Eutectic formulations of cyclobenzaprine hydrochloride

Abstract

To provide a composition that increases stability of cyclobenzaprine HCl (in the presence or absence of a basifying agent), and methods for manufacturing such a composition.SOLUTION: The present invention relates to pharmaceutical compositions and methods for manufacturing the pharmaceutical compositions, comprising a eutectic of cyclobenzaprine HCl and mannitol. A compound useful in embodiments of the present invention is cyclobenzaprine HCl. In some embodiments, the compound is micronized. In alternative embodiments, the compound is not micronized. In some embodiments, the compound may be present in one or more crystal isoforms.SELECTED DRAWING: Figure 6

Description

Technical Field

[0001] (Related Application) This application claims priority and benefit from U.S. Provisional Patent Application No. 62 / 052,238, filed on September 18, 2015, the content and disclosure of which are hereby incorporated by reference in its entirety herein.

Background Art

[0002] (Background of the Invention) Cyclobenzaprine, namely 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of locally initiated acute muscle spasm. (Katz, W. et al., Clinical Therapeutics 10:216-228 (1988)). Subsequent studies have shown that cyclobenzaprine is also effective in the treatment of fibromyalgia syndrome, post-traumatic stress disorder (PTSD), generalized anxiety disorder and depression. Further, the usefulness of cyclobenzaprine as a sleep-aiding agent to improve the quality of sleep or as a treatment for sleep disordered conditions has also been studied. However, the therapeutic agents approved by the FDA act on pain and mood, and there is currently no FDA-approved treatment method that acts on disrupted sleep and fatigue associated with fibromyalgia syndrome. Treatment with cyclobenzaprine may be particularly useful in treating sleep disordered conditions induced by, exacerbated by, or associated with fibromyalgia syndrome, long-term fatigue, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndromes (type II), drug administration, autoimmune diseases, stress or anxiety, or in treating diseases and symptoms of such diseases exacerbated by or induced by sleep disordered conditions. See, for example, U.S. Pat. Nos. 6,395,788 and 6,358,944, which are hereby incorporated by reference herein. The pharmaceutical active ingredient (or API), cyclobenzaprine HCl, is stable in oral pills, tablets or capsule formulations when combined with certain excipients. However, cyclobenzaprine HCl has slow absorption when taken orally (by mouth or po). To increase the absorption rate, tablets containing cyclobenzaprine HCl have been formulated into various sublingual (SL) preparations. However, both sublingual and oral formulations can have problems with the stability of the API and the physical composition itself, especially when a basifying agent (a chemical compound that increases the pH of the solution after dissolution of cyclobenzaprine HCl) is present. Therefore, compositions that enhance the stability of cyclobenzaprine HCl (with or without the presence of a basifying agent) and methods for manufacturing such compositions are useful.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] (Summary of the Invention) Some embodiments of the present invention are shown below: 1. A pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl. 2. The pharmaceutical composition according to claim 1, comprising 2.60% to 90% by weight of cyclobenzaprine HCl and 40% to 10% by weight of mannitol. 3. The pharmaceutical composition according to claim 2, comprising an amount of cyclobenzaprine HCl and mannitol selected from 3.60% ± 2% by weight of cyclobenzaprine HCl and 40% ± 2% by weight of mannitol, 65% ± 2% by weight of cyclobenzaprine HCl and 35% ± 2% by weight of mannitol, 70% ± 2% by weight of cyclobenzaprine HCl and 30% ± 2% by weight of mannitol, 75% ± 2% by weight of cyclobenzaprine HCl and 25% ± 2% by weight of mannitol, 80% ± 2% by weight of cyclobenzaprine HCl and 20% ± 2% by weight of mannitol, 85% ± 2% by weight of cyclobenzaprine HCl and 15% ± 2% by weight of mannitol, and 90% ± 2% by weight of cyclobenzaprine HCl and 10% ± 2% by weight of mannitol. 4. The pharmaceutical composition according to claim 3, comprising 4.75% ± 2% by weight of cyclobenzaprine HCl and 25% ± 2% by weight of mannitol. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the molar ratio of cyclobenzaprine HCl:mannitol is 1.76 ± 0.1. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cyclobenzaprine HCl is micronized cyclobenzaprine HCl. 7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising a basifying agent. 8. The pharmaceutical composition according to claim 7, wherein the basifying agent is K2HPO4. 9. The pharmaceutical composition according to claim 7, wherein the basifying agent is Na2HPO4. 10. The pharmaceutical composition according to claim 7, wherein the basifying agent is the anhydride of trisodium citrate. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition comprises granules. 12. The pharmaceutical composition according to claim 11, wherein the granules comprise cyclobenzaprine and mannitol. 13. The pharmaceutical composition according to claim 12, wherein the mannitol is β-mannitol and δ-mannitol. 14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the granule comprises an inner layer containing β-mannitol and an outer layer containing a eutectic of mannitol and cyclobenzaprine HCl. 15. A method for producing a eutectic composition according to any one of claims 1 to 14, comprising mixing cyclobenzaprine HCl and mannitol. 16. The method according to claim 15, wherein the mixing is wet granulation mixing. 17. The method according to claim 15 or 16, further comprising mixing alcohol with the cyclobenzaprine HCl and the mannitol. 18. The method according to claim 17, wherein the alcohol is methanol. 19. The method according to claim 17, wherein the alcohol is ethanol. 20. The method according to any one of claims 16 to 19, further comprising drying after the wet granulation. 21. The method according to claim 20, wherein the wet granulation and drying are repeated once or a plurality of times. 22. The method according to any one of claims 16 to 19, further comprising crystallization after the wet granulation. 23. The method according to claim 22, wherein the wet granulation and crystallization are repeated once or a plurality of times. 24. A method for producing a eutectic composition according to any one of claims 1 to 14, comprising fluid bed drying cyclobenzaprine HCl and mannitol. Claim 1 to 14 any one of the described eutectic composition manufacturing method. 25. The method according to any one of claims 15 to 24, wherein the eutectic composition contains β-mannitol. 26. The method according to claim 25, wherein the composition contains cyclobenzaprine HCl and the eutectic melts at 143.6 ± 3°C. 27. The method according to any one of claims 15 to 24, wherein the eutectic composition contains δ-mannitol. 28. The method according to claim 27, wherein the composition comprises cyclobenzaprine HCl and the eutectic melts at 134°C ± 3°C.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0017] (Detailed Description of the Invention) Unless otherwise specified, the scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. Generally, the nomenclature and techniques related to the technologies of pharmacology, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, genes and proteins and nucleic acid chemistry described in this specification are the customary ones well-known in the art.

[0018] The methods and techniques of the present invention are generally carried out in accordance with conventional methods well known in the art, unless otherwise specified, and in the manner described in various general and more specific references cited and considered throughout this specification.

[0019] The chemical terms used in this specification are used in accordance with the customary usage in the art, as specifically indicated by "The McGraw-Hill Dictionary of Chemical Terms", edited by Parker S., McGraw-Hill, San Francisco, California (1985).

[0020] All of the above and any other publications, patents and published patent applications referred to in this application are hereby specifically incorporated by reference into this specification. In case of conflict, this specification, including its explicit definitions, shall prevail.

[0021] Throughout this specification, the terms "comprise", "comprises" or "comprising" and the like are to be construed as meaning that the stated integer (or component) or group of integers (or components) is included, but not excluding any other integer (or component) or group of integers (or components).

[0022] The singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise.

[0023] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0024] The terms "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms encompass mammals such as humans, primates, livestock (including cows, pigs, etc.), pets (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0025] To "treat" a condition or a patient means to take action to obtain a beneficial or desired result, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, the reduction or improvement of one or more symptoms associated with the diseases or conditions described herein.

[0026] "Administering" a substance, compound, or agent to a subject or "administration" thereof can be carried out using one of various methods well known to those skilled in the art. For example, a compound or agent can be administered sublingually, intranasally, by inhalation into the lungs, or rectally. Also, administration can be carried out, for example, once or multiple times and / or over one or more extended periods. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug or to have another person administer a drug to the patient and / or provides a prescription for the drug to the patient is administering the drug to the patient. A physician who instructs a patient to self-administer a drug or to have another person administer a drug to the patient and / or provides a prescription for the drug to the patient is administering the drug to the patient.

