NZ730379B2 - Eutectic formulations of cyclobenzaprine hydrochloride - Google Patents

Abstract

The present invention relates to pharmaceutical compositions and methods of manufacturing the same, comprising a eutectic of Cyclobenzaprine HCl and mannitol, more specifically the invention relates to a eutectic comprising 65%+/-2% Cyclobenzaprine HCl by weight and 35%+/-2% d-mannitol by weight.

Description

EUTECTIC FORMULATIONS OF CYCLOBENZAPRINE HYDROCHLORIDE Related Application This application claims priority and bene?t from US. Provisional Patent Application 62/052,238, ?led September 18, 2015, the contents and disclosures of which are hereby orated by reference in their entirety.

Background of the Invention Cyclobenzaprine, or 3-(5H-dibenzo[a,d]cyclohepten-S-ylidene)-N,N— dimethyl-l-propanamine, was ?rst approved by the US. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local .

(Katz, W., et al., Clinical Therapeutics 10:216-228 (1988)). uent studies have shown cyclobenzaprine to also be effective in the treatment of ?bromyalgia syndrome, post-traumatic stress er (PTSD), generalized anxiety disorder and depression. Furthermore, the utility of cyclobenzaprine as an agent for improving the quality of sleep, as a sleep deepener, or for treating sleep disturbances has been investigated. However, while FDA- approved therapeutics address pain and mood, there are currently no FDA- approved treatments that s the disturbed sleep and fatigue associated with algia syndrome. Treatment with enzaprine may be particularly useful in treating sleep bances caused by, exacerbated by, or associated with 2O ?bromyalgia syndrome, prolonged fatigue, chronic fatigue, chronic fatigue syndrome, a sleep disorder, a genic pain disorder, chronic pain me (type II), the administration of a drug, autoimmune disease, stress or anxiety, or for treating an illness caused by or exacerbated by sleep disturbances, and symptoms of such illness. See, for example, U.S. Patent Nos. 6,395,788 and 6,358,944, incorporated herein by reference.

Cyclobenzaprine HCl Active Pharmaceutical Ingredient (or API) is stable in pill, tablet or capsule formulations for oral administration when combined with certain excipients. However, Cyclobenzaprine HCl has slow absorption when ingested by mouth (per oral, or po). To speed absorption, tablets containing Cyclobenzaprine HCl have been formulated in various sublingual (SL) preparations. r, both sublingual and oral formulations can have issues with the stability of the API and the physical compositions themselves, especially when a basifying agent (a chemical compound that increases the pH of solutions after dissolution of Cyclobenzaprine HCl) is present. Therefore, a ition that increases stability of Cyclobenzaprine HCl (with or without the presence of a basifying , and methods of manufacturing such a composition, would be useful.

Summary of the Invention [0004a] In a first aspect of the disclosure, there is provided a pharmaceutical composition comprising a eutectic of 35%±2% by weight d-mannitol and 65%±2% by weight Cyclobenzaprine HCl, wherein the eutectic is part of a granule comprising an inner layer comprising ß-mannitol and an outer layer comprising the eutectic of d-mannitol and Cyclobenzaprine HCl. [0004b] In a second aspect of the disclosure, there is ed a method of manufacturing the pharmaceutical composition of the first aspect, comprising mixing Cyclobenzaprine HCl, mannitol and a t. [0004c] In a third aspect of the sure, there is provided a method of manufacturing the ceutical composition of the first , comprising fluid bed drying Cyclobenzaprine HCl and mannitol in the presence of a solvent. - 2a - Some embodiments of the invention are: 1. A ceutical composition comprising a eutectic of mannitol and Cyclobenzaprine HCl. 2. The pharmaceutical composition of claim 1, comprising 60%-90% Cyclobenzaprine HCl and 40%- 10% mannitol by weight. 3. The pharmaceutical composition of claim 2, comprising amounts of Cyclobenzaprine HCl and mannitol ed from: 60%±2% Cyclobenzaprine HCl and 40%±2% ol, 65%±2% Cyclobenzaprine HCl and 35%±2% mannitol, 70%±2% Cyclobenzaprine HCl and 30%±2% mannitol, 75%±2% Cyclobenzaprine HCl and 25%±2% mannitol, 80%±2% Cyclobenzaprine HCl and 20%±2% [Followed by page 3] mannitol, 85%::2% Cyclobenzaprine HCl and % mannitol, and 90%::2% Cyclobenzaprine HCl and 10%::2% mannitol by weight. 4. The pharmaceutical ition of claim 3, comprising 75%::2% Cyclobenzaprine HCl and 25%::2% mannitol by weight.

. The pharmaceutical composition of any one of claims 1-4, wherein the Cyclobenzaprine HCl:mannitol molar ratio is 1.7620. 1. 6. The pharmaceutical composition of any one of claims 1-5, wherein the enzaprine HCl is micronized Cyclob ine HCl. 7. The ceutical ition of any one of claims 1-6, ?lI‘tl’lCI‘ comprising a basifying agent. 8. The pharmaceutical composition of claim 7, wherein the basifying agent is KzHPO4. 9. The pharmaceutical composition of claim 7, wherein the basifying agent is NazHPO4.

. The pharmaceutical composition of claim 7, wherein the basifying agent is trisodium citrate, ous. l l. The pharmaceutical composition of any one of claims 1-10, wherein said composition comprises granules. 12. The pharmaceutical composition of claim 11, wherein said granules comprise enzaprine and mannitol. 13. The pharmaceutical composition of claim 12, wherein said mannitol is B mannitol and 8 mannitol. 14. The pharmaceutical composition of any one of claims 1 1-13, wherein said granules comprise an inner layer comprising B mannitol and an outer layer comprising the eutectic of mannitol and Cyclobenzaprine HCl . A method ofmanufacturing a eutectic composition of any one of claims 1- 14, sing mixing Cyclob enzaprine HCl and mannitol. 16. The method of claim 15, wherein said mixing is wet granulation mixing. 17. The method of claim 15 or 16, further sing mixing an alcohol with said Cyclobenzaprine HCl and said mannitol. 18. The method of claim 17, wherein said alcohol is methanol. 19. The method of claim 17, wherein said alcohol is ethanol.

. The method of any one of claims 16-19, further comprising drying after said wet granulation. 21. The method of claim 20, wherein said wet granulation and drying are ed one or more times. 22. The method of any one of claims 16-19, further comprising crystallization after said wet granulation. 23. The method of claim 22, wherein said wet granulation and crystallization are repeated one or more times. 24. A method facturing a eutectic composition of any one of claims 1- 14, comprising ?uid bed drying Cyclobenzaprine HCl and mannitol . The method of any one of claims 15-24, wherein the eutectic ition comprises Bmannitol. 26. The method of claim 25, wherein the ition comprises Cyclobenzaprine HCl and the eutectic melts at 143.6:3 °C. 27. The method of any one of claims 15-24, wherein the eutectic composition comprises 8 mannitol. 28. The method of claim 27, wherein the composition comprises Cyclobenzaprine HCl and the eutectic melts at 134 oC::3 OC.

Brief Description of the Drawings Figure 1 depicts an exemplary differential scanning calorimetry (DSC) small peak for the 8 mannitol ic (melting point of 139.75 0C) formed by wet granulation with enzaprine HCl, mannitol, and water.

Figures 2 depicts a differential scanning calorimetry curve of a 8 mannitol eutectic formed by dissolving cyclobenzaprine and mannitol in a mixture of methanol and water, followed by rapid evaporation.

Figure 3 depicts an x-ray powder diffraction n of a 8 ol eutectic formed by dissolving cyclobenzaprine and mannitol in a mixture of methanol and water, followed by rapid evaporation.

Figure 4 depicts X-ray powder diffraction data for a 8 mannitol eutectic formed by dissolving cyclobenzaprine and mannitol in a mixture of methanol and water, followed by rapid evaporation.

Figure 5 depicts X-ray powder diffraction data for a 8 mannitol eutectic formed by freeze drying without annealing.

Figure 6 depicts a phase diagram for a 8 mannitol ic formed by freeze drying without annealing.

Figure 7 s X-ray powder diffraction data for a 8 mannitol eutectic formed by freeze drying with annealing.

