HK40047283B - Eutectic formulations of cyclobenzaprine hydrochloride - Google Patents

Description

Eutectic formulation of cyclobenzaprine hydrochloride

The application is a divisional application of which the mother application is China patent application 201580050140.2.

RELATED APPLICATIONS

The present application claims priority and benefit from U.S. provisional patent application 62/052,238 filed on 18, 9, 2015, the contents and disclosure of which are incorporated herein by reference in their entirety.

Background

Cyclobenzaprine or 3- (5H-dibenzo [ a, d ] cyclohepten-5-ylidene) -N, N-dimethyl-1-propylamine was first approved by the U.S. food and drug office 1977 for the treatment of acute muscle spasms of local origin. (Katz, W., et al Clinical Therapeutics 10:216-228 (1988)).

Subsequent studies have shown that cyclobenzaprine is also effective in treating fibromyalgia syndrome, post-traumatic stress disorder (PTSD), generalized anxiety disorder, and depression. In addition, the utility of cyclobenzaprine as an agent for improving sleep quality, as a sleep deepening agent, or for treating sleep disorders has also been studied. However, while FDA-approved therapeutic agents address pain and mood, there is currently no FDA-approved treatment for disturbed sleep and fatigue associated with fibromyalgia syndrome. Treatment with cyclobenzaprine may be particularly useful for treating sleep disorders caused by, exacerbated by, or associated with fibromyalgia syndrome, prolonged fatigue, chronic fatigue syndrome, sleep disorders, psychotic pain disorders, chronic pain syndrome (type II), drug administration, autoimmune diseases, stress or anxiety, or for treating diseases caused by or exacerbated by sleep disorders, and symptoms of such diseases. See, for example, U.S. patent nos. 6,395,788 and 6,358,944, which are incorporated herein by reference.

In combination with certain excipients, the cyclobenzaprine HCl active pharmaceutical ingredient (or API) is stable in a pill, tablet, or capsule formulation for oral administration. However, cyclobenzaprine HCl has slow absorption when ingested orally (orally or po). To accelerate absorption, tablets containing cyclobenzaprine HCl have been formulated in various Sublingual (SL) formulations. However, both sublingual and oral formulations can have stability problems of the API and the physical composition itself, especially in the presence of alkalizing agents (compounds that increase the pH of the solution after dissolution of cyclobenzaprine HCl). Thus, there would be a useful composition (with or without an alkalizing agent) and method of making the above composition that increases cyclobenzaprine HCl stability.

Summary of The Invention

Some embodiments of the invention are:

1. a pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl.

2. A pharmaceutical composition of embodiment 1 comprising 60% -90% cyclobenzaprine HCl and 40% -10% mannitol by weight.

3. A pharmaceutical composition of embodiment 2 comprising an amount of cyclobenzaprine HCl and mannitol selected from the group consisting of: 60% ± 2% cyclobenzaprine HCl and 40% ± 2% mannitol, 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% mannitol, 85% ± 2% cyclobenzaprine HCl and 15% ± 2% mannitol, and 90% ± 2% cyclobenzaprine HCl and 10% ± 2% mannitol by weight.

4. A pharmaceutical composition of embodiment 3 comprising 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol by weight.

5. The pharmaceutical composition of any of embodiments 1-4, wherein the cyclobenzaprine HCl: mannitol molar ratio is 1.76±0.1.

6. The pharmaceutical composition of any of embodiments 1-5, wherein the cyclobenzaprine HCl is micronized cyclobenzaprine HCl.

7. The pharmaceutical composition of any of embodiments 1-6, further comprising an alkalizing agent.

8. The pharmaceutical composition of embodiment 7, wherein the alkalizing agent is K ₂ HPO ₄ 。

9. The pharmaceutical composition of embodiment 7, wherein the alkalizing agent is Na ₂ HPO ₄ 。

10. The pharmaceutical composition of embodiment 7, wherein the alkalizing agent is trisodium citrate anhydrous.

11. The pharmaceutical composition of any of embodiments 1-10, wherein the composition comprises a granule.

12. The pharmaceutical composition of embodiment 11, wherein the granule comprises cyclobenzaprine and mannitol.

13. The pharmaceutical composition of embodiment 12, wherein the mannitol is β mannitol and δ mannitol.

14. The pharmaceutical composition of any of embodiments 11-13, wherein the granule comprises an inner layer comprising beta mannitol and an outer layer comprising a eutectic of mannitol and cyclobenzaprine HCl

15. A method of preparing the eutectic composition of any of embodiments 1-14, comprising mixing cyclobenzaprine HCl and mannitol.

