present disclosure refers to either these eutectic or granules.

[0006] In some embodiments of this disclosure, one or more dose units containing the cyclobenzaprine HCl eutectic are two dose units, each dose unit containing 2.8 mg of cyclobenzaprine HCl.

[0007] Another aspect of this disclosure is a multivariate dosing method for treating fibromyalgia and, in particular, one or more of its associated symptoms, pain, sleep disturbances and / or fatigue, in a subject in need thereof, the method being: For approximately two weeks, the subject was given one or more first dose units containing 2.8 mg of cyclobenzaprine HCl daily; and For as long as necessary, administer one or more second doses containing 5.6 mg of cyclobenzaprine HCl to the subject daily. This includes the process of administering the substance via the mucous membrane. Here, the above cyclobenzaprine HCl is in the form of a eutectic, Here, one or more dose units further contain a basicizing agent. Provide a method.

[0008] Another aspect of this disclosure is a multivariate dosing method for treating fibromyalgia and its associated symptoms of pain, sleep disturbances and / or fatigue in subjects in need thereof, the method being: For approximately two weeks, the subject was given one or more first dose units containing 2.8 mg of cyclobenzaprine HCl daily; and For as long as necessary, daily, the subject is given one or more second dose units containing 5.6 mg of cyclobenzaprine HCl. This includes the process of administering the substance via the mucous membrane. The first or more of the above-mentioned second dose units are administered after a two-week period of administration of the first or more of the above-mentioned first dose units. Here, the above cyclobenzaprine HCl is in the form of a eutectic, Here, one or more dose units further contain a basicizing agent. Provide a method.

[0009] Another aspect of this disclosure is a multivariate dosing method for treating fibromyalgia and its associated symptoms of pain, sleep disturbances and / or fatigue in subjects in need thereof, the method being: For approximately two weeks, the subject was given one or more first dose units containing 2.8 mg of cyclobenzaprine HCl daily; and For as long as necessary, daily, the subject is given one or more second dose units containing 5.6 mg of cyclobenzaprine HCl. This includes the process of administering the substance via the mucous membrane. The first or more of the above-mentioned second dose units are administered after a two-week period of administration of the first or more of the above-mentioned first dose units. In each of the one or more dose units described above, cyclobenzaprine HCl is in the form of a eutectic containing 75% ± 2% cyclobenzaprine and 25% ± 2% mannitol, and each of the one or more dose units described above further contains a basicizing agent. Provide a method.

[0010] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the first dosage unit may instead be selected from the group consisting of 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 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0011] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the second dosage unit may instead be selected from the group consisting of 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 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0012] In some embodiments, one or more dose units containing the cyclobenzaprine HCl eutectic are administered daily at bedtime.

[0013] In some embodiments, all dose units of the cyclobenzaprine HCl eutectic are administered daily at bedtime.

[0014] In some embodiments, the transmucosal administration includes sublingual, intraoral, intranasal, or palatal administration.

[0015] In some embodiments, the transmucosal administration is performed sublingually.

[0016] In some embodiments, 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, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of several organic acids, bicarbonates, and sulfides.

[0017] In some embodiments, 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, and trisodium citrate.

[0018] In some embodiments, the basifying agent is dipotassium hydrogen phosphate.

[0019] In some embodiments, the mannitol is β-mannitol or δ-mannitol.

[0020] In some embodiments, the mannitol is β-mannitol.

[0021] In some embodiments, the mannitol is δ-mannitol.

[0022] In some embodiments, the method of treatment reduces pain.

[0023] In some embodiments, the pain is measured by the daily diary pain severity score change from the baseline score compared to the placebo group using a numerical rating scale.

[0024] In some embodiments, the pain is reduced by more than 30%.

[0025] In some embodiments, the method of treatment improves the quality of sleep or reduces sleep disorders.

[0026] In some embodiments, the method of treatment reduces fatigue.

[0027] In some embodiments, the subject is a human.

[0028] Another aspect of the present disclosure is a composition for use in treating fibromyalgia and, in particular, one or more of its associated symptoms, pain, sleep disturbances and / or fatigue, the composition being suitable for transmucosal administration and comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% mannitol eutectic, 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic, 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol and 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic, or 65%±2% cyclobenzaprine HCl and 35%±2% The present invention provides a composition in the form of a eutectic containing granules comprising an outer layer of δ-mannitol eutectic and an inner layer of β-mannitol, wherein one or more dose units further comprise a basicizing agent.