Figure 8 depicts a phase diagram for a 8 ol eutectic formed by freeze drying with annealing.

Figure 9 depicts a differential scanning calorimetry curve for a 8 mannitol eutectic formed from a 65% enzaprine : 35% mannitol (w/w) mixture that underwent rapid evaporation in a 1:1 mixture of ol:water.

Figure 10 depicts differential scanning calorimetry data for a cyclobenzaprine HCl-mannitol mixture that was spray dried with ethanol and water.

Figure 11 depicts X-ray powder diffraction data comparing a cyclobenzaprine HCl-mannitol mixture that was spray dried with ethanol and water (top) and spray drying with water alone (bottom).

Detailed Description of the Invention Unless otherwise de?ned herein, scienti?c and technical terms used in this application shall have the meanings that are ly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, pharmacology, cell and tissue culture, molecular y, cell and cancer biology, neurobiology, neurochemistry, virology, logy, microbiology, genetics and protein and nucleic acid chemistry, described , are those well known and commonly used in the art.

The methods and techniques of the present invention are generally performed, unless otherwise indicated, according to conventional s well known in the art and as described in various general and more speci?c references that are cited and discussed throughout this speci?cation.

Chemistry terms used herein are used according to conventional usage in the art, as i?ed by “The McGraw-Hill Dictionary of Chemical Terms”, Parker 8., Ed., -Hill, San Francisco, CA. .

All of the above, and any other publications, patents and published patent applications referred to in this application are speci?cally incorporated by reference herein. In case of con?ict, the present speci?cation, including its speci?c de?nitions, will control.

[0021] Throughout this speci?cation, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other r (or components) or group of integers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.

The term “including” is used to mean ding but not limited to.” “Including” and “including but not limited to” are used interchangeably.

A “patien ”, ct”, or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e. g., canines, felines, etc.) and rodents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtain bene?cial or desired results, including al results. Bene?cial or d clinical results include, but are not limited to, ation or amelioration of one or more symptoms associated with a disease or condition as bed herein.

“Administering” or “administration of ’ a substance, a compound or an agent to a subject can be carried out using one of a variety of s known to those skilled in the art. For example, a compound or an agent can be administered sublingually or intranasally, by inhalation into the lung or rectally. Administering can also be performed, for example, once, a ity of times, and/or over one or more extended periods. In some s, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used , a ian who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the t.

In solid drug product formulation, the knowledge ofpossible interactions between the drug substance and the excipients is a crucial point for the prediction of chemical and physical stability.

Very often the excipients can modify the biological activity and chemical stability of the API because the dissolution or chemical structures are changed. In some cases, the ent can improve the chemical ity pro?le over time and avoid undesirable physical behavior of the ?nal dosage form.

A eutectic system is a mixture of chemical compounds or elements that has a single al composition that melts at a lower temperature than any other composition made up of the same ingredients. A composition comprising a eutectic is known as the eutectic ition and its g temperature is known as the eutectic temperature. To de?ne a eutectic ition, a binary phase diagram should be built by analyzing different compounds ratios.

The effect of a eutectic on tablet properties shows that compaction provides the te contact and mutual lity sufficient for eutectic formation. Eutectic compositions often have higher stability and/or dissolution rates than their non-eutectic counterparts. Because eutectics enhance dissolution, they can be employed to increase permeability in solid dispersions and dispersion systems. However, in the pment of certain tab leted dosage forms, undesired eutectic ion g cturing operation such as wet granulation), can lead to unwanted changes in physical or chemical teristics of the tablet, such as low eutectic melting temperature, sticking, unpredictable hardness, instability or dif?culties in accelerated assessment of stability.

Mannitol and Sorbitol are excipients commonly used in solid drug products. Mannitol and Sorbitol are 6-carbon sugar alcohols isomers. Sugar alcohols are hydrogenated carbohydrates whose carbonyl group has been reduced to a primary or secondary hydroxyl group. Other 6-carbon sugar alcohols include lnositol, Galactitol, Fucitol, and lditol.

Although Mannitol and Sorbitol can be included in pharmaceutical compositions, it is typically because they provide qualitative bene?ts such as sweet taste or a cooling effect in the mouth, but are physically inert. Thus, it was sing to discover that mannitol formed a eutectic composition with Cyclobenzaprine HCl that resulted in tablets that had pharmaceutically acceptable stability even with a basifying agent. By contrast, sorbitol dissolved 3O Cyclobenzaprine HCl upon heating (in a Differential Scanning Calorimetry apparatus), did not form a eutectic, and resulted in s that disintegrated at room temperature with a basifying agent; underscoring the unpredictability of eutectic formation and the protective effect of the eutectic formed with mannitol.

Without wishing to be bound by , it is possible that the two crystal lattices of mannitol and Cyclobenzaprine HCl co-penetrate and that this co-penetrating physical state provides protection of the enzaprine HCl from hydration and other chemical interactions.

Compounds The compound use?il in embodiments of the present invention is Cyclobenzaprine HCl. In some embodiments, the compound is micronized. In ative ments, the compound is not micronized. In some embodiments, the compound may be present in one or more crystal isoforms.

As used herein, “Cyclobenzaprine HCl” refers to the pharmaceutically able cyclobenzaprine hydrochloride salt of cyclobenzaprine.

Eutectic compositions In some embodiments, the ion provides a ceutical composition comprising a eutectic mixture of ol and an active pharmaceutical ingredient. In certain embodiments, the active pharmaceutical ingredient is Cyclobenzaprine HCl.

[0036] In some embodiments, the invention provides a pharmaceutical composition comprising a eutectic mixture of mannitol and Cyclob enzaprine HCl, e. g., a B mannitol eutectic, a 8 mannitol eutectic, or a combination thereof In certain embodiments (for example, when the composition comprises a B mannitol eutectic), the ic has a melting ature of 143.623 0C. In certain embodiments, a melting temperature of the eutectic is approximately 135.6 0C, 136.6 0C, 137.6 0C, 138.6 0C, 139.6 0C, 140.6 0C, 141.6 0C, 142.6 0C, 143.6 0C, 144.6 0C, 145.6 0C, 146.6 0C, 147.6 0C, 148.6 0C, 149.6 0C, 150.6 0C, 151.6 0C, 152.6 0C, or 153.6 °C. In certain embodiments (for example, when the composition comprises a 8 mannitol eutectic), the eutectic has a melting temperature of 13423 0C. In certain embodiments (for example, when the composition comprises a 8 mannitol eutectic), a melting temperature of the eutectic is approximately 124 0C, 125 0C, 126 0C, 127 0C, 128 0C, 129 0C, 130 0C, 131 0C, 132 0C, 133 0C, 134 0C, 135 0C, 136 0C, 137 0C, 138 0C, 139 0C, 140 0C, 141 0C, 142 0C, 143 0C, or 144 OC. The skilled worker will appreciate that a measured melting temperature may vary based on the apparatus and conditions being used; however, control samples of B and 8 mannitol easily can be used to guish between the melting temperatures of B and 8 ol in a given sample. In particular embodiments, the melting temperature of the eutectic is the temperature at which melting begins. In alternative embodiments, the melting temperature of the eutectic is the temperature at which maximum g is ed. In n embodiments, the composition comprises greater than 5% Cyclobenzaprine HCl and less than 95% mannitol by weight. In certain embodiments, the ition comprises 1%-5% Cyclobenzaprine HCl and 99%-95% ol by weight. In certain embodiments, the composition comprises 5%-10% Cyclobenzaprine HCl and % mannitol by weight. In certain embodiments, the composition comprises 10%-20% Cyclobenzaprine HCl and 90%—80% mannitol by weight. In certain embodiments, the composition ses % Cyclobenzaprine HCl and 90%-10% mannitol by weight, for example, 60%—90% Cyclobenzaprine HCl 2O and 40%-10% mannitol or 70%—80% Cyclobenzaprine HCl and 30%-20% mannitol by weight. Exemplary compositions comprise 60%::2% Cyclobenzaprine HCl and 40%::2% mannitol, % Cyclobenzaprine HCl and 35(V02:2% mannitol, 70%::2% Cyclobenzaprine HCl and 30%::2% ol, 75%::2% Cyclobenzaprine HCl and 25%::2% mannitol, 80%::2% Cyclobenzaprine HCl and 20%::2% mannitol, 85%::2% Cyclobenzaprine HCl and 15%::2% mannitol, and 90%::2% Cyclobenzaprine HCl and 10‘%::2% mannitol by weight. In certain embodiments (e.g., a composition comprising a B ol eutectic), a composition comprises 75%::10% Cyclobenzaprine HCl and 25%::10% mannitol by weight. In certain embodiments, a composition comprises 75%::2% Cyclob enzaprine HCl and 3O 25%::2% mannitol by weight. In n embodiments, a composition comprises 75% Cyclobenzaprine HCl and 25% ol by weight. In certain embodiments (e.g., a composition comprising a 8 mannitol eutectic), a composition comprises 65%::10% Cyclobenzaprine HCl and 0% mannitol by weight. In certain embodiments, a composition comprises 65%::2% Cyclob enzaprine HCl and %::2% mannitol by weight. In certain embodiments, a composition comprises 65% Cyclobenzaprine HCl and 35% mannitol by weight. In certain embodiments, the composition ses Cyclobenzaprine HCl and mannitol in a Cyclobenzaprine HCl:mannitol molar ratio of 1.70201 to 1.8020]. In certain embodiments, the molar ratio is about 1.6 to 2.0. In particular ments, the molar ration is 1.70::0.1, 0.1, 1.72::0.1, 1.73::0.1, 0.1, 1.75:0.1, 1.76::0.1, 1.77::0.1, 1.78:0.1, 1.79:0.1, or 1.80:0.1. In certain embodiments, the molar ratio is 5, 1.65205, 1.70205, 1.75205, 1.80205, 1.85:0.5, 1.90:0.5, 1.95:0.5, or 20:05.