[0027] In the formulation of solid drug products, knowledge of the possible interactions between the active pharmaceutical ingredient (API) and excipients is an important point for predicting chemical and physical stability.

[0028] Since solubility and chemical structure can be altered, in many cases excipients can modify the biological activity and chemical stability of the API. In some cases, it is also possible for excipients to improve the chemical stability profile over time and avoid undesirable physical effects of the final dosage form.

[0029] A eutectic system is a chemical compound or a mixture of elements having a single chemical composition that melts at a lower temperature than any other composition made of the same components. Compositions containing a eutectic are known as eutectic compositions, and their melting temperature is known as the eutectic temperature. To define a eutectic composition, a binary phase diagram should be constructed by analyzing different compound ratios.

[0030] The effect of eutectics on tablet properties indicates that compression provides sufficient intimate contact and compatibility for the formation of eutectics. Eutectic compositions often have higher stability and / or dissolution rates than their non-eutectic counterparts. Since eutectics enhance solubility, their use can increase permeability in solid dispersions and dispersive systems. However, in the development of certain tableted dosage forms, unwanted eutectic formation (during manufacturing operations such as wet granulation) can lead to undesirable changes in the physical or chemical properties of the tablets, such as low eutectic melting temperature, tackiness, unpredictable hardness, instability, or difficulties in rapid stability screening.

[0031] Mannitol and sorbitol are excipients commonly used in solid pharmaceutical products. Mannitol and sorbitol are six-carbon sugar alcohol isomers. Sugar alcohols are hydrogenated carbohydrates in which the carbonyl group has been reduced to a primary or secondary hydroxyl group. Other six-carbon sugar alcohols include inositol, galactitol, fucitol, and iditol.

[0032] Mannitol and sorbitol can be included in pharmaceutical compositions, typically because they are physically inert but provide qualitative benefits such as sweetness or a cooling effect in the mouth. Thus, the discovery that mannitol forms a eutectic composition with cyclobenzaprine HCl that results in tablets having pharmaceutically acceptable stability even with a basifying agent was surprising. In contrast, sorbitol, when heated (in a differential scanning calorimeter), dissolves cyclobenzaprine HCl, does not form a eutectic, and results in tablets that decompose with a basifying agent at room temperature, highlighting the uncertainty of eutectic formation and the protective effect of the eutectic formed with mannitol. Without wishing to be bound by theory, it is possible that the two crystal lattices of mannitol and cyclobenzaprine HCl penetrate each other, and this co-penetrative physical state may protect cyclobenzaprine HCl from hydration and other chemical interactions. (Compound)

[0033] A compound useful in embodiments of the present invention is cyclobenzaprine HCl. In some embodiments, the compound is micronized. In alternative embodiments, the compound is not micronized. In some embodiments, the compound may exist in one or more crystalline polymorphs.

[0034] As used herein, "cyclobenzaprine HCl" refers to a pharmaceutically acceptable hydrochloride salt of cyclobenzaprine. (Eutectic composition)

[0035] In some embodiments, the present invention provides a pharmaceutical composition comprising a eutectic mixture of mannitol and a pharmaceutical active ingredient. In certain embodiments, the pharmaceutical active ingredient is cyclobenzaprine HCl.

[0036] In some embodiments, the present invention provides a pharmaceutical composition comprising a eutectic mixture of mannitol and cyclobenzaprine HCl (e.g., β-mannitol eutectic, δ-mannitol eutectic, or a combination thereof). In certain embodiments (e.g., when the composition comprises a β-mannitol eutectic), the eutectic has a melting temperature of 143.6 ± 3 °C. In certain embodiments, the melting temperature of the eutectic is approximately 135.6 °C, 136.6 °C, 137.6 °C, 138.6 °C, 139.6 °C, 140.6 °C, 141.6 °C, 142.6 °C, 143.6 °C, 144.6 °C, 145.6 °C, 146.6 °C, 147.6 °C, 148.6 °C, 149.6 °C, 150.6 °C, 151.6 °C, 152.6 °C, or 153.6 °C. In certain embodiments (e.g., when the composition comprises a δ-mannitol eutectic), the eutectic has a melting temperature of 134 ± 3 °C. In certain embodiments (e.g., when the composition comprises a δ-mannitol eutectic), the melting temperature of the eutectic is approximately 124 °C, 125 °C, 126 °C, 127 °C, 128 °C, 129 °C, 130 °C, 131 °C, 132 °C, 133 °C, 134 °C, 135 °C, 136 °C, 137 °C, 138 °C, 139 °C, 140 °C, 141 °C, 142 °C, 143 °C, or 144 °C. One of ordinary skill in the art will understand that the measured melting temperature may vary depending on the apparatus and conditions used, however, the melting temperatures of β-mannitol and δ-mannitol in a given sample can be readily distinguished using control samples of β-mannitol and δ-mannitol. In certain embodiments, the melting temperature of the eutectic is the temperature at which melting begins. In an alternative embodiment, the melting temperature of the eutectic is the temperature at which maximum melting is observed. In certain embodiments, the composition comprises more than 5 wt% cyclobenzaprine HCl and less than 95 wt% mannitol. In certain embodiments, the composition comprises 1 wt% - 5 wt% cyclobenzaprine HCl and 99 wt% - 95 wt% mannitol. In certain embodiments, the composition comprises 5 wt% - 10 wt% cyclobenzaprine HCl and 95 wt% - 90 wt% mannitol. In certain embodiments, the composition comprises 10 wt% - 20 wt% cyclobenzaprine HCl and 90 wt% - 80 wt% mannitol.In certain embodiments, the composition comprises 10 wt% to 90 wt% of cyclobenzaprine HCl and 90 wt% to 10 wt% of mannitol, for example, 60 wt% to 90 wt% of cyclobenzaprine HCl and 40 wt% to 10 wt% of mannitol or 70 wt% to 80 wt% of cyclobenzaprine HCl and 30 wt% to 20 wt% of mannitol. Specific examples of the composition include 60 wt% ± 2 wt% of cyclobenzaprine HCl and 40 wt% ± 2 wt% of mannitol, 65 wt% ± 2 wt% of cyclobenzaprine HCl and 35 wt% ± 2 wt% of mannitol, 70 wt% ± 2 wt% of cyclobenzaprine HCl and 30 wt% ± 2 wt% of mannitol, 75 wt% ± 2 wt% of cyclobenzaprine HCl and 25 wt% ± 2 wt% of mannitol, 80 wt% ± 2 wt% of cyclobenzaprine HCl and 20 wt% ± 2 wt% of mannitol, 85 wt% ± 2 wt% of cyclobenzaprine HCl and 15 wt% ± 2 wt% of mannitol, and 90 wt% ± 2 wt% of cyclobenzaprine HCl and 10 wt% ± 2 wt% of mannitol. In certain embodiments (e.g., compositions comprising a β-mannitol eutectic), the composition comprises 75 wt% ± 10 wt% of cyclobenzaprine HCl and 25 wt% ± 10 wt% of mannitol. In certain embodiments, the composition comprises 75 wt% ± 2 wt% of cyclobenzaprine HCl and 25 wt% ± 2 wt% of mannitol. In certain embodiments, the composition comprises 75 wt% of cyclobenzaprine HCl and 25 wt% of mannitol. In certain embodiments (e.g., compositions comprising a δ-mannitol eutectic), the composition comprises 65 wt% ± 10 wt% of cyclobenzaprine HCl and 35 wt. It contains mannitol at ±10% by weight. In certain embodiments, the composition contains 65% by weight ±2% of cyclobenzaprine HCl and 35% by weight ±2% of mannitol. In certain embodiments, the composition contains 65% by weight of cyclobenzaprine HCl and 35% by weight of mannitol. In certain embodiments, the composition contains cyclobenzaprine HCl and mannitol at a molar ratio of cyclobenzaprine HCl:mannitol of 1.70±0.1 to 1.80±0.1. In certain embodiments, the molar ratio is about 1.6 to 2.0. In certain embodiments, the molar ratio (ration) is 1.70±0.1, 1.71±0.1, 1.72±0.1, 1.73±0.1, 1.74±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 1.60±0.5, 1.65±0.5, 1.70±0.5, 1.75±0.5, 1.80±0.5, 1.85±0.5, 1.90±0.5, 1.95±0.5, or 2.0±0.5. In certain embodiments, the molar ratio is 1.76±0.1. In certain embodiments, the molar ratio is 1.76±0.5.