[0029] Another aspect of the present disclosure provides a composition for use in treating fibromyalgia and its associated symptoms of pain, sleep disorders and / or fatigue, the composition being suitable for transmucosal administration and comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprising a basicizing agent.

[0030] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic in the above composition for use may instead be selected from the group consisting of a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic, a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol with a 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.

[0031] In some embodiments, the cyclobenzaprine HCl eutectic in the above composition for use comprises 75% ± 2% cyclobenzaprine and 25% ± 2% mannitol eutectic.

[0032] In some embodiments, the compositions of the present disclosure are administered in two dose units, each dose unit containing 2.8 mg of cyclobenzaprine HCl in a eutectic form.

[0033] In some embodiments, the above composition is administered at bedtime.

[0034] In some embodiments, the transmucosal administration includes sublingual, intraoral, intranasal, or palatal administration.

[0035] In some embodiments, the transmucosal administration is sublingual.

[0036] In some embodiments, 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, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of several organic acids, bicarbonates, and sulfides.

[0037] In some embodiments, 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.

[0038] In some embodiments, the basicizing agent is potassium phosphate (dibasic).

[0039] In some embodiments, the mannitol is β-mannitol or δ-mannitol.

[0040] In some embodiments, the mannitol is β-mannitol.

[0041] In some embodiments, the mannitol is δ-mannitol.

[0042] In some embodiments, the associated symptom is pain.

[0043] In some embodiments, the pain is measured using a numerical rating scale, by the change in the daily pain diary severity score from the baseline score compared to the placebo group.

[0044] In some embodiments, the above-mentioned pain is reduced by more than 30%.

[0045] In some embodiments, the above-mentioned related symptom is a sleep disorder. In some embodiments, the associated symptom is fatigue. [Brief explanation of the drawing]

[0046] [Figure 1] Figure 1 shows a graph of the least squares mean change from baseline in the Numerical Rating Scale (NRS) pain score. Pain scores were measured once a week for 14 weeks and compared between the placebo group (N=255) and the cyclobenzaprine HCl group (N=248). [Figure 2] Figure 2 shows the Continuous Responder Analysis (CRA) graph. It shows the percentage of pain responders in the placebo group and the cyclobenzaprine HCl group across the entire range of cutoff points (e.g., 0% to 100%). [Modes for carrying out the invention]

[0047] Detailed explanation This disclosure provides, in some embodiments, methods and compositions for treating fibromyalgia and its associated symptoms of pain, sleep disturbances and fatigue in subjects in need thereof, the compositions being suitable for once-daily transmucosal administration, comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprising a basicizing agent.

[0048] definition The term "as used herein" refers to the entire application.

[0049] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings generally understood by those skilled in the art. In case of any conflict, this specification, including its definitions, shall prevail.

[0050] It should be understood that any of the embodiments described herein, including those described under various aspects and parts of this disclosure (including embodiments described only in the Examples), may be combined with one or more other embodiments of this disclosure unless expressly abandoned or inappropriate. The combinations of embodiments are not limited to those specific combinations claimed through a number of dependent claims.

[0051] All publications, patents, and published patent applications referenced herein are incorporated herein by reference. In case of any conflict, this specification shall prevail, including their specific definitions.

[0052] Throughout this specification, variations of the phrase such as “comprise,” “comprises,” or “comprising” are understood to indicate the inclusion of the integer (or component) or group of integers (or components) mentioned, but not the exclusion of any other integer (or component) or group of integers (or components).

[0053] The term "including," as used herein, means "including but not limited to." "Including" and "including but not limited to" are interchangeable. Therefore, it is understood that these terms imply the inclusion of the integers (or components) or groups of integers (or components) mentioned, but not the exclusion of any other integers (or components) or groups of integers (or components).

[0054] As used herein, the term “about” refers to a value or parameter that includes (and describes) embodiments relating to that value or parameter itself. For example, a statement referring to “about X” includes a statement of “X.” As used herein, the term “about” allows for a variation of ±10% within its range of significant figures.

[0055] Any examples following the term "e.g." or "for example" are not necessarily exhaustive or limiting.