In certain embodiments the molar ratio is 1.76::0. 1. In certain embodiments the molar ratio is 1.76::0.5.

In certain embodiments, additional mannitol is added to the eutectic, e. g., as a diluent or as a component of an explo sant (an agent that facilitates disintegration in the oral caVity, such as Pearlitol® Flash). In these embodiments, the total amount of ol will be higher than the amount of mannitol present in the eutectic as originally formed. For example, when additional ol is added, the composition can comprise approximately 90% by weight, approximately 85% by weight, approximately 80% by weight, approximately 75% by weight, approximately 70% by weight, approximately 65% by , approximately 60% by weight, or approximately 55% by weight of mannitol. An exemplary composition with added mannitol is: (Corresponding Eutectic by Wet Active to 10 mg of Granulation Ingredient Cyclob enzaprine MannitolSD200 PearlitolSD200 442.0 Colloidal Silica Aerosi1200 Fumarate Total Weight 100.0 mg 650.0 g r bene?t of the eutectic compositions of the invention is increased stability of a tablet containing Cyclobenzaprine HCl. In some embodiments, the invention provides a pharmaceutical ition comprising Cyclobenzaprine HCl and mannitol, wherein the composition has an increased stability in tablet form as compared to the same tablet without mannitol, e. g., to a tablet comprising sorbitol but not mannitol. Indeed, a tablet containing Cyclobenzaprine HCl, K2HPO4, and mannitol was stable for three months at 40 oC and 75% relative humidity. By contrast, a tablet containing Cyclobenzaprine HCl, KZHPO4, and ol stored at the same conditions disintegrated before reaching even reaching one week.

In some embodiments, the invention provides a ceutical composition comprising Cyclob enzaprine HCl and mannitol, wherein the ition has an increased dissolution rate of a stable tablet compared to Cyclobenzaprine HCl alone or in a formulation ning one or more excipients that are not basifying agents. For example, the composition at 5 s can exhibit 100%, greater than 95%, greater than 90%, greater than 85%, greater than 80%, greater than 75%, greater than 70%, r than 65%, greater than 60%, greater than 55%, greater than 50%, greater than 45%, greater than 40%, greater than 35%, r than 30%, or greater than 25% dissolution when mixed with 100 mL of50 mM Citrate pH 4 at 37.0 :: 0.5 0C. For example, the composition at 10 minutes can exhibit 100%, greater than 95%, greater than 90%, greater than 85%, r than 80%, greater than 75%, greater than 65%, greater than 60%, greater than 55%, r than 50%, dissolution when mixed with 100 mL of 50 mM Citrate pH 4 at 37.0 :: 0.5 °C. For example, the ition at 240 s can exhibit 100%, greater than 95%, r than 90%, greater than 85%, greater than 80%, greater than 75%, greater than 65%, greater than 60%, greater than 55%, greater than 50%, dissolution when mixed with 100 mL of 50 mM Citrate pH 4 at 37.0 :: 0.5 °C. For very soluble compounds (e.g., Cyclobenzaprine HCl), a continuous ?ow dissolution apparatus can be used to measure dissolution.

Mannitol is e of llizing in three polymorphic states: (X, B, and 8. These three forms can be distinguished by X-ray powder diffraction, and each polymorph has a different melting point. See, e.g., Sharma and Kalonia, AAPS PharmaSciTech 5(1):E10 (2004). Even more sing than the ation of a ?rst eutectic with Cyclobenzaprine HCl and mannitol (B polymorph) was the observation of a second eutectic with a different polymorphic form of mannitol (8 polymorph). The eutectic comprising 8 ol and Cyclob enzaprine HCl (also referred to herein as the “8 mannitol ic”) has several advantages over the eutectic comprising B mannitol and Cyclobenzaprine HCl (also referred to herein as the “B mannitol eutectic”). Prime among these are a lower melting point than the B mannitol eutectic and enhanced dissolution over the B mannitol eutectic.

Another advantage is greater stability in pharmaceutical compositions (including tablets) than the B mannitol eutectic including compositions that contain a basifying agent. Yet another advantage is greater local tolerability in pharmaceutical compositions (including tablets) than the B mannitol eutectic including compositions that contain a basifying agent. Improved dissolution and conversion to enzaprine free base also should improve tolerability, including reduced transient numbing of the tongue during administration of a tablet under the tongue to improve sublingual absorption.

In some ments, the invention provides a ic pharmaceutical composition comprising Cyclob enzaprine HCl and mannitol, wherein the mannitol is in its B polymorphic state. In some embodiments, the invention provides a eutectic pharmaceutical composition comprising Cyclobenzaprine HCl and mannitol, wherein the mannitol is in its 8 polymorphic state. In certain embodiments, the pharmaceutical composition comprising the mannitol in its B polymorphic state is a sublingual composition. In certain ments, the pharmaceutical composition comprising the mannitol in its B polymorphic state is an oral composition. In certain embodiments, the pharmaceutical composition comprising the mannitol in its 8 polymorphic state is a sublingual composition. In certain ments, the pharmaceutical composition comprising the mannitol in its 8 polymorphic state is an oral composition. In particular embodiments wherein the composition is an oral composition, the oral ition is bioequivalent to 5mg Cyclobenzaprine HCl oral tablets (e. g., Flexeril 5mg). In particular ments wherein the composition is an oral composition, the oral composition is bio equivalent to 10mg Cyclobenzaprine HCl oral tablets (e.g., Flexeril 10mg).

Flexeril tablets are composed of hydroxypropyl cellulose, ypropyl methylcellulose, iron oxide, e, magnesium stearate, starch, and titanium dioxide. Dosing 10 mg t.i.d. in normal healthy volunteers, the AUC at steady state (after 4 days of dosing) was 177 ng.hr/mL (range, 80-319 ng.hr/mL) and the Cmax was 25.9 ng/mL (range, 12.8-46.1 ng/mL). Additional pharmacokinetic properties of orally stered Cyclobenzaprine can be found, for example, in Winchell et al., J Clin Pharmacol. 42(1):61-9 (2002) and Hucker et al., J Clin Pharmacol. 17(11-12):719-27 (1977).

In some embodiments, the invention es a composition comprising eutectic of mannitol and Cyclob enzaprine HCl. The d worker will understand that these compositions may be suitable for administration in a variety of ways, such as those bed herein. For example, a composition may be suitable for administration orally (administration n the Cyclobenzaprine is absorb ed in the gastrointestinal tract), or for transmucosal absorption (e.g., sub lingual, buccal, or intranasal absorption, or by inhalation).