[0037] In certain embodiments, additional mannitol is added to the eutectic as, for example, a diluent or as a component of an explosant (an agent that promotes oral disintegration, such as Pearlitol® Flash). In such embodiments, the total amount of mannitol will be greater than the amount of mannitol present in the eutectic originally formed. For example, when additional mannitol is added, the composition may contain approximately 90% by weight, approximately 85% by weight, approximately 80% by weight, approximately 75% by weight, approximately 70% by weight, approximately 65% by weight, approximately 60% by weight, or approximately 55% by weight of mannitol. Specific examples of compositions with added mannitol are as follows: In certain embodiments, additional mannitol is added to the eutectic as, for example, a diluent or as a component of an explosant (an agent that promotes oral disintegration, such as Pearlitol® Flash). In such embodiments, the total amount of mannitol will be greater than the amount of mannitol present in the eutectic originally formed. For example, when additional mannitol is added, the composition may contain approximately 90% by weight, approximately 85% by weight, approximately 80% by weight, approximately 75% by weight, approximately 70% by weight, approximately 65% by weight, approximately 60% by weight, or approximately 55% by weight of mannitol. Specific examples of compositions with added mannitol are as follows:

Table 1

[0038] Another advantage of the commingled composition of the present invention is the enhanced stability of tablets containing cyclobenzaprine HCl. In some embodiments, the present invention provides a pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, where the composition has a high stability in tablet form compared to the same tablets in the absence of mannitol, for example, tablets containing sorbitol instead of mannitol. In fact, tablets containing cyclobenzaprine HCl, K2HPO4 and mannitol were stable for 3 months at 40 °C and 75% relative humidity. In contrast, the same tablets containing cyclobenzaprine HCl, K2HPO4 and sorbitol, stored under the same conditions, disintegrated in less than 1 week.

[0039] In some embodiments, the present invention provides a pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein the composition exhibits an increased dissolution rate of stable tablets compared to the case of cyclobenzaprine HCl alone or in a formulation containing one or more excipients that are not basic agents. For example, when mixed with 100 mL of 50 mM citric acid pH 4 at 37.0 ± 0.5 °C, the composition at the 5-minute mark may exhibit a solubility of 100%, greater than 95%, greater than 90%, greater than 85%, greater than 80%, greater than 75%, greater than 70%, greater than 65%, greater than 60%, greater than 55%, greater than 50%, greater than 45%, greater than 40%, greater than 35%, greater than 30%, or greater than 25%. For example, when mixed with 100 mL of 50 mM citric acid pH 4 at 37.0 ± 0.5 °C, the composition at the 10-minute mark may exhibit a solubility of 100%, greater than 95%, greater than 90%, greater than 85%, greater than 80%, greater than 75%, greater than 65%, greater than 60%, greater than 55%, greater than 50%. For example, when mixed with 100 mL of 50 mM citric acid pH 4 at 37.0 ± 0.5 °C, the composition at the 240-minute mark may exhibit a solubility of 100%, greater than 95%, greater than 90%, greater than 85%, greater than 80%, greater than 75%, greater than 65%, greater than 60%, greater than 55%, greater than 50%. For highly soluble compounds (e.g., cyclobenzaprine HCl), solubility can be measured using a continuous flow elution device.

[0040] Mannitol can crystallize in three polymorphic forms, α, β, and δ. 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 surprising than the observations for the first eutectic of cyclobenzaprine HCl and mannitol (β polymorph) were the observations for a second eutectic of mannitol in a different polymorphic form (δ polymorph). The eutectic containing δ-mannitol and cyclobenzaprine HCl (also referred to herein as the “δ-mannitol eutectic”) has several advantages over the eutectic containing β-mannitol and cyclobenzaprine HCl (also referred to herein as the “β-mannitol eutectic”). Among these advantages are a lower melting point than the β-mannitol eutectic and increased solubility over the β-mannitol eutectic. Another advantage is that the stability of pharmaceutical compositions (including tablets) is higher than that of the β-mannitol eutectic, including compositions containing a basifying agent. Yet another advantage is that the local tolerability of pharmaceutical compositions (including tablets) is higher than that of the β-mannitol eutectic, including compositions containing a basifying agent. Tolerability should also be improved, including reduced transient tongue numbness upon sublingual administration of tablets and improved sublingual absorption, if dissolution and conversion to the cyclobenzaprine free base are improved.

[0041] In some embodiments, the present invention provides a eutectic pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein mannitol is in its β polymorphic form. In some embodiments, the present invention provides a eutectic pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein mannitol is in its δ polymorphic form. In certain embodiments, the pharmaceutical composition comprising mannitol in its β polymorphic form is a sublingual composition. In certain embodiments, the pharmaceutical composition comprising mannitol in its β polymorphic form is an oral composition. In certain embodiments, the pharmaceutical composition comprising mannitol in its δ polymorphic form is a sublingual composition. In certain embodiments, the pharmaceutical composition comprising mannitol in its δ polymorphic form is an oral composition. In certain embodiments where the composition is an oral composition, the oral composition exhibits bioequivalence to a 5 mg cyclobenzaprine HCl oral tablet (e.g., Flexeril 5 mg). In certain embodiments where the composition is an oral composition , the oral composition exhibits bioequivalence to a 10 mg cyclobenzaprine HCl oral tablet (e.g., Flexeril 10 mg). Flexeril tablets are composed of hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose, magnesium stearate, starch, and titanium dioxide. When 10 mg was administered three times a day to volunteer healthy subjects, the steady-state AUC (after 4 days of dosing) was 177 ng.hr / mL (range, 80 - 319 ng.hr / mL), and C max was 25.9 ng / mL (range, 12.8 - 46.1 ng / mL). Further pharmacokinetic properties of orally administered 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).

[0042] In some embodiments, the present invention provides a composition comprising a eutectic of mannitol and cyclobenzaprine HCl. One of ordinary skill in the art will understand that these compositions may be suitable for administration in a variety of ways, such as those described herein. For example, the composition may be suitable for oral administration (when cyclobenzaprine is absorbed in the gastrointestinal tract) or transmucosal absorption (e.g., sublingual, oral, or nasal absorption or by inhalation).

[0043] In some embodiments, the present invention provides a composition that is a granular composition. In certain embodiments, the granules are granules comprising cyclobenzaprine HCl and mannitol. In specific embodiments, the granules comprise excess mannitol. In more specific embodiments, the granules comprise β-mannitol, δ-mannitol, or both. Granules comprising excess mannitol may particularly contain both β-mannitol and δ-mannitol. For example, granules produced by a method such as fluid bed drying may comprise an inner layer of β-mannitol and an outer layer of a δ-mannitol-cyclobenzaprine eutectic. (Method for producing a eutectic composition)

[0044] One skilled in the art will recognize that the eutectic composition of the present invention can be manufactured according to any of a number of known methods. In some embodiments, the present invention provides a method for producing the eutectic composition of the present invention, including grinding the API (cyclobenzaprine HCl) with mannitol, mixing the API (cyclobenzaprine HCl) with mannitol, or a combination thereof. For example, the API and mannitol can be ground in a mortar or mixed in a high-shear granulator. In high-shear mixing, a high-speed impeller and chopper blades are used to combine the dry powders and uniformly mix the components. To some extent, particle size reduction is possible due to the shear force and high speed of the mixing blades. The API and mannitol can also be ground and mixed, for example, in a Turbula® Shaker-Mixer. In certain embodiments, the API and mannitol can be mixed by pressure, for example, by roller compression. In roller compression, the fine powder is pushed between two counter-rotating rolls to press-mold the raw material into a solid compress or sheet (referred to as flakes). The size of the flakes is reduced until the desired particle size is reached. In certain embodiments, a eutectic composition can be formed by dissolving mannitol and mixing it with cyclobenzaprine HCl. In certain embodiments, the API is a micronized API (for example, micronized cyclobenzaprine HCl).