[0056] Unless otherwise specified by the context, singular terms shall include their plural forms, and plural terms shall include their singular forms.

[0057] The articles “a” (one, a), “an” (one, a), and “the” (above, this, that) are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the articles.

[0058] Although the numerical ranges and parameters disclosed are approximate, the numbers shown in the specific examples are reported as accurately as possible. However, any number inherently contains a certain degree of error that inevitably arises from the standard deviation found in each of those test measurements. Furthermore, it should be understood that all ranges disclosed herein encompass any and all subranges contained therein. For example, the stated range "1 to 10" should be considered to encompass any and all subranges between the minimum value of 1 and the maximum value of 10 (and including both ends); that is, all subranges starting with the minimum value of 1 or a value greater than 1 (e.g., 1 to 6.1) and ending with the maximum value of 10 or a value less than 10 (e.g., 5.5 to 10).

[0059] Where aspects and embodiments are described in terms of the Markush Group or other grouping of options, the application encompasses not only the entire enumerated group as a whole, but also each member of that group, each of its principal groups and all possible subgroups, as well as its principal group lacking one or more of its members.

[0060] While exemplary methods and materials are described herein, similar or equivalent methods and materials may also be used in the implementation or testing of various aspects and embodiments. These materials, methods, and examples are illustrative and not intended to be limiting.

[0061] To make this disclosure easier to understand, certain terms are first defined. These definitions should be read and understood in light of the rest of this disclosure as they would be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be generally understood by those skilled in the art. Further definitions are given throughout the detailed description.

[0062] As used herein, the terms “to treat” and its cognates refer to the complete or partial improvement or regulation of fibromyalgia or at least one recognized symptom therein. In some embodiments, “to treat” refers to pain reduction. In some embodiments, “to treat” refers to improvement in pain score as a symptom associated with fibromyalgia, i.e., pain reduction. In some embodiments, “to treat” refers to sleep disturbance reduction. In some embodiments, “to treat” refers to improvement in sleep quality. In some embodiments, “to treat” refers to fatigue reduction. In some embodiments, “to treat” refers to “much improved” or “very much improved” in the context of these associated symptoms.

[0063] In embodiments of this disclosure, the cyclobenzaprine HCl eutectic is administered together with a basicizing agent. See, for example, WO2013 / 188847 (incorporated herein by reference).

[0064] The “basifying agent” included in some embodiments of this disclosure 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 several organic acids (including bicarbonates), and sulfides. In some embodiments, the basicizing agent is potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2PO4) or dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K2HPO4). In some embodiments, the basicizing agent is a component (and excipient) in the tablet, and the basicizing agent exerts its effect while the tablet is dispersed in the mucous substance, while a portion of the formulation remains in the mucous substance after the tablet has dissolved and remains dissolved for a certain period of time. Dipotassium hydrogen phosphate (K2HPO4) is a basicizing agent that has a particular effect on cyclobenzaprine HCl. Another basicizing agent that has a particular effect on cyclobenzaprine HCl is potassium dihydrogen phosphate (KH2PO4). Another basicizing agent that has a particular effect on cyclobenzaprine HCl is disodium hydrogen phosphate (Na2HPO4). Another basicizing agent that has a particular effect on cyclobenzaprine HCl is tripotassium citrate. Another basicizing agent that has a specific effect on cyclobenzaprine HCl is trisodium citrate.

[0065] In some embodiments, the cyclobenzaprine HCl eutectic of the present disclosure is selected from the group consisting of one of the eutectic or granules referred to in paragraph

[0005] above. In some embodiments of the present disclosure, the cyclobenzaprine HCl is in the form of a 75% ± 2% cyclobenzaprine HCl and a 25% ± 2% mannitol eutectic. In some embodiments of the present disclosure, the cyclobenzaprine HCl is in the form of a 75% ± 2% cyclobenzaprine HCl and a 25% ± 2% β-mannitol eutectic. See, for example, WO2014 / 145156 (incorporated herein by reference).

[0066] As used herein, the terms “eutectic” or “in eutectic form” mean 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 eutectic elements 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. Because eutectic elements enhance dissolution, they can be used to increase permeability in solid dispersions and dispersion systems.