In some embodiments, the invention provides a composition that is a granulate composition. In n embodiments, the es are granules comprising cyclobenzaprine HCl and ol. In particular embodiments, the granules comprise an excess of mannitol. In more particular embodiments, the granules comprise Bmannitol, 8 ol, or both. Granules sing an excess of mannitol, in particular, may contain both B mannitol and 8 mannitol. For example, a granule produced by a method such as ?uid bed drying may comprise an inner layer of B mannitol and an outer layer of 8 ol-cyclobenzaprine eutectic.

Methods ofmanufacturing eutectic compositions The d worker will appreciate that a eutectic composition of the invention can be manufactured according to any of a numb er n methods.

In some embodiments, the invention provides methods for producing a eutectic composition of the invention comprising g an API (Cyclob enzaprine HCl) with mannitol, mixing an API (Cyclobenzaprine HCl) with mannitol, or a combination thereof. For example, the API and mannitol can be milled in an agate mortar or mixed in a high shear granulator. High shear mixing combines dry powders using a high speed impellor and chopper blades to mly mix the ingredients. Some particle size reduction is possible due to the shear force and the high speed of the mixing blades. The API and mannitol also can be milled and mixed in, for example, a Turbula® Shaker-Mixer. In certain embodiments, the API and mannitol can be mixed via compression, for e, via roller tion. Roller compaction forces ?ne powders between two counter-rotating rolls and presses the raw materials into a solid compact or sheet (referred to as ?akes). The ?akes are reduced in size until they reach a desired grain size. In certain embodiments, mannitol can be melted and mixed with Cyclobenzaprine HCl to form a eutectic composition. In certain embodiments, the API is a micronized API (e. g., micronized Cyclobenzaprine HCl).

[0045] In some embodiments, the invention provides methods for producing a eutectic composition of the invention comprising spray drying a solution of an API (Cyclobenzaprine HCl) with mannitol. The skilled worker will appreciate that spray drying is routine, and parameters for spray drying can be determined without undue experimentation. For example, spray drying can be performed under any of 3O the following conditions: _ 16 _ T Inlet (0C): 0 T Outlet (0C): 73-90 Feed rate (ml/min): 4-6 Flow Rate (L/h): 600-800 Aspiration (100%): 100 delta Pressure (mbar): 2-20 These conditions also may be scaled up or modi?ed to provide higher throughput manufacturing.

In some embodiments, a composition comprising a 8 mannitol eutectic of cyclobenzaprine HCl and mannitol is produced by mixing mannitol and cyclobenzaprine HCl. This mixing can be, for e, wet granulation, including high shear wet granulation. Figure 1 shows an exemplary differential scanning calorimetry (DSC) small peak for the 8 mannitol eutectic ng point of 139.75 °C) formed by wet granulation with cyclobenzaprine HCl, mannitol, and water.

Wet granulation can be followed by ?uid bed drying, and ally milling, to produce the composition. Without wishing to be bound by theory, during wet granulation it is possible that cyclobenzaprine and mannitol (which starts in its B form) become able and then some or all of the wet edges of B mannitol crystals in the paste formed by wet granulation crystallize into the B and/or 8 mannitol eutectic with Cyclobenzaprine HCl. This may occur as the solvent evaporates and the processes of crystal co-p enetration and re-crystallization into the eutectics s during the mixing phase or the drying phase, either directly or through a metamorphic able amorphous intermediate and sub sequent nucleation with the B and/or 8 ol eutectic. In some ments, wet granulation and drying can be performed in iterative cycles to stimulate or enhance the formation of a 8 ol eutectic. Without wishing to be bound by theory, performing wet granulation and drying in cycles may enhance the formation of a 8 mannitol eutectic because, while an individual cycle may produce a fraction of the total 8 ol ic possible, each cycle helps ate the formation of onal 8 mannitol.

In some embodiments, a composition comprising a 8 ol eutectic of cyclobenzaprine HCl and mannitol is produced by ?uid bed drying (also known as ?uidized bed drying). Without g to be bound by theory, ?uid bed drying may have advantages over other methods of eutectic formation because it provides controlled, gentle and even drying of wet solids. The intensive heat/mass exchange of the ?uidized bed product makes this method particularly ive and time-saving. The technology is also suitable for po st-drying of spray granulated or extruded products with very low residual moisture.

In certain embodiments, ?uid bed drying can be used in the formation of a cyclobenzaprine drug product. The drying process with ?uid bed drying can reduce the drying time in the drying oven approximately twenty- fold over other s. In addition, ?uid bed drying provides controlled and uniform drying conditions compared to potentially uneven drying in trays. Moreover, ?uid bed drying can improve homogeneous distribution of an active pharmaceutical ingredient on the surface of one or more excipients.

Fluid bed drying technology can be used when a liquid solution containing a solubilized drug substance (e.g., cyclobenzaprine HCl) is sprayed on the surface of excipient particles. In this way, the nebulized solution on the excipient particle surfaces creates a positive interaction between the solution and the solid particles. During the drying step under hot air ?ow, water is removed from the surface and the active pharmaceutical ingredient links to the ent particle. In some embodiments, a cyclobenzaprine HCl solution (e.g., cyclobenzaprine HCl and water) is sprayed onto mannitol, forming a ic between the cyclobenzaprine and mannitol. Without wishing to be bound by theory, when a solution of an active pharmaceutical ingredient (e. g., cyclobenzaprine HCl) is spread by a nozzle on the surface, and a eutectic forms, the ic particles may physically interact with particles comprising one or more 3O excipients, creating granules with ble dimensions.

Another advantage of ?uid bed drying is that drying takes place in a thermodynamic equilibrium. The inlet air temperature is ed such that only as much moisture evaporates from the surface of the granulate as is transported through the capillaries from the interior of the granulate to the surface. During this moisture migration, the active pharmaceutical ingredient can link to the substance on which it has been sprayed. For example, when cyclob enzaprine HCl is sprayed onto mannitol, the cyclobenzaprine HCl and ol mix in the correct ratio to form a eutectic, even though there is an excess of mannitol not needed for eutectic formation. Even more surprisingly, this process produced a eutectic of cyclobenzaprine and 8 mannitol even though the mannitol on which the cyclobenzaprine HCl was B mannitol. Properly used, ?uidized bed drying es an efficient solution to create an appropriate e particle size for good tableting with even active pharmaceutical ingredient distribution throughout the tablet and without undesired crumbling.

[0051] In some embodiments, an l is used to stimulate or enhance the formation of a 8 mannitol ic. Exemplary alcohols include, but are not limited to, ethanol, methanol, and isopropanol. In certain embodiments, ethanol is used to stimulate or enhance the formation a 8 mannitol eutectic in combination with spray drying (see Figure 10 for differential scanning calorimetry data and Figure 1 1 for X-ray powder diffraction data comparing spray drying with ethanol and water and spray drying with water alone). For example, a 1:1 ethanol:water mixture with 5% (w/w) of a mixture of cyclob enzaprine and mannitol can be introduced during spray drying to create a 8 mannitol eutectic. In alternative embodiments, ethanol is used to stimulate or e the formation a 8 mannitol eutectic in combination with wet granulation mixing. In yet other ments, l is used to stimulate or enhance the formation a 8 mannitol eutectic in combination with freeze . In still other embodiments, ethanol is used to ate or enhance the formation a 8 mannitol eutectic in combination with rapid evaporation. In still additional embodiments, l is used to stimulate or enhance the formation a 8 3O mannitol eutectic in combination with ?uid bed drying. In certain embodiments, methanol is used to stimulate or enhance the formation a 8 mannitol ic in ation with spray drying. In alternative ments, methanol is used to stimulate or enhance the formation a 8 mannitol eutectic in combination with wet granulation mixing. In yet other embodiments, methanol is used to stimulate or enhance the formation a 8 mannitol eutectic in combination with freeze drying. In still other embodiments, methanol is used to ate or enhance the formation a 8 mannitol eutectic in combination with rapid evaporation. In still additional embodiments, methanol is used to stimulate or enhance the formation a 8 mannitol eutectic in ation with ?uid bed drying. An exemplary protocol for spray drying to obtain a 8 mannitol ic via spray drying with l is as follows: Equipment: Buchi Mini Spry Dryer SD B 290 Ethanol:water t in the ratio 1:1 v/v Cyclobenzaprine:mannitol e (at a ratio of, for example, 65 :35) tration in the solution: 5% w/w Spray drying conditions: Inlet temperature = 150 oC Outlet temperature = 90 °C Solution flow rate =c.a 6 mL/min Delay time before removing the powder from the equipment (requested for the complete recrystallization of the powder distributed on the equipment) = 1-2 hours In some embodiments, a s of rapid evaporation is used to stimulate or enhance the formation of a 8 mannitol eutectic. Rapid evaporation refers to the mixture of cyclobenzaprine HCl and mannitol with a solvent (e.g., water or a mixture of water and an alcohol such as methanol or ethanol) followed by a step in which the solvent is quickly evaporated, e.g., by passing hot air over the solution.