[0045] In some embodiments, the present invention provides a method for producing the eutectic composition of the present invention, including spray-drying a solution of the API (cyclobenzaprine HCl) and mannitol. One skilled in the art will recognize that spray-drying is common and that parameters regarding spray-drying can be determined without undue experimentation. For example, spray-drying can be carried out under any of the following conditions: T inlet (°C): 120 - 150 T outlet (°C): 73 - 90 Feed rate (ml / min): 4 - 6 Flow rate (L / h): 600 - 800 Suction (100%): 100 Delta pressure (mbar): 2 - 20 Furthermore, by scaling up or modifying these conditions, higher-level high-throughput manufacturing can be achieved.

[0046] In some embodiments, a composition comprising a δ-mannitol eutectic consisting of cyclobenzaprine HCl and mannitol is produced by mixing mannitol and cyclobenzaprine HCl. This mixing may be, for example, wet granulation including high-shear wet granulation. Figure 1 shows a differential scanning calorimetry (DSC) minor peak as a specific example of a δ-mannitol eutectic (melting point 139.75 °C) formed by wet granulation using cyclobenzaprine HCl, mannitol, and water. Following wet granulation, fluid bed drying and optional milling can be performed to produce the composition. Without wishing to be bound by theory, during wet granulation, cyclobenzaprine and mannitol (starting in its β-form) become metastable, and then some or all of the wet ends of the β-mannitol crystals in the paste formed by wet granulation can crystallize into a β- and / or δ-mannitol eutectic with cyclobenzaprine HCl. This may occur as the solvent evaporates, and the process of crystal co-penetration and recrystallization into the eutectic occurs either directly or via nucleation with a modified metastable amorphous intermediate state and subsequent β- and / or δ-mannitol eutectics during the mixing or drying period. In some embodiments, wet granulation and drying can be performed in iterative cycles to stimulate or enhance the formation of the δ-mannitol eutectic. Without wishing to be bound by theory, although only a small amount of the total possible δ-mannitol eutectic may be produced in each individual cycle, the formation of the δ-mannitol eutectic can be enhanced by performing wet granulation and drying periodically because the spread of additional δ-mannitol formation is aided by each cycle.

[0047] In some embodiments, a composition comprising a δ mannitol eutectic of cyclobenzaprine HCl and mannitol is produced by fluid bed drying (also known as fluidized bed drying). Without wishing to be bound by theory, fluid bed drying may be advantageous over other eutectic formation methods as it enables gentle, uniform, and controlled drying of wet solids. Due to the intense heat / mass transfer of the fluid bed product, this method is particularly effective and time-saving. This technique is also suitable for post-drying spray granulated or extruded products with very low residual moisture.

[0048] In certain embodiments, fluid bed drying can be used in the formation of cyclobenzaprine pharmaceutical products. In the drying process using fluid bed drying, the drying time in a drying oven can be reduced to approximately one-twentieth of that of other methods. Additionally, in fluid bed drying, the drying conditions are controlled and uniform compared to tray drying where unevenness may occur. Furthermore, fluid bed drying can improve the uniform distribution of the pharmaceutical active ingredient on the surface of one or more excipients.

[0049] The fluid bed drying technique can be used when spraying a solution containing a solubilized drug substance (e.g., cyclobenzaprine HCl) onto the surface of excipient particles. In such a method, a positive interaction is created between the solution and the solid particles by the atomized solution on the surface of the excipient particles. During the drying step in a hot air stream, water is removed from the surface and the pharmaceutical active ingredient binds to the excipient particles. In some embodiments, a cyclobenzaprine HCl solution (e.g., cyclobenzaprine HCl and water) is sprayed onto mannitol to form an eutectic between cyclobenzaprine and mannitol. Without wishing to be bound by theory, when a solution of the pharmaceutical active ingredient (e.g., cyclobenzaprine HCl) is diffused onto the surface by a nozzle and an eutectic forms, the eutectic particles can physically interact with particles containing one or more excipients to produce granules of a desired size. When the solution of the pharmaceutical active ingredient (e.g., cyclobenzaprine HCl) is diffused onto the surface by a nozzle and an eutectic forms, the eutectic particles can physically interact with particles containing one or more excipients to produce granules of a desired size.

[0050] Another advantage of fluidized bed drying is that drying is performed in thermodynamic equilibrium. The inlet air temperature determines the amount of moisture that is transported through the pores from the interior of the granulate to the surface. The moisture content is selected so that moisture evaporates from the surface of the granules. During this moisture transfer, the active pharmaceutical ingredient can bind to the material onto which it is sprayed. For example, when cyclobenzaprine HCl is sprayed onto mannitol, the correct ratio of cyclobenzaprine HCl and mannitol mix to form a eutectic, even though there is an excess of mannitol not required for eutectic formation. Even more surprisingly, this process produced a eutectic of cyclobenzaprine and delta mannitol, even though the mannitol onto which the cyclobenzaprine HCl was sprayed was beta mannitol. When used properly, fluid bed drying provides an effective solution to produce a granule particle size suitable for good tableting with an even distribution of the active pharmaceutical ingredient throughout the tablet and without undesirable disintegration.

[0051] In some embodiments, alcohol is used to stimulate or enhance the formation of the δ-mannitol eutectic. Examples of alcohol as a specific example include, but are not limited to, ethanol, methanol, and isopropanol. In certain embodiments, ethanol is used in combination with spray drying to stimulate or enhance the formation of the δ-mannitol eutectic (see FIG. 10 for differential scanning calorimetry data and FIG. 11 for X-ray powder diffraction data comparing spray drying with ethanol and water to spray drying with only water). For example, during spray drying, a 1:1 ethanol:water mixture can be introduced together with a 5% (w / w) mixture of cyclobenzaprine and mannitol to produce the δ-mannitol eutectic. In an alternative embodiment, ethanol is used in combination with wet granulation mixing to stimulate or enhance the formation of the δ-mannitol eutectic. In yet another embodiment, ethanol is used in combination with freeze drying to stimulate or enhance the formation of the δ-mannitol eutectic. In yet another embodiment, ethanol is used in combination with rapid evaporation to stimulate or enhance the formation of the δ-mannitol eutectic. In still further embodiments, ethanol is used in combination with fluid bed drying to stimulate or enhance the formation of the δ-mannitol eutectic. In certain embodiments, methanol is used in combination with spray drying to stimulate or enhance the formation of the δ-mannitol eutectic. In an alternative embodiment, methanol is used in combination with wet granulation mixing to stimulate or enhance the formation of the δ-mannitol eutectic. In yet another embodiment, methanol is used in combination with freeze drying to stimulate or enhance the formation of the δ-mannitol eutectic. In yet another embodiment, methanol is used in combination with rapid evaporation to stimulate or enhance the formation of the δ-mannitol eutectic. In still further embodiments, methanol is used in combination with fluid bed drying to stimulate or enhance the formation of the δ-mannitol eutectic. A specific example of a protocol for spray drying to obtain the δ-mannitol eutectic by spray drying with ethanol is as follows. Equipment: Buchi Mini Spry Dryer SD B290 Solvent of ethanol:water with a 1:1 v / v ratio (For example, in a ratio of 65:35) Concentration in the cyclobenzaprine:mannitol mixture solution: 5% w / w Spray drying conditions: Inlet temperature = 150 °C Outlet temperature = 90 °C Solution flow rate = approximately 6 mL / min (Required for complete recrystallization of the powder distributed on the equipment) Delay time before removing the powder from the equipment = 1 - 2 hours

[0052] In some embodiments, a rapid evaporation process is used to stimulate or enhance the formation of the δ-mannitol eutectic. Rapid evaporation refers to the step of rapidly evaporating the solvent, for example, by passing hot air through the solution, after mixing a mixture of cyclobenzaprine HCl and mannitol with a solvent (such as water, or a mixture of water and an alcohol like methanol or ethanol). When cyclobenzaprine HCl, mannitol, and water are mixed, it may form a paste (as in wet granulation) or a solution. As an example, a mixture of 65% cyclobenzaprine:35% mannitol (w / w) subjected to rapid evaporation in a 1:1 mixture of methanol:water (final concentration of the cyclobenzaprine / mannitol mixture between 5% and 20%) forms the δ-mannitol eutectic approximately 30 minutes after drying (see Figure 9). See also Figures 2 - 4 for the δ-mannitol eutectic formed by dissolving cyclobenzaprine and mannitol in a mixture of methanol and water and then subjecting it to rapid evaporation.