[0067] Any suitable transmucosal administration route may be used to provide the subjects with the dosage units of the Disclosure. Transmucosal administration, including sublingual, intraoral, intranasal, and palatal administration, may be used where appropriate. In some embodiments, the dosage form is a sublingual tablet, sublingual film, liquid, sublingual powder, or sublingual spray.

[0068] Methods for treatment In some embodiments, the present disclosure provides a method for treating fibromyalgia and its associated symptoms of pain, sleep disturbances and / or fatigue, the method comprising the step of administering to a subject in need thereto 5.6 mg of cyclobenzaprine HCl per day in one or more dose units by transmucosal administration, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprising a basicizing agent. In some embodiments, the cyclobenzaprine HCl eutectic is a eutectic of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol.

[0069] In some other embodiments, the cyclobenzaprine HCl is in the form of a eutectic selected from the group consisting of 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 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. In some embodiments, the eutectic is a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments, the cyclobenzaprine HCl eutectic is a mixture of a 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic and a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments, the cyclobenzaprine HCl eutectic is a granule comprising an outer layer of 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0070] In some embodiments, the cyclobenzaprine HCl eutectic is administered in one or more dose units. In some embodiments, the cyclobenzaprine HCl eutectic is administered in two dose units. In some embodiments, the cyclobenzaprine HCl eutectic is administered in two dose units, each dose unit containing 2.8 mg of cyclobenzaprine HCl.

[0071] In another context, a multivariate dosing method for treating fibromyalgia and, in particular, one or more of its associated symptoms, pain, sleep disturbances and / or fatigue, in a subject in need thereof, wherein the method is For approximately two weeks, the above subjects were administered 2.8 mg of cyclobenzaprine HCl in one or more units of the first dose daily; and For as long as necessary, administer 5.6 mg of cyclobenzaprine HCl daily to the subject in one or more second dose units. This includes the process of administering the drug via the mucous membrane. Here, the above cyclobenzaprine HCl is in the form of a eutectic, Here, one or more dose units as described above further include a basicizing agent. This is disclosed herein.

[0072] In another context, a multivariate dosing method for treating fibromyalgia and its associated symptoms of pain, sleep disorders and / or fatigue in subjects in need thereof, wherein the method is For approximately two weeks, the above subjects were administered 2.8 mg of cyclobenzaprine HCl in one or more units of the first dose daily; and For as long as necessary, administer 5.6 mg of cyclobenzaprine HCl daily to the subject in one or more second dose units. This includes the process of administering the drug via the mucous membrane. The first or more of the above-mentioned second dose units are administered after a two-week period of administration of the first or more of the above-mentioned first dose units. Here, the above cyclobenzaprine HCl is in the form of a eutectic, Here, one or more dose units of the above further include a basicizing agent. A method is disclosed herein.

[0073] In some embodiments, the cyclobenzaprine HCl of the first dosage unit is in the form of a eutectic containing 75% ± 2% cyclobenzaprine and 25% ± 2% mannitol. In some embodiments, the cyclobenzaprine HCl of the second dosage unit is in the form of a eutectic containing 75% ± 2% cyclobenzaprine and 25% ± 2% mannitol.

[0074] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the first dosage unit may instead be selected from the group consisting of 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 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the first dosage unit is a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the first dosage unit is a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol and 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the first dosage unit is a granule comprising an outer layer of 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0075] In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the second dosage unit may instead be selected from the group consisting of 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 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the second dosage unit is a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the second dosage unit is a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol and 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic. In some embodiments of the present disclosure, the cyclobenzaprine HCl eutectic of the second dosage unit is a granule comprising an outer layer of 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0076] In another context, a multivariate dosing method for treating fibromyalgia and its associated symptoms of pain, sleep disorders and / or fatigue in subjects in need thereof, wherein the method is For approximately two weeks, the above subjects were administered 2.8 mg of cyclobenzaprine HCl in one or more units of the first dose daily; and For as long as necessary, administer 5.6 mg of cyclobenzaprine HCl daily to the subject in one or more second dose units. This includes the process of administering the drug via the mucous membrane. The first or more of the above-mentioned second dose units are administered after a two-week period of administration of the first or more of the above-mentioned first dose units. In each of the one or more dose units mentioned above, cyclobenzaprine HCl is in the form of a eutectic containing 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and each of the one or more dose units mentioned above further contains a basicizing agent. A method is disclosed herein.