16. The method of embodiment 15, wherein the mixing is wet granulation mixing.

17. The method of embodiment 15 or 16, further comprising mixing an alcohol with the cyclobenzaprine HCl and the mannitol.

18. The method of embodiment 17, wherein the alcohol is methanol.

19. The method of embodiment 17, wherein the alcohol is ethanol.

20. The method of any of embodiments 16-19, further comprising drying after the wet granulation.

21. The method of embodiment 20, wherein the wet granulation and drying are repeated one or more times.

22. The method of any of embodiments 16-19, further comprising crystallizing after the wet granulation.

23. The method of embodiment 22, wherein the wet granulation and crystallization are repeated one or more times.

24. A method of preparing the eutectic composition of any of embodiments 1-14, comprising fluidized bed drying cyclobenzaprine HCl and mannitol.

25. The method of any one of embodiments 15-24, wherein the eutectic composition comprises β mannitol.

26. The method of embodiment 25, wherein the composition comprises cyclobenzaprine HCl and the eutectic melts at 143.6 ± 3 ℃.

27. The method of any one of embodiments 15-24, wherein the eutectic composition comprises delta mannitol.

28. The method of embodiment 27, wherein the composition comprises cyclobenzaprine HCl and the eutectic melts at 134 ℃ ± 3 ℃.

Drawings

FIG. 1 depicts an exemplary Differential Scanning Calorimetry (DSC) of a small peak corresponding to a delta mannitol eutectic (melting point 139.75 ℃) formed by wet granulation with cyclobenzaprine HCl, mannitol, and water.

Fig. 2 depicts differential scanning calorimetry curves of delta mannitol eutectic mixtures, which are formed as follows: cyclobenzaprine and mannitol were dissolved in a methanol and water mixture followed by rapid evaporation.

Fig. 3 depicts an X-ray powder diffraction pattern of a delta mannitol eutectic, formed as follows: cyclobenzaprine and mannitol were dissolved in a methanol and water mixture followed by rapid evaporation.

Fig. 4 depicts X-ray powder diffraction data for delta mannitol eutectic, which is formed as follows: cyclobenzaprine and mannitol were dissolved in a methanol and water mixture followed by rapid evaporation.

Fig. 5 depicts X-ray powder diffraction data for delta mannitol eutectic, which is formed as follows: freeze-dried but not annealed.

Fig. 6 depicts a phase diagram of delta mannitol eutectic, formed as follows: freeze-dried but not annealed.

Fig. 7 depicts X-ray powder diffraction data for delta mannitol eutectic, which is formed as follows: freeze-dried and annealed.

Fig. 8 depicts a phase diagram of delta mannitol eutectic mixture formed as follows: freeze-dried and annealed.

Fig. 9 depicts differential scanning calorimetry curves of delta mannitol eutectic mixtures, which are formed as follows: let 65% cyclobenzaprine: a mixture of 35% mannitol (w/w) was rapidly evaporated in a 1:1 mixture of methanol to water.

FIG. 10 depicts differential scanning calorimetry data of cyclobenzaprine HCl-mannitol mixtures, spray dried with ethanol and water.

Figure 11 depicts X-ray powder diffraction data comparing the spray dried (upper) cyclobenzaprine HCl-mannitol mixture with ethanol and water and spray dried (lower) with water alone.

Detailed Description

Unless defined otherwise herein, scientific and technical terms used herein shall have the meaning commonly understood by one of ordinary skill in the art. In general, the techniques and nomenclature used for pharmacology, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

Unless otherwise indicated, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and described in various general and more specific references that are cited and discussed throughout this specification.

Chemical terms used herein are used according to conventional usage in The art, such as "The McGraw-Hill Dictionary of Chemical Terms", parker s., ed., mcGraw-Hill, san Francisco, c.a. (1985).

The above-mentioned entireties and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

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

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

The term "comprising" is used to mean "including but not limited to. "including" and "including, but not limited to," are used interchangeably.

"patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

"treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms associated with a disease or condition as described herein.

The "administration" or "administration" of a substance, compound or agent to a subject can be performed using one of a variety of methods known to those of skill in the art. For example, the compound or agent can be administered sublingually or intranasally, by inhalation to the lung or rectally. Administration can also be performed, for example, 1 time, multiple times, and/or over one or more extended periods of time. In certain aspects, administering includes directly administering itself, and indirectly administering includes prescribing a drug. For example, as used herein, a physician directs the patient to administer a drug by himself or by others and/or provides the patient with a drug prescription for administration of a drug to the patient.

In solid pharmaceutical product formulations, knowledge of the possible interactions between the drug substance and the excipients is critical to predicting chemical and physical stability.

Excipients are often capable of modifying the biological activity and chemical stability of an API due to changes in dissolution or chemical structure. In some cases, excipients can improve the chemical stability characteristics over time and avoid undesirable physical behavior of the final dosage form.