[0053] In some embodiments, lyophilization is used to stimulate or enhance the formation of the δ-mannitol eutectic. In certain embodiments, the lyophilization is performed without slow cooling. For the δ-mannitol eutectics formed by lyophilization without slow cooling, see FIGS. 5 and 6, which show the X-ray powder diffraction data and the phase diagrams, respectively. These traces showed a low crystallinity in the initial composition, but after the crystallization period, the δ-mannitol eutectic crystals formed more clearly. In alternative embodiments, the lyophilization is performed with slow cooling. For the δ-mannitol eutectics formed by performing slow cooling and then lyophilization, see FIGS. 7 and 8, which show the X-ray powder diffraction data and the phase diagrams, respectively. These traces showed a low crystallinity in the initial composition, but after the crystallization period, the δ-mannitol eutectic crystals formed more clearly. (Method for detecting eutectic composition)

[0054] Methods for detecting eutectic compositions are well known. One of ordinary skill in the art will recognize that eutectic compositions can be detected by any of these methods. For example, by using rapid differential scanning calorimetry ("DSC") to evaluate the heat evolved from the eutectic melting and comparison with the heat of fusion of the eutectic composition, the eutectic melting point can be detected. During the slow scan of the DSC, the formation of the eutectic is promoted even when the two components (such as mannitol and cyclobenzaprine HCl) may not have been mixed before the start of the experiment due to the temperature rise in the crucible. In contrast, in a rapid DSC scan, the temperature in the crucible rises rapidly during the analysis and reaches rapidly the value at which mannitol melts, thus reducing the time available for the eutectic composition to form in the crucible. Another useful method is to measure the compression force versus the DSC eutectic melting point. In this method, a mixture is prepared in a known ratio and then subjected to a clearly defined compression force. Next, DSC analysis is performed, and then the eutectic heat of fusion versus the compression force is recorded and plotted. By comparing these values with the values obtained at the eutectic ratio, the percentage of eutectic in the formulation is obtained.

[0055] Another method that can be used to detect the amount of eutectic in a composition is the comparison of 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 the tensile strength of the tablet is correlated. There is a proportional linear correlation between tensile strength and intimate contact area. The slope of this correlation gives the percentage of eutectic formed.

[0056] There is a linear correlation between the percentage of eutectic composition in a preparation and the porosity of the powder in the composition. In this method, samples are prepared with different ratios of components (provided that at least one of the components has a variety of different particle sizes), the specific surface area and the porosity of the powder are measured, and a standard curve is constructed by plotting the porosity against the percentage of eutectic. Since there is a linear correlation between the two parameters, the slope of this correlation recorded for the eutectic mixture gives the percentage of eutectic formed.

[0057] The dissolution rate can also be used to detect the percentage of eutectic, since eutectic may have higher solubility and higher bioavailability. In this method, the intrinsic dissolution rate of the single components (using a disk sample holder in a defined suitable medium) is calculated, and then the dissolution rate of the eutectic mixture is calculated. Based on the thermodynamic parameters (entropy), eutectic naturally has a faster dissolution rate than other mixtures. These analyses can also provide information about the tablet performance in terms of bioavailability. This approach can also evaluate the higher bioavailability of eutectic versus mixtures of individual components.

[0058] Scanning electron microscopy (SEM) can be used for the eutectic and the mixture by performing EM scans of each pure component and observing the different crystal morphologies by distinguishing particles of different shapes. (Method of administering the eutectic composition)

[0059] Suitable methods for administering the pharmaceutical composition of the present invention to a subject vary, for example, depending on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject is experiencing symptoms of a disease or condition at the time of administration, the degree of the symptoms, and the chemical and biological properties of the API (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the pharmaceutical composition is administered for oral or transmucosal absorption.

[0060] Methods for administering compositions for oral absorption are well known in the art. For example, the composition can be orally administered by tablets, capsules, pills, or powders. In these embodiments, the composition is absorbed by the gastrointestinal tract after being swallowed. In certain embodiments, the composition lacks a film or membrane (e.g., a semipermeable membrane).

[0061] Methods for administering compositions for transmucosal absorption are well known in the art. For example, the composition can be administered for oral absorption by buccal tablets, troches, oral powders, and oral sprays. The composition can be administered for sublingual absorption by sublingual tablets, sublingual films, liquids, sublingual powders, and sublingual sprays. In certain embodiments, the composition lacks a film or membrane (e.g., a semipermeable membrane). The composition can be administered for nasal absorption by nasal sprays. The composition can be administered for pulmonary absorption by aerosolized compositions and dry powders for inhalation. Since mannitol powder is an inhalation product (trade name: Aridol®; Pharmaxis Ltd.) in the United States, inhalation can be a particularly beneficial form of administration. When administered by spray or aerosolized composition, the composition can be prepared as a solution in saline, can use benzyl alcohol or other suitable preservatives, or can contain absorption promoters, fluorocarbons, and / or other solubilizing or dispersing agents to enhance bioavailability.

[0062] The dosage and usage can be determined by those skilled in the art according to the needs of the subject to be treated. The expert can consider factors such as the age or weight of the subject, the severity of the disease or condition being treated, and the response of the subject to the treatment. The compositions of the present invention can be administered, for example, as needed or routinely. In some embodiments, the composition can be administered immediately before bedtime or several hours before bedtime. Administration before bedtime can be beneficial by providing a therapeutic effect before the symptoms of the disease or condition being treated begin. The dosing can be carried out over various periods. For example, the usage can be continued 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 a longer period. In some embodiments, the usage can be continued for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or a longer period can be continued (Therapeutic use)

[0063] The pharmaceutical compositions of the present invention can be used to treat or prevent the development of fibromyalgia syndrome, also known as fibrositis (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 chronic non-inflammatory rheumatic disorder. The American College of Rheumatology (ACR) published classification criteria for fibromyalgia in 1990 (Wolfe, F. et al., Arthritis and Rheumatism 33:160-172(1990)). Subsequently, it was published that modifications had been made to the ACR criteria (Wolfe et al., J Rheumatol 38(6):1113-22(2011)). The diagnostic criteria also include "Outcome Measures in It has also been published by the "Rheumatology" clinical trials or the international network of research groups called OMERACT (Mease P et al., J Rheumatol. 2009;36(10):2318-29). Fibromyalgia has traditionally been characterized by stiffness or spreading pain, aching pain, muscle pain, sleep disturbances or fatigue. The pain is generally widespread and often localized to specific "tender points", which can cause widespread pain and muscle spasms when touched. Other symptoms include mental and emotional disorders such as decreased concentration and hypersensitivity, neuropsychiatric symptoms such as depression and anxiety, joint swelling, headache, and numbness. Fibromyalgia is associated with a lack of refreshing sleep, lethargy, drowsiness, reflux, mental fog and cognitive impairment, including cases where it is difficult to perform parallel tasks. Fibromyalgia also often coexists with sleep disorders, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the present invention can be used to treat any one of the conditions shown above, and any combination thereof.

[0064] Some experts may further classify fibromyalgia into two categories, namely primary fibromyalgia or secondary - associated fibromyalgia. Generally, primary fibromyalgia syndrome can be considered as fibromyalgia that occurs when there is no other serious condition, and secondary - associated fibromyalgia can be considered as fibromyalgia that occurs when there is another serious medical disorder that may have been induced by or is simply associated with the patient's fibromyalgia. Secondary or associated fibromyalgia can include fibromyalgia in patients suffering from typical or definite rheumatoid arthritis, osteoarthritis of the knee or hand, low back pain syndrome, neck pain syndrome, cancer pain syndrome, temporomandibular joint disorder, migraine, menopause, post - traumatic stress disorder and interstitial cystitis or bladder pain syndrome (or combinations thereof).