[0077] In some embodiments, the one or more second dose units are administered after the administration of the one or more first dose units.

[0078] In some embodiments, one or more of the dosage units containing the cyclobenzaprine HCl eutectic are administered at bedtime. In some embodiments, all of the dosage units containing the cyclobenzaprine HCl eutectic are administered daily at bedtime.

[0079] In some embodiments, transmucosal administration includes sublingual, intraoral, intranasal, or palatal administration. In some embodiments, transmucosal administration includes sublingual administration. In some embodiments, transmucosal administration includes intraoral administration. In some embodiments, transmucosal administration includes intranasal administration. In some embodiments, transmucosal administration includes palatal administration.

[0080] In some embodiments, the dosage form is a sublingual tablet, a sublingual film, a liquid, a sublingual powder, or a sublingual spray. In some embodiments, the dosage form is a sublingual tablet. In some embodiments, the dosage form is a sublingual film. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a sublingual powder. In some embodiments, the dosage form is a sublingual spray.

[0081] In some embodiments, 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, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of several organic acids (including bicarbonates), and sulfides. In some embodiments, 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. In some embodiments, the basicizing agent is potassium dihydrogen phosphate. In some embodiments, the basicizing agent is dipotassium hydrogen phosphate. In some embodiments, the basicizing agent is tripotassium phosphate. In some embodiments, the basicizing agent is sodium carbonate. In some embodiments, the basicizing agent is sodium bicarbonate. In some embodiments, the basicizing agent is calcium carbonate. In some embodiments, the basicizing agent is calcium bicarbonate. In some embodiments, the basicizing agent is TRIS buffer. In some embodiments, the basicizing agent is sodium dihydrogen phosphate. In some embodiments, the basicizing agent is disodium hydrogen phosphate. In some embodiments, the basicizing agent is trisodium phosphate. In some embodiments, the basicizing agent is potassium carbonate. In some embodiments, the basicizing agent is potassium bicarbonate.In some embodiments, the basicizing agent is potassium acetate. In some embodiments, the basicizing agent is sodium acetate. In some embodiments, the basicizing agent is dipotassium citrate. In some embodiments, the basicizing agent is tripotassium citrate. In some embodiments, the basicizing agent is disodium citrate and trisodium citrate.

[0082] In some embodiments, the mannitol is β-mannitol or δ-mannitol. In some embodiments, the mannitol is β-mannitol. In some embodiments, the mannitol is δ-mannitol.

[0083] In some embodiments, the treatment reduces pain-related symptoms. In some embodiments, the treatment significantly reduces pain. In some embodiments, pain is measured using a numerical rating scale by the change in daily pain diary severity score from baseline compared to the placebo group. In some embodiments, pain is reduced by more than 30%.

[0084] In some embodiments, the treatment reduces sleep quality-related symptoms or reduces sleep disorders. In some embodiments, the treatment significantly improves sleep quality or reduces sleep disorders.

[0085] In some embodiments, the above treatment reduces fatigue-related symptoms. In some embodiments, the above treatment significantly reduces fatigue.

[0086] In another context, a composition for use in treating a subject considered to have fibromyalgia and its associated symptoms of pain, sleep disturbance and / or fatigue is disclosed herein, the composition being suitable for transmucosal administration and comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol, and the one or more dose units further comprising a basicizing agent.

[0087] In another context, a composition for use in treating a subject considered to have fibromyalgia and, in particular, one or more of its associated symptoms, pain, sleep disturbances and / or fatigue, is disclosed herein, the composition being suitable for transmucosal administration, comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol, and the one or more dose units further comprising a basicizing agent.

[0088] Another aspect of the present disclosure is a composition for use in treating subjects believed to have fibromyalgia and its associated symptoms of pain, sleep disturbances and / or fatigue, the composition being suitable for transmucosal administration and comprising 5.6 mg cyclobenzaprine HCl in one or more dose units, wherein the cyclobenzaprine HCl is in the form of a eutectic comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol, and the one or more dose units further comprising a basicizing agent.