A eutectic mixture system is a compound or mixture of elements having a single chemical composition that melts at a lower temperature than any other composition of that same composition. The composition comprising the eutectic mixture is referred to as a eutectic mixture composition and its melting temperature is referred to as the eutectic temperature. To define the eutectic composition, a binary phase diagram should be established by analyzing the different compound ratios.

The effect of the eutectic mixture on the tablet properties shows that compaction provides sufficient intimate contact and mutual solubility for the eutectic mixture to form. Eutectic mixture compositions often have higher stability and/or dissolution rates than their non-eutectic mixture counterparts. Because the eutectic mixtures enhance dissolution, they can be used to increase permeability in solid dispersions and dispersion systems. However, in developing certain tableting dosage forms, undesirable eutectic formation (during manufacturing operations such as wet granulation) can lead to undesirable changes in physical or chemical characteristics of the tablet, such as low melting temperature, sticking, unpredictable hardness, instability, or difficulty in assessing stability.

Mannitol and sorbitol are excipients commonly used in solid pharmaceutical products. Mannitol and sorbitol are 6-carbon sugar alcohol isomers. Sugar alcohols are hydrogenated carbohydrates whose carbonyl groups have been reduced to primary or secondary hydroxyl groups. Other 6-carbon sugar alcohols include inositol, galactitol, fucosyl alcohol, and iditol.

Although mannitol and sorbitol can be included in the pharmaceutical composition, they are generally because they provide quality benefits such as sweetness or a cooling effect in the mouth and are physically inert. Thus, it was unexpectedly found that mannitol forms a eutectic composition with cyclobenzaprine HCl, which results in a tablet having pharmaceutically acceptable stability even in the presence of an alkalizing agent. In contrast, cyclobenzaprine HCl dissolved in sorbitol did not form a eutectic upon heating (in a differential scanning calorimetry apparatus), and yielded a tablet that disintegrated in the presence of an alkalizing agent at room temperature; this emphasizes the unpredictability of forming the eutectic and the protective effect of the eutectic with mannitol. Without being limited by theory, it is possible that the two lattices of mannitol and cyclobenzaprine HCl interpenetrate and that this interpenetrating physical state provides protection to the cyclobenzaprine HCl from hydration and other chemical interactions.

Compounds of formula (I)

The compound used in embodiments of the present invention is cyclobenzaprine HCl. In certain embodiments, the compound is micronized. In alternative embodiments, the compound is not micronized. In certain embodiments, the compound may be present in one or more crystal isoforms.

As used herein, "cyclobenzaprine HCl" refers to the pharmaceutically acceptable cyclobenzaprine hydrochloride salt of cyclobenzaprine.

Eutectic mixture composition

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

In certain embodiments, the present invention provides pharmaceutical compositions comprising a eutectic of mannitol and cyclobenzaprine HCl, for example, a beta mannitol eutectic, a delta mannitol eutectic, or a combination thereof. In certain embodiments (e.g., where the composition comprises a beta mannitol eutectic), the eutectic has a melting temperature of 143.6±3 ℃. In certain embodiments, the melting temperature of the eutectic is about 135.6 ℃,136.6 ℃,137.6 ℃,138.6 ℃,139.6 ℃,140.6 ℃,141.6 ℃,142.6 ℃,143.6 ℃,144.6 ℃,145.6 ℃,146.6 ℃,147.6 ℃,148.6 ℃,149.6 ℃,150.6 ℃,151.6 ℃,152.6 ℃, or 153.6 ℃. In certain embodiments (e.g., where the composition comprises a delta mannitol eutectic), the eutectic has a melting temperature of 134±3℃. In certain embodiments (e.g., where the composition comprises a delta mannitol eutectic), the melting temperature of the eutectic is about 124 ℃,125 ℃,126 ℃,127 ℃,128 ℃,129 ℃,130 ℃,131 ℃,132 ℃,133 ℃,134 ℃,135 ℃,136 ℃,137 ℃,138 ℃,139 ℃,140 ℃,141 ℃,142 ℃,143 ℃, or 144 ℃. Those skilled in the art will appreciate that the measured melting temperature may vary based on the equipment and conditions used; however, control samples of β and δ mannitol can be used to easily distinguish the melting temperatures of β and δ mannitol in a given sample. In a particular embodiment, the melting temperature of the eutectic mixture is the temperature at which melting begins. In an alternative embodiment, the melting temperature of the eutectic mixture is the temperature at which maximum melting is observed. In certain embodiments, the composition comprises greater than 5% cyclobenzaprine HCl and less than 95% mannitol by weight. In certain embodiments, the composition comprises 1% -5% cyclobenzaprine HCl and 99% -95% mannitol by weight. In certain embodiments, the composition comprises 5% -10% cyclobenzaprine HCl and 95% -90% mannitol by weight. In certain embodiments, the composition comprises 10% -20% cyclobenzaprine HCl and 90% -80% mannitol by weight. In certain embodiments, the composition comprises 10% -90% cyclobenzaprine HCl and 90% -10% mannitol by weight, e.g., 60% -90% cyclobenzaprine HCl 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, 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% 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., compositions comprising a beta mannitol eutectic), the compositions comprise 75% ± 10% cyclobenzaprine HCl and 25% ± 10% mannitol by weight. In certain embodiments, the composition comprises 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol by weight. In certain embodiments, the composition comprises 75% cyclobenzaprine HCl and 25% mannitol by weight. In certain embodiments (e.g., compositions comprising delta mannitol eutectic), the compositions comprise 65% ± 10% cyclobenzaprine HCl and 35% ± 10% mannitol by weight. In certain embodiments, the composition comprises 65% ± 2% cyclobenzaprine HCl and 35% ± 2% mannitol by weight. In certain embodiments, the composition comprises 65% cyclobenzaprine HCl and 35% mannitol by weight. In certain embodiments, the composition comprises cyclobenzaprine HCl and mannitol, wherein the cyclobenzaprine HCl to mannitol molar ratio is from 1.70±0.1 to 1.80±0.1. In certain embodiments, the molar ratio is about 1.6 to 2.0. In particular embodiments, the molar ratio 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.