[0065] The compositions of the present invention can also be used to treat or prevent the progression (onset, establishment or persistence) of PTSD symptoms after a trauma event. A trauma event is defined as a direct personal experience that includes witnessing an event that involves actual or threatened death or serious injury as a real or imminent situation, or other threat to physical integrity, or the death, trauma or threat to physical integrity of another person, or learning of an unexpected or unnatural death, serious harm, or threat of death or trauma experienced by a family member or other close relation. Directly experienced trauma events include, but are not limited to, combat, violent personal assault (sexual assault, physical attack, mugging, robbery), being kidnapped, taken hostage, terrorist attack, torture, being held captive or imprisoned in a forced detention facility, natural or man-made disasters, serious motor vehicle accidents, or being diagnosed with a life-threatening illness. In the case of children, sexual trauma events can include developmentally inappropriate sexual experiences without actual violence or trauma in an imminent situation. Witnessed events include, but are not limited to, watching the serious injury or unnatural death of another person due to a violent attack, accident, war or disaster, or unexpectedly witnessing a dead body or part of a dead body. Learned The events experienced by others can include, but are not limited to, learning about violent personal attacks, serious accidents or severe trauma experienced by a family member or close friend, the sudden and unexpected death of a family member or close friend, or learning that one's child has a life-threatening illness. When the stressor is intentional (e.g., torture or rape), the disorder can be particularly severe and long-lasting. The onset of PTSD symptoms typically occurs immediately after the traumatic event, with the symptoms of PTSD emerging and becoming increasingly severe over time. One theory about how PTSD progresses is that there is a type of "learning" or reinforcement process while the memory of the trauma is deeply ingrained in the mind. As these memories become more firmly established (a process called consolidation), the severity and frequency of symptoms such as flashbacks and nightmares increase. Intervention during this critical period can prevent the most severe cases of PTSD from developing in some patients. The consolidation of PTSD symptoms typically occurs during the weeks and months following the traumatic event. The person's memory of the event becomes more vivid and specific, and is re-experienced as flashbacks or nightmares with increasing frequency. During this time, hyperarousal symptoms and avoidance behaviors become more severe and can lead to a state of helplessness. The persistence of PTSD symptoms occurs once the memory of the trauma has been consolidated, and the re-experienced symptoms (flashbacks and nightmares) and hyperarousal symptoms become chronic and remain at a level where the patient is functionally unable to do anything.

[0066] The compositions of the present invention can be used to treat different phases in the progression of PTSD at various time intervals after a trauma event. For example, treatment of PTSD in the initial phase may require administration of the composition of the present invention soon after the trauma event, e.g., within the first week, within the second week, within the third week, or within the fourth week or later. In contrast, when treating PTSD in the established phase, a professional may be able to administer the composition of the present invention later after the trauma event and during the progression of symptoms, e.g., within the first month, within the second month, or within the third month or later. The persistent phase of PTSD can be treated with the composition of the present invention administered 3 months or later after the trauma event, e.g., within the third month, within the fourth month, within the fifth month, or later. As a result of treatment in the initial, established, or persistent phase, PTSD symptoms are improved or eliminated.

[0067] The compositions of the present invention can also be used to treat traumatic brain injury (TBI). TBI is associated with sleep disorders, sleep disruption, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the present invention can also be used to treat any of the above conditions, either in combination with or independently of the treatment of TBI.

[0068] The compositions of the present invention can also be used for chronic traumatic encephalopathy (CTE). CTE is associated with sleep disorders, sleep disruption, fatigue, non-restorative sleep, anxiety, and depression. The compositions and methods of the present invention can also be used to treat any of the above conditions, either in combination with or independently of the treatment of CTE.

[0069] The compositions and methods of the present invention can be used to treat sleep disorders or sleep disruption conditions. "Sleep disorder" can be any one of four major categories of sleep dysfunction (DSM-IV, pp. 551-607; see also The International Classification of Sleep Disorders: (ICSD) Diagnostic and Coding Manual, 1990, American Sleep Disorders Association). The first category, primary sleep disorders, includes sleep disorders that do not result from another mental disorder, substance, or general medical condition. Examples of these include, but are not limited to, primary insomnia, primary hypersomnia, narcolepsy, circadian rhythm sleep disorders, nightmare disorder, sleep terror disorder, somnambulism, REM sleep behavior disorder, sleep paralysis, shift work disorder, and other related disorders; substance-induced sleep disorders; and sleep disorders due to general medical conditions. Primary insomnia non-restorative sleep is a major problem where the energy has not recovered It is described by the DSM-IV-TR as a type of primary insomnia, which is awakening in a state of malaise or without any sense of refreshment. The second category includes sleep disorders caused by substances such as medications and dependence-producing drugs. The third category includes sleep-disruptive states resulting from the effects of systemic medical conditions on the sleep / wake system. The fourth category of sleep disorders includes those resulting from identifiable mental disorders such as mood disorders or anxiety disorders. The fifth category of sleep disorders includes those described as non-restorative sleep. One definition of non-restorative sleep is that the main problem is awakening in a state of malaise or without any sense of refreshment, which is a type of primary insomnia (A1.3) as shown in the DSM-IV-TR. The symptoms of each category of sleep disorders are known in the art. A "sleep-disruptive state" may be one in which sleep that restores fatigue is impaired. Such a clinical diagnosis can be made based on the patient's self-report of fatigue upon awakening or the patient's record of poor sleep quality. Such interference with good-quality sleep may be determined by an increase in the cyclic alternating pattern (CAP) A2 or A3 rate or cycle duration or an increase in the normalized CAP A2+A3 determined by CAP(A2+A3) / CAP(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 intrusion in non-REM sleep, or light sleep or frequent awakenings associated with a lack of delta waves during deep body-restorative sleep. Such a "sleep-disruptive state" may or may not progress to the level of "sleep disorder" as defined by the DSM-IV, but the "sleep-disruptive state" and "sleep disorder" may share one or more symptoms. The symptoms of a sleep-disruptive state are known in the art. Known symptoms include drowsiness or a sense of dissociation, lethargy, fatigue, and difficulty concentrating during waking hours.Sleep-related conditions that can be treated with the methods and compositions of the present invention include sleep disorders (e.g., endogenous sleep disorders such as parasomnias (e.g., sleep state misperception, psychophysiological insomnia, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, restless legs syndrome, and periodic limb movement disorder); environmental sleep disorders, adjustment sleep disorders, insufficient discipline sleep disorders, stimulant-dependent sleep disorders, alcohol-dependent sleep disorders, toxin-induced sleep disorders, sleep-onset related disorders, hypnotic-dependent sleep disorders, inappropriate sleep hygiene, altitude insomnia, sleep deprivation syndrome, night eating syndrome, and nocturnal drinking syndrome; and circadian rhythm sleep disorders such as jet lag syndrome, delayed sleep phase syndrome, advanced sleep phase syndrome, shift work sleep disorder, non-24-hour sleep-wake syndrome, and irregular sleep-wake pattern), sleep-associated symptoms (e.g., arousal disorders such as somnambulism, confusional arousals, and sleep terrors and sleep-wake transition disorders such as rhythmic movement disorder, sleep talking and sleepwalking, and nocturnal leg cramps), and sleep disorders associated with medical or psychiatric conditions or disorders. The compositions of the present invention can also be used in the treatment of muscle spasms. Muscle spasms can be associated with muscle pain, e.g., back pain. The compositions and methods of the present invention can also be used to treat any of the above conditions, either in combination with or independently of the treatment of muscle spasms. (Basic agent)

[0070] The composition of the present invention may contain a basifying agent. As used herein, "basifying agent" refers to an agent that raises the pH of a solution containing cyclobenzaprine HCl (e.g., a substance that increases the local pH of a liquid containing cyclobenzaprine HCl, such as 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), trisodium citrate anhydrous, bicarbonate or carbonate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of some organic acids (including bicarbonate), and sulfides). Without wishing to be bound by theory, the basifying agent may also provide beneficial pharmacokinetic attributes to a pharmaceutical composition containing cyclobenzaprine HCl while destabilizing cyclobenzaprine HCl due to the interaction between HCl and the basifying agent. Thus, the eutectic compositions described herein may be particularly useful in compositions containing a basifying agent. While providing beneficial pharmacokinetic attributes to a pharmaceutical composition containing cyclobenzaprine HCl, the basifying agent may destabilize cyclobenzaprine HCl due to the interaction between HCl and the basifying agent. Thus, the eutectic compositions described herein may be particularly useful in compositions containing a basifying agent. (Excipient)