[0089] In some embodiments, compositions for use in treating subjects believed to have fibromyalgia and its associated symptoms of pain, sleep disorders and / or fatigue, which are suitable for transmucosal administration, are disclosed herein, comprising 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic. In some embodiments, compositions for use in treating subjects believed to have fibromyalgia and its associated symptoms of pain, sleep disorders and / or fatigue, which are suitable for transmucosal administration, are disclosed herein, comprising a mixture of 75% ± 2% cyclobenzaprine HCl and 25% ± 2% β-mannitol and 65% ± 2% cyclobenzaprine HCl and 35% ± 2% δ-mannitol eutectic. In some embodiments, compositions for use in treating subjects believed to have fibromyalgia and its associated symptoms of pain, sleep disturbances and / or fatigue are disclosed herein, the compositions being suitable for transmucosal administration and comprising granules having an outer layer of 65% ± 2% cyclobenzaprine HCl and a 35% ± 2% δ-mannitol eutectic and an inner layer of β-mannitol.

[0090] In some embodiments, the associated symptoms are pain, sleep disturbances, and / or fatigue. In some embodiments, the associated symptom is pain. In some embodiments, the associated symptom is sleep disturbances. In some embodiments, the associated symptom is pain. In some embodiments, the associated symptom is fatigue. [Examples]

[0091] Examples Example 1. Test Design A randomized, double-blind, placebo-controlled trial was conducted in patients with fibromyalgia at 39 locations in the United States with a total sample size of N=503. Subjects were randomized in a 1:1 ratio. The placebo-comparative arm (N=255) received a placebo once daily at bedtime, while the experimental arm (N=248) received 5.6 mg cyclobenzaprine HCl once daily at bedtime in two dose units administered via mucosal administration (the cyclobenzaprine HCl was in the form of a eutectic containing 75%±2% cyclobenzaprine HCl and 25%±2% mannitol, with each dose unit further containing a basicizing agent). All subjects received one tablet of either 2.8 mg cyclobenzaprine HCl or placebo for the first two weeks as described above. This was increased over the remaining 12 weeks to two tablets of 2.8 mg cyclobenzaprine HCl (total 5.6 mg) or two placebo tablets, as described above. The primary endpoint of the above study was 14 weeks, at which point 82.3% of the experimental arm and 83.5% of the placebo arm completed the study.

[0092] Example 2. Primary and Secondary Endpoints The primary outcome measure of mean pain score at week 14 was measured using a numerical rating scale (NRS) by the mean weekly change from baseline in daily pain diary severity score (cyclobenzaprine HCl vs. placebo). The mean weekly change from baseline in daily pain diary severity NRS score for the experimental arm (mean LS [SE]: -1.9 [0.12] units) versus placebo (-1.5 [0.12] units) was analyzed using mixed model repeated measures analysis with multiple imputation (MMRM with MI) (mean LS [SE] difference: -0.4 [0.16] units, p=0.010). Pain improved in the experimental arm compared to the placebo group at week 14 and throughout the duration of the 14-week trial (Figure 1, Table 1, and Table 2). Daily pain diaries were also analyzed using continuous responder analysis (CRA). This involved measuring the proportion of respondents across a range of cutoff points for the percentage of pain respondents (e.g., 0% to 100%) (Figure 2). Statistical analysis showed a 30% or higher reduction in pain, with 30% responder analysis showing 46.8% in the experimental arm and 34.9% in the placebo arm (logistic regression; odds ratio [95% CI]: 1.67 [1.16, 2.40]; p=0.006) (Figure 2). From the higher proportion in the experimental arm, an improved reduction in pain was shown compared to the placebo group at all cutoff points up to >=95%. [Table 1] [Table 2]

[0093] Key secondary endpoints at week 14 included (1) changes in patient overall impression (PGIC) (responder analysis); (2) Fibromyalgia Impression Scale-Revised (FIQ-R) symptom domain scores (mean change); (3) FIQ-R functional domain scores (mean change); (4) PROMIS Sleep Disturbance instrument T-score (mean change); (5) PROMIS Fatigue instrument T-score (mean change); and (6) daily NRS diary assessment of sleep quality (mean change) (Table 2). Responder analysis of PGIC showed a tendency for a higher proportion of respondents to be in the cyclobenzaprine HCl unit group (37.5%) compared to the placebo group (29.4%) (rated as "very improved" or "greatly improved" at week 14). The results were not statistically significant (logistic regression; odds ratio [95% CI]: 1.44 [0.99, 2.10]; p=0.058). PGIC is a general measure of patient self-reported benefit not linked to any specific symptom of fibromyalgia.