The cyclobenzaprine HCl, mannitol, and water can be mixed to form a paste (as in wet granulation) or can be mixed to form a solution. By way of example, a 65% enzaprine : 35% mannitol (w/w) mixture that has undergone rapid evaporation in a 1 :1 mixture of methanol:water (final concentration of the cyclobenzaprine/mannitol mixture between 5% and 20%) forms a 8 mannitol eutectic after approximately 30 minutes of drying (see Figure 9). See also Figures 2-4 for 8 mannitol eutectic formed by dissolving cyclobenzaprine and mannitol in a mixture ofmethanol and water, followed by rapid evaporation.

In some embodiments, freeze drying is used to stimulate or e the formation of a 8 mannitol eutectic. In certain embodiments, the freeze drying is performed without annealing. See Figures 5 and 6, which show X-ray powder diffraction data and a phase diagram, respectively, for a 8 mannitol eutectic formed by freeze drying t annealing. Although these traces show low crystallinity in the initial composition, after a period of crystallization, 8 mannitol eutectic crystals more clearly . In alternative embodiments, the freeze drying is performed with ing. See Figures 7 and 8, which show X-ray powder diffraction data and a phase diagram, respectively, for a 8 mannitol eutectic formed by freeze drying with annealing. Although these traces show low llinity in the initial composition, after a period of crystallization, 8 mannitol eutectic crystals more clearly formed. s ofdetecting eutectic compositions Methods of detecting ic compositions are well known. The d worker will appreciate that eutectic compositions can be detected by any of these methods. For example, rapid differential ng calorimetry (“DSC”) can be used to detect a ic melting point by evaluating the amount of heat recorded from eutectic melting and comparing it with the melting heat of the eutectic composition. During a slow scan of DSC, the increased temperature in the crucible facilitates the formation of the eutectic even when the two components (such as Mannitol and cyclob ine HCl may not have been mixed before the start of the experiment.) In contrast, a rapid DSC scan s the time during which eutectic compositions can form in the crucible because the temperature inside the crucible rapidly increases during the analysis and rapidly reaches the values at which the mannitol melts. Another useful method is measuring compaction force vs. DSC 3O eutectic melting point. In this method, mixtures are ed with known ratios and then submitted to well-de?ned compaction forces. DSC analyses are then performed and the heat of the eutectic melting versus the forces is then recorded and plotted. These values are ed with those ed with the eutectic ratio, providing the percentage of ic in the formulation.

An additional method that can be used to detect the amount of eutectic in a composition is to compare tensile strength and compression force. In this method, tablets are prepared with only mannitol and API at different compression forces. For each tablet prepared, the percentage of eutectic formed versus tensile strength of the tablets is ated. There is a proportionally linear correlation between the tensile strength and the intimate contact area. The slope of this correlation provides the tage of the eutectic .

There is a linear correlation between the percentage of eutectic composition in a ation and the porosity of powders in a composition. In this , a rd curve can be generated by preparing samples with different ratios of components in which at least one of the components has a variety of different particle sizes, measuring the ic surface area and the porosity of the powders and plotting porosity against the percentage of eutectic. Because there is a linear ation between the two parameters, the slope of this correlation with what is recorded for the eutectic mixture provides the percentage of the eutectic formed

[0057] Dissolution rate also can be used to detect the percent of eutectic because a eutectic may have higher dissolution and higher bioavailability. In this method, the intrinsic dissolution rate (using disk sample holder in a de?ned and riate medium) of the single components is calculated, followed by the dissolution rate of the eutectic mixture. Based on the thermodynamic parameters (entropy), the eutectic should have a more rapid dissolution rate than the other mixtures. By these analyses, it is also le to obtain information on the performance of a tablet in terms of bioavailability. This approach also can evaluate the higher bioavailability of a eutectic versus mixtures of the individual components.

Scanning Electron Microscopy (SEM) can be used by performing a 3O scanning EM of each pure component, on the eutectic, and on the mixtures, and observing the different crystal logy by ng out the differently shaped particles.

Methods ofadministering eutectic itions Appropriate methods of administering a pharmaceutical composition of the invention to a t will depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, r the subject is experiencing symptoms of a disease or condition at the time of administering, the extent of the symptoms, and the chemical and biological properties of the API (e. g. solubility, digestibility, bioavailability, ity and ty). In some embodiments, the pharmaceutical composition is administered for oral or ucosal absorption.

Methods of administering compositions for oral absorption are well known in the art. For example, a ition may be administered orally through tablets, capsules, pills, or powders. In these embodiments, the compositions are absorbed by the gastrointestinal tract after swallowing. In certain embodiments, the composition lacks a film or membrane (e. g., a semipermeable membrane). s of administering compositions for transmucosal absorption are well known in the art. For example, a composition may be administered for buccal absorption through buccal tablets, lozenges, buccal powders, and buccal spray solutions. A composition may be administered for sublingual tion through sublingual tablets, sublingual films, liquids, sublingual powders, and gual spray solutions. In certain embodiments, the composition lacks a film or membrane (e.g., a semipermeable membrane). A composition may be administered for intranasal absorption through nasal sprays. A composition may be stered for pulmonary absorption through aero solized compositions and inhalable dried powders. Because mannitol powder is an inhalation product in the US. (trade name: Aridol®; Pharmaxis Ltd.), inhalation may be an especially benef1cial form of administration. When stered via sprays or aerosolized compositions, a composition may be prepared with saline as a solution, employ 3O benzyl alcohol or other suitable preservatives, or include absorption promoters to enhance bioavailability, ?uorocarbons, and/or other solubilizing or dispersing agents.

Doses and dosing regimens can be determined by one of skill in the art according to the needs of a subject to be treated. The d worker may take into consideration factors such as the age or weight of the subject, the severity of the disease or ion being treated, and the response of the t to treatment. A composition of the invention can be administered, for example, as needed or on a daily basis. In some embodiments, a composition can be administered immediately prior to sleep or several hours before sleep. Administration prior to sleep may be beneficial by providing the therapeutic effect before the onset of the symptoms of the disease or condition being treated. Dosing may take place over varying time periods. For example, a dosing n may last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In some embodiments, a dosing n will last 1 month, 2 months, 3 months, 4 , 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or .

Therapeutic uses The pharmaceutical compositions of the invention may be employed for treating or preventing the development of ?bromyalgia syndrome, also known as f1brositis (see, e. g., Moldofsky et al,. J Rheumatol 38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500 (2011)). Fibromyalgia is a c, nonin?ammatory rheumatic disorder. The American College of Rheumato logy (ACR) published classification criteria for f1bromyalgia in 1990 (Wolfe, F., et al., Arthritis and Rheumatism 33: 160-172 (1990)). Subsequently, a modi?cation to the ACR criteria been published (Wolfe et al., J Rheumatol 38(6):1113-22 (2011)).

Diagnostic criteria have also been published by an international network of working groups called, “Outcome es in Rheumatology” clinical trials or OMERACT (Mease P, et al. J Rheumatol. 2009;3 6(10):2318-29.). Fibromyalgia is traditionally characterized by stiffness or diffuse pain, aches, muscle soreness, sleep disturbances or fatigue. The pain is lly read and sometimes localized at specific ”tender points,” which may bring on widespread pain and muscle spasm when touched. Other symptoms include mental and emotional disturbances such as poor concentration and irritability, neurop sychiatric symptoms such as depression and anxiety, joint swelling, headache, numbness.