[0071] In some embodiments, the composition of the present invention is useful as a medicine. In some embodiments, the present invention provides the use of the composition of the present invention in the manufacture of a medicine. In some embodiments, it may be beneficial to include one or more excipients in the composition of the present invention. Those skilled in the art will recognize that the choice of any one excipient can affect the choice of any other excipient. For example, the combination of excipients may have an undesirable effect, so the choice of a particular excipient may exclude the use of one or more additional excipients. Those skilled in the art can empirically determine which additional excipient(s), if any, to include in the formulation of the present invention. For example, cyclobenzaprine HCl can be combined with at least one pharmaceutically acceptable carrier such as a solvent, diluent, binder, humectant, disintegrating agent, dissolution retardant agent, disintegrant, lubricant, absorption enhancer, wetting agent, solubilizing agent, glidant, sweetening agent or flavoring agent. A "pharmaceutically acceptable carrier" includes a diluent or excipient that is compatible with the other components of the formulation and is not harmful to the recipient. The pharmaceutically acceptable carrier can be selected according to standard pharmaceutical practice based on the desired route of administration. (Diluent)

[0072] In some embodiments, it may be beneficial to include a diluent in the composition of the present invention. Diluents are commonly used in pharmaceutical compositions to increase the volume of the composition. Diluents are well known in the art. Thus, while not intending to create an extensive list of diluents described herein, diluents are provided as merely illustrative examples that can be used in the compositions and methods of the present invention.

[0073] Examples of bulking agents can 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, pentoses, ribose, xylose, galactose, glucose, hexoses, idose, mannose, talose, heptoses, glucose, fructose, methyl α-D-glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, gulose, idose, talose, erythrulose, ribulose, xylulose, psicose, tagatose, glucosamine, galactosamine, arabinan, fructan, fucan, galactan, galacturonan, glucan, mannan, xylan, inulin, levan, fucoidan, carrageenan, galactocarolose, pectin, amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, xanthan gum, sucrose, trehalose, dextran, lactose, alditol, inositol, sorbitol, mannitol, glycine, aldonic acid, uronic acid, aldaric acid, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acid, corn starch, and alginic acid. (Disintegrant)

[0074] In some embodiments, it may be beneficial to include a disintegrant in the composition of the present invention. The disintegrant aids in the disintegration of the solid composition and promotes the delivery of the active pharmaceutical composition. Disintegrants are well known in the art. Some disintegrants have rapid properties and are thus referred to as super disintegrants, and the present It can also be used as a disintegrant in the case of clarity. Therefore, although there is no intention to create an extensive list of the disintegrants described herein, disintegrants are provided as mere specific examples that can be used in the compositions and methods of the present invention. Disintegrants as specific examples include crospovidone, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, sodium starch glycolate, carboxymethyl calcium crosscarmellose sodium, polyvinyl pyrrolidone, lower alkyl-substituted hydroxypropyl cellulose, Indion 414, starch, pregelatinized starch, calcium carbonate, rubber, sodium alginate, and Pearlitol Flash (registered trademark). Pearlitol Flash (registered trademark) (Roquette) is a mannitol-corn starch disintegrant specially designed for orally disintegrating tablets (ODTs). Certain disintegrants have foaming properties. (Lubricant)

[0075] In some embodiments, it may be beneficial to include a lubricant in the composition of the present invention. The lubricant helps the ability of the powder to flow freely. Lubricants are well known in the art. Therefore, although there is no intention to create an extensive list of the lubricants described herein, lubricants are provided as mere specific examples that can be used in the compositions and methods of the present invention. Lubricants as specific examples include colloidal silica (silicon dioxide), magnesium stearate, starch, talc, glyceryl behenate, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate. (Glidant)

[0076] In some embodiments, it may be beneficial to include a lubricant in the compositions of the present invention. The lubricant helps to prevent the components of the composition from agglomerating. Lubricants are well known in the art. Accordingly, while not intending to create an extensive list of the lubricants described herein, lubricants are provided as mere examples that can be used in the compositions and methods of the present invention. Examples of lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, plant-based fatty acids, talc, mineral oil, light mineral oil, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, safflower oil, canola oil, coconut oil, and soybean oil), silica, zinc stearate, ethyl oleate, and ethyl laurate. (Sweetening agent)

[0077] In some embodiments, it may be beneficial to include a sweetening agent in the compositions of the present invention. The sweetening agent helps to improve the palatability of the composition by imparting a sweet taste to the composition. Sweetening agents are well known in the art. Accordingly, while not intending to create an extensive list of the sweetening agents described herein, sweetening agents are provided as mere examples that can be used in the compositions and methods of the present invention. Examples of sweetening agents include, but are not limited to, saccharide families such as monosaccharides, disaccharides, trisaccharides, polysaccharides, and oligosaccharides; sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin, and polydextrose; saccharin and its salts such as sodium salts and calcium salts; cyclamic acid and its salts; dipeptide sweeteners; chlorinated sugar derivatives such as sucralose and dihydrochalcones; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, and hexa-resorcinol, and combinations thereof. Hydrogenated starch hydrolysates, as well as potassium salts, calcium salts, and sodium salts of 3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide may also be used. (Flavoring agent)

[0078] In some embodiments, it may be beneficial to include a flavoring agent in the compositions of the invention. The flavoring agent helps to improve the palatability of the composition by imparting a desired flavor thereto. Flavoring agents are well known in the art. Thus, while not intending to create an extensive list of flavoring agents described herein, flavoring agents are provided as merely illustrative examples that may be used in the compositions and methods of the invention. Illustrative flavoring agents include, but are not limited to, natural and / or synthetic (i.e., artificial) compounds such as mint, peppermint, spearmint, hinokitiol, menthol, anise, cherry, strawberry, watermelon, grape, banana, peach, pineapple, 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, and combinations thereof. (Colorant)

[0079] Colorants can be used to color code the composition, for example, to identify the type and dosage of a therapeutic agent contained therein. Colorants are well known in the art. Thus, while not intending to create an extensive list of colorants described herein, colorants are provided as merely illustrative examples that may be used in the compositions and methods of the invention. Illustrative colorants include, but are not limited to, FD & C colorants, natural fruit juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, and natural and / or artificial compounds such as combinations thereof. (Combination Therapy)

[0080] As described above, the compositions and methods of the present invention can be used to treat PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorders, non-restorative sleep, chronic pain, and anxiety disorders. Also, any of the above treatment methods can be used in combination with psychotherapeutic interventions to improve the outcome of the treatment. Psychotherapeutic interventions as specific examples include psychological debriefing, cognitive behavioral therapy and eye movement desensitization and reprocessing, systematic desensitization, relaxation training, biofeedback, cognitive processing therapy, stress inoculation training, assertiveness training, virtual reality exposure therapy, combination of stress inoculation training and virtual reality exposure therapy, combination of virtual reality exposure therapy and relaxation training, and cognitive therapy, aiming to modify traumatic memories or reduce the emotional response to traumatic memories. The goal of the intervention in each case includes modifying traumatic memories or reducing the emotional response to traumatic memories. The desired outcome is generally an improvement in the symptoms of PTSD or a reduction in the occurrence of symptoms, as demonstrated with respect to physiological responses, anxiety, depression, and feelings of alienation.

[0081] In some embodiments of the present invention, the composition is combined with a drug that can further reduce the symptoms of PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, or anxiety disorder. Such drugs include alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and analgesics. Anticonvulsants as specific examples include carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. A specific example of an alpha-1-adrenergic receptor antagonist is prazosin. Specific examples of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, and venlafaxine. Analgesics as specific examples include pregabalin, gabapentin, acetaminophen, tramadol, and non-steroidal anti-inflammatory drugs (e.g., ibuprofen and naproxen sodium). Further drugs that can be used in combination with the composition of the present invention include sodium oxybate, zolpidem, pramipexole, modafinil, temazepam, zaleplon, and armodafinil.