[0094] The experimental arm showed nominal improvement in sleep (Table 2). Sleep quality diary assessments with cyclobenzaprine HCl dose units (-2.0 [0.12] units) compared to placebo (-1.5 [0.12] units) were nominally significant (LS mean difference: -0.6 [0.17] units; p<0.001). For the PROMIS sleep disorder meter, the experimental arm was also nominally significant over the placebo arm with respect to the T score (LS mean difference: -2.9 [0.82] units; p<0.001). The effect sizes for sleep diary assessments and the PROMIS sleep disorder meter were 0.31 and 0.32, respectively. The experimental arm also showed nominal improvement over placebo with respect to the PROMIS fatigue meter T score (-1.8 [0.76] units; p=0.018). The syndromeal activity of cyclobenzaprine HCl doses was tested using the Fibromyalgia Impression Questionnaire-R (FIQ-R). The experimental arm showed nominal improvement over the placebo arm in both the symptom domain (-4.3 [1.60] units; p=0.007) and the functional domain (-4.4 [1.69] units; p=0.009).

[0095] Example 3. Safety Results The cyclobenzaprine HCl dose units of this disclosure were well tolerable. In the experimental arms, the most commonly reported adverse events were infusion site reactions, including tongue / oral numbness, tongue / oral pain and / or discomfort, dysgeusia, and tongue / oral burning, which were more frequent in the experimental arms than in the placebo arms (Table 3). Tongue / oral numbness or burning and dysgeusia were local effects that were time-related to dose administration and transient (<60 minutes) in most cases. The only adverse event occurring under systemic treatment, occurring in 5.0% or higher of each arm, was somnolence / sedation in 5.6% of the experimental arms, which was consistent with known side effects of oral cyclobenzaprine on the market. Adverse events resulted in early study discontinuation in 8.9% of those receiving cyclobenzaprine HCl dose units compared to 3.9% in placebo recipients. A total of seven serious adverse events occurred in the trial, none of which were considered to be related to the study drug; five in the placebo arm and two in the experimental arm. Of the two events in the experimental arm, one was a car accident with multiple fractures, and the other was pneumonia secondary to an infection. [Table 3]

[0096] Example 4. More detailed analysis of adverse events that occurred under treatment. A more detailed analysis of adverse events is reported in Table 4. In the experimental arm, oral adverse events were commonly reported treatment-related adverse events (TEAEs), including hypoaesthesia (oral), paresthesia (oral), dysgeusia, glossodynia, and dry mouth, and these were more frequent in the experimental arm than in the placebo arm. The incidence of oral TEAEs was 40.7% in the cyclobenzaprine HCl dose group and 9.0% in the placebo group. Oral hypoaesthesia was the most common adverse event and was never considered serious, but it resulted in only one discontinuation. Sedation and fatigue were the only systemic treatment-related adverse events and occurred in 3.6% of participants in the experimental arm. Adverse events resulted in early study discontinuation in 8.9% of those receiving cyclobenzaprine HCl doses compared to 3.9% in the placebo recipients. [Table 4]

Claims

1. A combination for use in the treatment of fibromyalgia and one or more of its associated symptoms selected from the group consisting of pain, sleep disorders or fatigue in a subject in need of such treatment, said combination comprising a total of 5.6 mg cyclobenzaprine HCl in one or more separate dosage units, each of said one or more dosage units suitable for transmucosal administration, said cyclobenzaprine HCl being selected from the group consisting of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic by weight, 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol with 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, and 65%±2% cyclobenzaprine HCl and granules comprising an outer layer of 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol, each of said one or more dosage units further comprising a basifying agent.

2. A combination for use in the treatment of fibromyalgia and one or more of its associated symptoms selected from the group consisting of pain, sleep disorders or fatigue in a subject in need of such treatment, said combination comprising 2.8 mg cyclobenzaprine HCl in one or more separate dosage units, each of said one or more dosage units suitable for transmucosal administration, said cyclobenzaprine HCl being selected from the group consisting of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic by weight, 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic by weight with 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, or 65%±2% 1. A combination in the form of a eutectic comprising granules comprising an outer layer of cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol, each of said one or more dosage units further comprising a basifying agent.