Fibromyalgia is associated with reshing sleep, tiredness, sleepiness, re?ux, mental fog and cognitive impairments including dif?culty tasking.

Fibromyalgia also is often comorbid with sleep disorders, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention can be used to treat any one of the above-identif1ed conditions, and any combination thereof.

[0064] Some practitioners ?lI‘tl’lCI‘ fy f1bromyalgia into two categories-- y or secondary-concomitant f1bromyalgia. Generally, primary ?bromyalgia syndrome can be considered f1bromyalgia occurring in the absence of another signi?cant condition whereas secondary-concomitant f1bromyalgia can be considered ?bromyalgia occurring in the presence of another signi?cant medical disorder, which may have been caused by or is merely associated with the patient's f1bromyalgia. Secondary or concomitant f1bromyalgia can include ?bromyalgia in patients with classical or de?nite rheumatoid arthritis, rthritis of the knee or hand, low back pain mes, cervical pain syndromes, cancer pain syndromes, temporomandibular joint disorders, migraine headaches, menopause, post- traumatic stress disorder and interstitial cystitis or painful bladder syndrome (or combinations thereof).

The itions of the invention also may be ed for ng or preventing the pment (either the initiation, consolidation or perpetuation) of a PTSD symptom following a traumatic event. A traumatic event is de?ned as a direct personal ence that es actual or threatened death or s injury, or other threat to one's physical integrity, or witnessing an event that involves death, injury, or a threat to the physical integrity of another person; or learning about unexpected or violent death, serious harm, or threat of death or injury experienced by a family member or other close associate. Traumatic events 3O that are experienced directly include, but are not d to, military combat, violent personal assault l assault, physical attack, robbery, mugging), being kidnapped, being taken hostage, ist attack, e, incarceration as a prisoner ofwar or in a concentration camp, natural or manmade disasters, severe automobile accidents, or being diagnosed with a life-threatening illness. For children, sexually traumatic events may include developmentally inappropriate sexual experiences without threatened or actual violence or injury. Witnessed events include, but are not limited to, observing the serious injury or unnatural death of another person due to violent assault, accident, war, or disaster or unexpectedly sing a dead body or body parts. Events experienced by others that are learned about may include, but are not limited to, violent personal assault, serious accident, or serious injury experienced by a family member or a close friend, learning about the sudden, unexpected death of a family member or a close friend, or learning that one's child has a life-threatening disease. The disorder may be ally severe or long lasting when the stressor is of human design (e. g., torture or rap e). The initiation of a PTSD symptom typically occurs immediately following the traumatic event, during which the symptoms of PTSD app ear and become increasingly severe. One theory of how PTSD develops is that there is a type of ing” or reinforcement s during which the memories of the trauma are engrained in the mind. As these memories become more ?xed (a process called consolidation), symptoms such as ?ashbacks and nightmares grow in severity and frequency. Interventions during this critical time may prevent some ts from developing lown PTSD. The consolidation of a PTSD symptom typically occurs during the weeks and months following a traumatic event. A person's memories of that event become consolidated into highly Vivid and concrete es that are re-exp erienced with increasing frequency either as ?ashbacks or nightmares. During this time, hyp erarousal symptoms and avoidant behavior can become increasingly severe and disabling. The perpetuation of a PTSD symptom occurs once traumatic memories are consolidated, and the re- experienced symptoms acks and nightmares) and rousal symptoms become persistent and remain at a level that is functionally disabling to the patient. 3O [0066] The compositions of the invention may be used to treat ent phases of PTSD development at various time intervals after a traumatic event. For example, ng the initiation phase of PTSD may require the administration of a composition of the ion soon after the traumatic event, for example within the ?rst week, within the second week, within the third week, or within the fourth week or later. By contrast, when treating the consolidation phase of PTSD, the skilled worker may be able to administer a composition of the invention later after the traumatic event and later during the development of the symptoms, for example, within the ?rst month, within the second month, or within the third month or later. The perpetuation phase of PTSD may be treated with a composition of the ion administered 3 months or longer after the traumatic event, for example within the third month, within the fourth month, within the ?fth month, or later. As a result of treatment at the initiation, consolidation, or perpetuation phase, PTSD ms will be ameliorated or be eliminated.

The compositions of the invention also can be used to treat tic brain injury (TBI). TBI is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention also can be used to treat any of the above conditions, in combination with or independently of treating TBI.

The compositions of the invention also can be used to c traumatic encephalopathy (CTE). CTE is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the invention also can be used to treat any of the above conditions, in combination with or ndently of treating CTE.

The compositions and methods of the invention may be used to treat sleep disorders or sleep disturbances. A “sleep er” may be any one of four major categories of sleep dys?Jnction (DSM-IV, pp. 551-607; see also The International Classi?cation of Sleep Disorders: (ICSD) Diagnostic and Coding Manual, 1990, American Sleep Disorders Association). One category, primary sleep disorders, comprises sleep disorders that do not result from another mental disorder, a substance, or a general medical condition. They include without limitation primary insomnia, primary omnia, narcolepsy, ian rhythm sleep disorder, 3O nightmare disorder, sleep terror disorder, sleepwalking disorder, REM sleep behavior disorder, sleep paralysis, ght reversal and other related disorders; substance-induced sleep disorders; and sleep disorders due to a l medical condition. Primary insomnia non-restorative sleep is described by the DSM-lV-TR as a type of primary insomnia wherein the predominant problem is waking up feeling unrefreshed or nonrefreshed. A second category comprises those sleep disorders attributable to substances, including medications and drugs of abuse. A third ry comprises sleep disturbances arising from the effects of a general medical condition on the sleep/wake system. A fourth ry of sleep disorders comprises those resulting from an identi?able mental disorder such as a mood or anxiety disorder. A ?fth ry of sleep disorders comprises those described as non-restorative sleep. One de?nition of non-restorative sleep is in the - TR as a type ofprimary insomnia (A1.3) wherein the inant problem is waking up feeling unrefreshed or nonrefreshed. ms of each category of sleep disorder are known in the art. A “sleep disturbance” may be an impairment in refreshing sleep. Such a clinical diagnosis may be made based on a patient's self described g of fatigue upon waking or the patient's report ofpoor quality sleep. Such impediments to good quality sleep may be described as shallow sleep or frequent awakenings which may be associated with an increase in the Cyclic ating Pattern (CAP) A2 or A3 rate or cycle duration or an increase in the normalized CAP A2 + A3 which is ined by CAP (A2+A3)/CAP 2O (A1+A2+A3) in non-REM sleep (see, e.g., Moldofsky et al,. J Rheumatol 38(12):2653-2663 (2011) and Thomas, J Rheumatol 38(12):2499-2500 (2011)), alpha rhythm contamination in non-REM sleep, or absence of delta waves during deeper physically restorative sleep. Such “sleep bances” may or may not rise to the level of a “sleep disorder” as de?ned in the DSM-IV, although they may share one or more symptom in common. ms of sleep bances are known in the art. Among the known symptoms are groggy or spacey feelings, tiredness, feelings of being run down, and having dif?culty concentrating during waking hours. Among the sleep -related conditions that may be treated with the methods and compositions of the invention are dyssomnias (e. g., intrinsic sleep 3O disorders such as sleep state misperception, psychophysiological insomnia, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, restless leg syndrome, and periodic limb movement er; extrinsic sleep disorders such as environmental sleep er, adjustment sleep disorder, limit-setting sleep disorder, stimulantdependent sleep disorder, l-dep endent sleep disorder, toxin-induced sleep disorder, sleep onset association disorder, ic dependent sleep disorder, inadequate sleep hygiene, altitude insomnia, cient sleep syndrome, nocturnal eating me, and nocturnal drinking syndrome; and circadian rhythm sleep disorders such as jet lag syndrome, delayed sleep phase me, ed sleep phase me, shift work sleep disorder, non-24 hour sleep-wake disorder, and irregular sleep-wake patterns), parasomnias (e. g., arousal disorders such as sleepwalking, confusional arousals, and sleep terrors and sleep-wake transition disorders such as rhythmic movement disorder, sleep talking and sleep starts, and nocturnal leg cramps), and sleep disorders associated with medical or psychiatric conditions or disorders. The compositions of the invention also can be used to treat muscle spasms. Muscle spasms can be associated with muscle pain, e. g., back pain. The compositions and methods of the invention also can be used to treat any of the above conditions, in combination with or independently of treating muscle spasms.