[0082] It goes without saying that the described embodiments of the present invention are merely some demonstrations of the application of the principles of the present invention. Many modifications can be made by those skilled in the art based on the teachings presented herein without departing from the true spirit and scope of the present invention.

[0083] The following examples are presented as representative of the present invention. These examples and other equivalent embodiments will be apparent in view of the present disclosure, the drawings, and the appended claims, and thus these examples should not be regarded as limiting the scope of the present invention.

Example

[0084] (Example 1) Wet Granulation The following protocol was used to generate the δ mannitol eutectic with cyclobenzaprine HCl. 1. Charge 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. 2. Optionally, mix cyclobenzaprine HCl and mannitol for 5 minutes using an impeller rotation speed of 500 rpm. 3. Mix for 1 minute under the following conditions. Impeller rotation speed: 200 rpm, chopper rotation speed: 2000 rpm, time: 2 minutes. 4. While mixing, spray water (10% w / w) onto the powder blend. 5. Mix for an additional 1 minute. 6. Dry in a fluid bed dryer to a loss on drying (LOD) of 2.0% or less (NMT) under the following conditions. Air flow: 100 m 3 / hour, wet bulb temperature: 65°C, LOD: 0.31%. 7. Collect samples. As an example, the cyclobenzaprine HCl-mannitol δ eutectic can be prepared by wet granulation by mixing 368.4 g of cyclobenzaprine HCl, 328.9 g of Pearlitol 100SD, and 55.8 g of water. Using these amounts, dry granules with a net yield of 662.2 g were produced with a total recovery rate of 95%.

[0085] The eutectic mixture formed by the above method was then blended with the following other excipients as follows. Cyclobenzaprine eutectic mixture: 232.4 g Dye D&C Yellow #10 Lake: 0.667 g Pearlitol Flash: 1144 g Crospovidone-Kollidon CL: 87.7 g Potassium dibasic phosphate anhydrous: 52.7 g Natural and artificial spearmint flavor: 83.3 g Colloidal silicon dioxide: 22.0 g Sodium stearyl fumarate (PRUV): 43.8 Regarding tableting, as a specific example of forming tablets with a weight variation of less than 2%, a disintegration time of approximately 40 to 50 seconds, and a hardness of approximately 3 kp, the compression parameters include compression at 30 rpm using a compression force of 5.0 kN with optional pre-compression (3.0 kN). Alternative specific example compression parameters include compression at 40 rpm (compression force of 5.5 kN, pre-compression force of 3.0 kN), resulting in tablets with a weight variation of less than 2%, a disintegration time of approximately 90 seconds, and a hardness of 3.0 to 3.5 kp. (Example 2) Fluid bed drying

[0086] To prepare tablets containing cyclobenzaprine using fluid bed drying, the following protocol - was used. β-mannitol with a particle size of less than 20 microns was deposited in a basin at the bottom of the fluid bed dryer. Then, a warm air stream was raised to create intense Turbulence was induced. After all the objects in the chamber were engulfed in a controlled and constant level of turbulence, an aqueous solution containing cyclobenzaprine was connected to a nozzle present at the center of the facility. This liquid was diffused by a peristaltic pump into mannitol particles in the turbulence from the bottom towards the filter, and small, almost mist-like droplets moistened the surface of the mannitol particles. This liquid phase present on the surface of mannitol caused partial solubilization of the mannitol particle surface. The process of hot air removing moisture started in the metastable period and then a eutectic that crystallized formed on the surface of the particles. Preliminary analysis carried out by thermal analysis (differential scanning calorimetry) on the granules and X-ray powder diffraction (XRPD) confirmed the presence of the eutectic components inside the mixture and the uniform distribution of cyclobenzaprine HCl throughout the matrix. Without wishing to be bound by theory, this interaction of cyclobenzaprine with mannitol, which is induced by spraying to form a eutectic, may promote higher chemical stability of the active ingredient than a simple mechanical mixture. Interestingly, in this process, granules with a β-mannitol core and an outer surface of δ-mannitol-cyclobenzaprine eutectic were produced. These granules had improved tableting properties compared to eutectics formed by other methods. In one embodiment, for example, the following items are provided. (Item 1) A pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl. (Item 2) The pharmaceutical composition according to Item 1, comprising 60% to 90% by weight of cyclobenzaprine HCl and 40% to 10% by weight of mannitol. (Item 3) The pharmaceutical composition according to item 2, comprising an amount of cyclobenzaprine HCl and mannitol selected from 60% by weight ± 2% by weight of cyclobenzaprine HCl and 40% by weight ± 2% by weight of mannitol, 65% by weight ± 2% by weight of cyclobenzaprine HCl and 35% by weight ± 2% by weight of mannitol, 70% by weight ± 2% by weight of cyclobenzaprine HCl and 30% by weight ± 2% by weight of mannitol, 75% by weight ± 2% by weight of cyclobenzaprine HCl and 25% by weight ± 2% by weight of mannitol, 80% by weight ± 2% by weight of cyclobenzaprine HCl and 20% by weight ± 2% by weight of mannitol, 85% by weight ± 2% by weight of cyclobenzaprine HCl and 15% by weight ± 2% by weight of mannitol, and 90% by weight ± 2% by weight of cyclobenzaprine HCl and 10% by weight ± 2% by weight of mannitol. (Item 4) The pharmaceutical composition according to item 3, comprising 75% by weight ± 2% by weight of cyclobenzaprine HCl and 25% by weight ± 2% by weight of mannitol. (Item 5) The pharmaceutical composition according to any one of items 1 to 4, wherein the molar ratio of cyclobenzaprine HCl to mannitol is 1.76 ± 0.1. (Item 6) The pharmaceutical composition according to any one of items 1 to 5, wherein the cyclobenzaprine HCl is micronized cyclobenzaprine HCl. (Item 7) The pharmaceutical composition according to any one of items 1 to 6, further comprising a basifying agent. (Item 8) The pharmaceutical composition according to item 7, wherein the basifying agent is K2HPO4. (Item 9) The pharmaceutical composition according to item 7, wherein the basifying agent is Na2HPO4. (Item 10) The pharmaceutical composition according to item 7, wherein the basifying agent is the anhydride of trisodium citrate. (Item 11) The pharmaceutical composition according to any one of items 1 to 10, wherein the composition comprises granules. (Item 12) The pharmaceutical composition according to item 11, wherein the granule contains cyclobenzaprine and mannitol. (Item 13) The pharmaceutical composition according to item 12, wherein the mannitol is β-mannitol and δ-mannitol. (Item 14) The pharmaceutical composition according to any one of items 11 to 13, wherein the granule contains an inner layer containing β-mannitol and an outer layer containing a eutectic of mannitol and cyclobenzaprine HCl. (Item 15) A method for producing a eutectic composition according to any one of items 1 to 14, comprising mixing cyclobenzaprine HCl and mannitol. (Item 16) The method according to item 15, wherein the mixing is wet granulation mixing. (Item 17) The method according to item 15 or 16, further comprising mixing alcohol with the cyclobenzaprine HCl and the mannitol. (Item 18) The method according to item 17, wherein the alcohol is methanol. (Item 19) The method according to item 17, wherein the alcohol is ethanol. (Item 20) The method according to any one of items 16 to 19, further comprising drying after the wet granulation. (Item 21) The method according to item 20, wherein the wet granulation and drying are repeated once or a plurality of times. (Item 22) The method according to any one of items 16 to 19, further comprising crystallization after the wet granulation. (Item 23) The method according to item 22, wherein the wet granulation and crystallization are repeated once or a plurality of times. (Item 24) A method for producing a eutectic composition according to any one of items 1 to 14, comprising fluidized bed drying of cyclobenzaprine HCl and mannitol. (Item 25) The method according to any one of Items 15 to 24, wherein the eutectic composition contains β-mannitol. (Item 26) The method according to Item 25, wherein the composition contains cyclobenzaprine HCl and the eutectic melts at 143.6 ± 3°C. (Item 27) The method according to any one of Items 15 to 24, wherein the eutectic composition contains δ-mannitol. (Item 28) The method according to Item 27, wherein the composition contains cyclobenzaprine HCl and the eutectic melts at 134°C ± 3°C.

Claims

The disease to be treated by the pharmaceutical composition of the present invention.

Images