3. 3. The combination of claim 1 or 2, wherein the cyclobenzaprine HCl eutectic comprises, by weight, 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic.

4. 2. The combination of claim 1, wherein the one or more dosage units containing cyclobenzaprine HCl eutectic are two dosage units, each dosage unit containing 2.8 mg of cyclobenzaprine HCl.

5. The combination of claim 2, wherein the one or more dosage units containing the cyclobenzaprine HCl eutectic are one dosage unit, each dosage unit containing 2.8 mg of cyclobenzaprine HCl.

6. The combination of claim 1 or 2, 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, borates, hydroxides, silicates, nitrates, dissolved ammonia, bicarbonates, and sulfides.

7. The combination of claim 6, wherein the basifying agent is dipotassium hydrogen phosphate.

8. The combination of claim 1 or 2, wherein each of the one or more dosage units is suitable for administration at bedtime.

9. The combination described in claim 1 or 2, wherein the transmucosal administration includes sublingual, buccal, nasal or palatal administration.

10. The combination described in claim 9, wherein the transmucosal administration is sublingual administration.

11. A combination as described in claim 1 or 2, wherein the symptom associated with fibromyalgia is pain.

12. The combination of claim 11, which reduces the pain by more than 30%.

13. The combination described in claim 12, wherein the reduction in pain is measured by daily pain diary numeric rating scale severity score change from baseline score.

14. A combination according to claim 1 or 2, wherein the symptom associated with fibromyalgia is a sleep disorder.

15. The combination of claim 14, which reduces the sleep disorder or improves sleep quality.

16. A combination as described in claim 1 or 2, wherein the symptom associated with fibromyalgia is fatigue.

17. The combination of claim 16, which reduces fatigue.

18. The combination described in claim 1 or 2, wherein the subject is a human.

19. A combination for use in the treatment of fibromyalgia and one or more of its associated symptoms selected from the group consisting of pain, sleep disorders or fatigue in a subject in need thereof, said combination comprising: (1) one or more first dosage units containing a total of 2.8 mg of cyclobenzaprine HCl and a basifying agent; and (2) one or more second dosage units containing a total of 5.6 mg of cyclobenzaprine HCl and a basifying agent; each of the one or more first dosage units and each of the one or more second dosage units are suitable for transmucosal administration; wherein the cyclobenzaprine HCl is in the form of a eutectic selected from the group consisting of a 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol eutectic by weight, a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, a mixture of 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol by weight with a 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight, and a granule comprising an outer layer of 65%±2% cyclobenzaprine HCl and 35%±2% δ-mannitol eutectic by weight and an inner layer of β-mannitol.

20. 20. The combination of claim 19, wherein the cyclobenzaprine HCl of the one or more first dosage units and the cyclobenzaprine HCl of the one or more second dosage units are in the form of a eutectic comprising 75%±2% cyclobenzaprine HCl and 25%±2% β-mannitol by weight.

21. The combination of claim 19 or 20, 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, borates, hydroxides, silicates, nitrates, dissolved ammonia, bicarbonates, and sulfides.

22. The combination of claim 21, wherein the basifying agent is dipotassium hydrogen phosphate.

23. The combination of claim 19 or 20, wherein each of the one or more first dosage units and each of the one or more second dosage units are suitable for administration at bedtime.

24. 21. The combination of claim 19 or 20, wherein the transmucosal administration comprises sublingual, buccal, nasal or palatal administration.

25. 25. The combination of claim 24, wherein the transmucosal administration is sublingual administration.

26. The combination of claim 19 or 20, wherein the symptom associated with fibromyalgia is pain.

27. The combination described in claim 26, which reduces the pain by more than 30%.

28. The combination described in claim 26, wherein the reduction in pain is measured by daily pain diary numeric rating scale severity score change from baseline score.

29. The combination described in claim 19 or 20, wherein the symptom associated with fibromyalgia is a sleep disorder.

30. The combination of claim 29, which reduces the sleep disorder or improves sleep quality.

31. The combination described in claim 19 or 20, wherein the symptom associated with fibromyalgia is fatigue.

32. The combination of claim 31, which reduces fatigue.

33. The combination of claim 19 or 20, wherein the subject is a human.

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