Basifying agents

[0070] The compositions of the invention may include a basifying agent. As used herein, a “basifying agent” refers to an agent (e.g., a substance that increases the local pH of a liquid comprising Cyclobenzaprine HCl, including potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH2P04), dipotassium hydrogen phosphate assium phosphate, dibasic potassium phosphate, KZHPO4), tripotassium phosphate (K3PO4), sodium dihydrogen ate (monosodium phosphate, monobasic sodium phosphate, NaHzPO4), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, NazHPO4), trisodium phosphate (Na3P04), trisodium e anhydrous, bicarbonate or ate salts, , hydroxide, silicate, nitrate, dissolved 3O ammonia, the conjugate bases of some organic acids (including bicarbonate), and sul?de) that raises the pH of a solution containing Cyclobenzaprine HCl. Without wishing to be bound by , a basifying agent, while providing bene?cial pharmacokinetic attributes to pharmaceutical compositions comprising Cyclobenzaprine HCl, also may destabilize the Cyclobenzaprine HCl due to interactions between the HCl and basifying agent. Thus, a eutectic composition as described herein may be ally useful in compositions comprising a basifying agent.

Excipien IS In some embodiments, a composition of the invention is useful as a medicament. In some embodiments, the invention provides for the use of a composition of the ion in the manufacture of a medicament. In some embodiments, it maybe bene?cial to include one or more excipients in the compositions of the invention. One of skill in the art would appreciate that the choice of any one ent may influence the choice of any other excipient. For example, the choice of a ular excipient may preclude the use of one or more additional excipient because the combination of excipients would produce undesirable effects. One of skill in the art would be able to empirically determine which additional excipients, if any, to include in the ations of the invention.

For example, Cyclobenzaprine HCl can be combined with at least one pharmaceutically acceptable carrier such as a solvent, g agents, binder, ant, egrating agent, solution retarder, disintegrant, glidant, absorption accelerator, wetting agent, solubilizing agent, lubricant, sweetening agent, or ?avorant agent. A “pharmaceutically acceptable carrier” refers to any diluent or excipient that is compatible with the other ingredients of the formulation, and which is not deleterious to the recipient. A pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.

Bulking agents In some embodiments, it may be ial to include a bulking agent in the compositions of the invention. g agents are commonly used in 3O pharmaceutical compositions to provide added volume to the composition. g agents are well known in the art. Accordingly, the bulking agents bed herein are not intended to constitute an exhaustive list, but are provided merely as exemplary bulking agents that may be used in the compositions and methods of the invention.

Exemplary bulking agents may include carbohydrates, sugar alcohols, amino acids, and sugar acids. Bulking agents include, but are not limited to, mono-, di-, or poly-, carbohydrates, starches, aldoses, ketoses, amino sugars, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, ose, glucose, , idose, mannose, talose, heptose, glucose, fructose, methyl a-D- glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, gulose, idose, talose, erythrulose, ribulose, xylulose, psicose, tagatose, glucosamine, galactosamine, arabinans, fructans, fucans, galactans, galacturonans, glucans, s, xylans, , levan, fucoidan, carrageenan, galactocarolose, pectins, amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, , agarose, n, chondroitin, dermatan, hyaluronic acid, n gum, sucrose, trehalose, dextran, lactose, alditols, inositols, sorbitol, mannitol, glycine, aldonic acids, uronic acids, aldaric acids, gluconic acid, orbic acid, ascorbic acid, glucaric acid, onic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acids, maize starch, and alginic acid.

Disintegrants In some embodiments, it may be bene?cial to include a disintegrant in the compositions of the invention. Disintegrants aid in the breakup of solid compositions, facilitating delivery of an active pharmaceutical composition. egrants are well known in the art. Some disintegrants have been referred to as superdisintegrants because they have fast properties, and may be used as disintegrants in the context of the invention. ingly, the disintegrants described herein are not ed to constitute an exhaustive list, but are provided merely as exemplary disintegrants that may be used in the compositions and 3O methods of the invention. Exemplary disintegrants include cro spovidone, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, WO 44796 2015/051068 sodium starch glycolate, calcium carboxymethyl croscarmellose sodium, polyvinylpyrrolidone, lower alkyl-sub stituted hydroxypropyl cellulose, lndion 414, starch, pre-gelatinized starch, calcium carbonate, gums, sodium te, and tol Flash®. Pearlitol Flash® (Roquette) is a mannitol-maize starch disintegrant that is speci?cally designed for orally dispersible tablets (ODT).

Certain disintegrants have an escent y.

Glidants In some embodiments, it may be bene?cial to include a glidant in the compositions of the invention. ts aid in the ability of a powder to ?ow freely. Glidants are well known in the art. Accordingly, the glidants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary ts that may be used in the compositions and methods of the invention. Exemplary glidants include colloidal silica (silicon dioxide), magnesium stearate, starch, talc, glycerol te, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate.

Lubricants In some embodiments, it may be bene?cial to include a lubricant in the compositions of the invention. Lubricants help keep the components of a composition from clumping. Lubricants are well known in the art. Accordingly, the lubricants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary lubricants that may be used in the compositions and methods of the invention. Exemplary lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, ble based fatty acids, talc, l oil, light mineral oil, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sun?ower oil, sesame oil, olive oil, corn oil, saf?ower oil, canola oil, coconut oil and soybean oil), silica, zinc stearate, ethyl oleate, ethyl laurate.

Sweeteners In some embodiments, it may be bene?cial to include a sweetener in the compositions of the invention. Sweeteners help improve the palatability of the composition by conferring a sweet taste to the composition. ners are well known in the art. Accordingly, the sweeteners described herein are not intended to tute an tive list, but are provided merely as exemplary sweeteners that may be used in the compositions and methods of the invention. Exemplary sweeteners include, without limitation, compounds ed from the saccharide family such as the mono-, di-, tri-, poly-, and oligosaccharides; sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin and polydextrose; saccharin and salts thereof such as sodium and calcium salts; cyclamic acid and salts thereof; dipeptide sweeteners; chlorinated sugar derivatives such as sucralose and dihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and the like, and combinations thereof.

Hydrogenated starch hydrolysate, and the potassium, calcium, and sodium salts of 3,6-dihydromethyl1,2,3-oxathiazinone-2,2-dioxide many also be used.

Flavorants In some embodiments, it may be bene?cial to include a ?avorant in the itions of the invention. Flavorants help improve the palatability of the composition by conferring a more ble taste to the composition. Flavorants are well known in the art. Accordingly, the ?avorants described herein are not intended to constitute an exhaustive list, but are ed merely as exemplary ?avorants that may be used in the itions and s of the invention.

Exemplary ?avorants e, without limitation, natural and/or synthetic (i.e., arti?cial) compounds such as mint, peppermint, spearmint, wintergreen, menthol, anise, cherry, strawberry, watermelon, grape, , peach, ple, apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, lime, fruit punch, passion fruit, pomegranate, chocolate (e. g., white, milk, dark), vanilla, caramel, coffee, hazelnut, cinnamon, combinations thereof, and the like. _ 33 _ Coloring Agents Coloring agents can be used to color code the composition, for example, to indicate the type and do sage of the therapeutic agent therein. Coloring Agents are well known in the art. Accordingly, the coloring agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary coloring agents that may be used in the itions and methods of the invention.

Exemplary coloring agents e, without limitation, natural and/or artif1cial compounds such as FD & C coloring agents, natural juice trates, pigments such as um oxide, n dioxide, and zinc oxide, combinations thereof, and the like.

Combination therapy As described above, the compositions and methods of the invention may be used to treat PTSD, sion, f1bromyalgia, traumatic brain , sleep disorder, non-restorative sleep, chronic pain, and anxiety disorder. Any of the methods of treatment described also may be combined with a psychotherapeutic ention to improve the outcome of the treatment. Exemplary therapeutic interventions directed at either modifying traumatic memories or reducing nal responses to tic memories, including psychological debrie?ng, cognitive behavior therapy and eye movement desensitization and reprocessing, systematic desensitization, relaxation training, biofeedback, cognitive processing y, stress inoculation training, assertiveness training, exposure therapy, combined stress inoculation training and exposure therapy, combined exposure therapy, and relaxation training and cognitive therapy. In each case, the goal of the intervention involves either modifying traumatic memories or reducing nal responses to traumatic memories. The intended result is generally an improvement in the symptoms of PTSD or the reduction of occurrences of symptoms, as evidenced in terms ofphysiological responding, anxiety, depression, and feelings of alienation.

In some ments of the invention, a composition is combined with a 3O drug which may ?lI‘tl’lCI‘ alleviate the symptoms of PTSD, depression, f1bromyalgia, tic brain injury, sleep disorder, storative sleep, chronic pain, or anxiety er. The drugs include an alpha— 1 -adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin ke inhibitor, a serotonin-norepinephrine reuptake inhibitor, and an analgesic.

Exemplary anticonvulsants include carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. An exemplary alphaadrenergic receptor antagonist is prazosin. ary selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include, bupropion, citalopram, desvenlafaxine, tine, escitalopram, ?uoxetine, escitalopram, ?uvoxamine, milnacipran, paroxetine, sertraline, trazodone, and venlafaxine. Exemplary analgesics include pregabalin, gabapentin, acetaminophen, ol, and non-steroidal anti-in?ammatory drugs (e. g., ibuprofen and naproxen sodium). Additional drugs that can be used in combination with the compositions of the invention include sodium oxybate, zolpidem, pramipexole, modafmil, temazepam, zaleplon, and armodaf1nil.

It is to be understood that the embodiments of the present invention which have been described are merely illustrative of some of the ations of the principles of the present invention. Numerous modi?cations may be made by those skilled in the art based upon the ngs presented herein without departing from the true spirit and scope of the invention.

The following examples are set forth as being representative of the present invention. These examples are not to be construed as limiting the scope of the invention as these and other lent embodiments will be nt in view of the present disclosure, ?gures, and accompanying claims.

Example 1: Wet granulation To produce a 5 mannitol eutectic with cyclobenzaprine HCl, the following protocol was used: . Load 52.830 % cyclobenzaprine HCl (w/w) (e.g., 368.4 g) and 47.170 % mannitol (w/w) (e. g., 328.9 g) into a high shear granulator.

Optionally, mix the cyclobenzaprine HCl and mannitol for 5 minutes using an impeller speed of 500 rpm.

. Mix for 1 minute under the following conditions: impeller speed, 200 rpm; chopper speed, 2000 rpm; time, 2 min.

While continuing to mix, spray water (10% w/w) onto powder blend.

Mix for 1 onal minute.

Dry in fluid bed dryer to a loss on drying (LOD) of not more than (NMT) 2.0% under the following conditions: air flow, 100 m3/h; wet temperature: 65 OC; LOD: 0.31%.

Collect the sample.

As one example, a cyclobenzaprine HCl-mannitol 8 eutectic can be prepared by wet granulation by mixing 368.4 g of cyclobenzaprine HCl, 328.9 g Pearlitol 100SD, and 55.8 g water. Using those amounts produced a net yield of 662.2 g of dried granules, for a total of 95% ry.

A eutectic mixture formed by the above method was then d with other ents as follows: Cyclobenzaprine eutectic e: 232.4 g Dye D&C Yellow #10 Lake: 0.667 g Pearlitol Flash: 1 144 g Crospovidone — Kollidon CL: 87.7 g Dibasic potassium phosphate, anhydrous: 52.7 g Spearmint ?avor, natural and artificial: 83.3 g WO 44796 2015/051068 dal silicon dioxide: 22.0 g Sodium stearyl fumarate (PRUV): 43.8 For tableting, exemplary compression parameters include compression at 30 rpm with a compression force of 5.0 kN, optionally with pre-compression (3.0 kN) to form a tablet with a weight variation of less than 2%, a disintegration time of approximately 40— 50 seconds, and a hardness of approximately 3 kp. Alternative exemplary compression parameters e compression at 40 rpm (5.5 kN compression force, 3.0 kN pre-compression force), resulting in a tablet weight variation of less than 2%, a disintegration time of approximately 90 seconds and a hardness of3.0 - 3.5 kp.

Example 2: Fluid bed dr?ng To create a tablet comprising cyclob ine using ?uid bed drying, the ing protocol was used: B mannitol with a particle size below 20 microns was deposited in the basin at the bottom of the ?uid bed dryer. A warm ?ow of air was then initiated to induce vigorous turbulence inside the chamber. After all the matter in the chamber was under controlled and constant ence, a water solution with cyclob enzaprine was linked to the nozzle present in the center of the equipment. This liquid was spread by a peristaltic pump on the mannitol particles in turbulance from the 2O bottom to the ?lter and small, almost nebulized drops were wet the surface of the mannitol particles. This liquid phase present on the surface of the mannitol induced partial solubilization of the mannitol particle surfaces. Through the process of the hot air removing the moisture, the eutectic formed on the surface of the les, beginning in the metastable phase and subsequently crystallizing.

Preliminary analyses carried out by Thermal Analysis (Differential Scanning Calorimetry) and X-ray Powder Diffraction (XRPD) on the granules con?rm the presence of the eutectic components inside the mixture and homogeneous distribution of the cyclobenzaprine HCl in the entire matrix. Without wishing to be bound by theory, this interaction of the cyclobenzaprine with ol induced by spraying to form the eutectic may promote more al stability of the drug substance than a simple mechanical mixture. Interestingly, the process produced granules with a B mannitol core and a 8 mannitol-cyclobenzaprine eutectic outer surface. These granules had improved ing properties over eutectics formed by other methods.

Claims (21)

We claim:

1. A pharmaceutical composition sing a eutectic of 35%±2% by weight d- mannitol and 65%±2% by weight Cyclobenzaprine HCl, wherein the eutectic is part of a granule comprising an inner layer comprising ß-mannitol and an outer layer comprising the eutectic of itol and enzaprine HCl.

2. The pharmaceutical composition of claim 1, further comprising a eutectic of 75%±2% by weight Cyclobenzaprine HCl and 25%±2% by weight ß-mannitol.

3. The pharmaceutical composition of claim 1 or 2, wherein the Cyclobenzaprine HCl is micronized Cyclobenzaprine HCl.

4. The pharmaceutical composition of any one of claims 1-3, further sing a basifying agent.

5. The pharmaceutical composition of claim 4, wherein the basifying agent is K2HPO4.

6. The pharmaceutical composition of claim 4, wherein the ing agent is Na2HPO4.

7. The pharmaceutical composition of claim 4, wherein the basifying agent is anhydrous trisodium citrate.

8. A method of manufacturing the pharmaceutical composition of any one of claims 1-7, sing mixing Cyclobenzaprine HCl, mannitol and a solvent.

9. The method of claim 8, n said mixing is wet granulation mixing.

10. The method of claim 8 or 9, wherein the solvent is water, an alcohol, or a mixture thereof.

11. The method of claim 10, wherein said alcohol is methanol.

12. The method of claim 10, wherein said alcohol is ethanol.

13. The method of any one of claims 9-12, further comprising drying after said wet granulation. AH26(42597457_1):JIN

14. The method of claim 13, wherein said wet granulation and drying are ed one or more times.

15. The method of any one of claims 9-12, further comprising crystallizing the Cyclobenzaprine HCl-mannitol mixture after said wet granulation.

16. The method of claim 15, wherein said wet granulation and crystallizing are repeated one or more times.

17. A method of manufacturing the pharmaceutical composition of any one of claims 1-7, comprising fluid bed drying Cyclobenzaprine HCl and mannitol in the presence of a solvent.

18. The method according to claim 17, wherein the solvent is water, an alcohol or a mixture thereof.

19. The method ing to claim 18, wherein the alcohol is methanol.

20. The method according to claim 18, wherein the alcohol is ethanol.

21. The method of claim 17, wherein a solution of enzaprine HCl is sprayed onto ß-mannitol particles inside a fluid bed dryer. TONIX PHARMA HOLDINGS LTD By the Attorneys for the Applicant SPRUSON & ON AH26(42597457_1):JIN “\f/fw 6mm .}z\% com " Domm?mw AQL 00$.va \mexgmmmw N 0mm K \\s