In certain embodiments, additional mannitol is added to the eutectic mixture, for example as a diluent or as a bursting agent (popping) component (agents that promote disintegration in the oral cavity such asFlash). In these embodiments, mannitolThe total amount of (2) is higher than the amount of mannitol present in the initially formed eutectic mixture. For example, where additional mannitol is added, the composition can comprise about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, or about 55% mannitol by weight. Exemplary compositions containing added mannitol are:

yet another benefit of the eutectic composition of the present invention is the increased stability of the cyclobenzaprine HCl containing tablets. In certain embodiments, the invention provides pharmaceutical compositions comprising cyclobenzaprine HCl and mannitol, wherein the composition in tablet form has increased stability compared to the same tablet without mannitol, e.g., a tablet comprising sorbitol instead of mannitol. In fact, contains cyclobenzaprine HCl, K ₂ HPO ₄ And mannitol are stable for 3 months at 40 ℃ and 75% relative humidity. By comparison, HCl, K containing cyclobenzaprine stored under the same conditions ₂ HPO ₄ And sorbitol, disintegrate before reaching even 1 week.

In certain embodiments, the present invention provides a pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein the composition has an increased dissolution rate of a stable tablet as compared to cyclobenzaprine HCl alone or in a formulation comprising one or more excipients that are not alkalizing agents. For example, the composition can exhibit a dissolution 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% at 5 minutes when mixed with 100mL of 50mM citrate (pH 4) at 37.0±0.5 ℃. For example, the composition can exhibit 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% dissolution at 10 minutes when mixed with 100mL of 50mM citrate (pH 4) at 37.0±0.5 ℃. For example, the composition can exhibit 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% dissolution at 240 minutes when mixed with 100mL of 50mM citrate (pH 4) at 37.0±0.5 ℃. For very soluble compounds (e.g., cyclobenzaprine HCl), a continuous flow dissolution apparatus can be used to measure dissolution.

Mannitol is capable of crystallizing in 3 polymorphic states: α, β, and δ. These 3 forms can be characterized by X-ray powder diffraction and each polymorph has a different melting point. See, e.g., sharma and Kalonia, AAPS PharmaSciTech (1): E10 (2004). Even more surprising than the first eutectic of cyclobenzaprine HCl and mannitol (β polymorph) was observed, was the second eutectic with a different polymorphic form of mannitol (δ polymorph). Eutectic mixtures comprising delta mannitol and cyclobenzaprine HCl (also referred to herein as "delta mannitol eutectic") have several advantages over eutectic mixtures comprising beta mannitol and cyclobenzaprine HCl (also referred to herein as "beta mannitol eutectic"). Among them are in particular a lower melting point than the beta mannitol eutectic and an increased dissolution relative to the beta mannitol eutectic. Yet another advantage is a higher stability in pharmaceutical compositions (including tablets), including compositions containing alkalizing agents, compared to beta mannitol eutectic mixtures. Yet another advantage is a higher local tolerance in pharmaceutical compositions (including tablets), including compositions containing alkalizing agents, compared to the beta mannitol eutectic mixture. Improved dissolution and conversion to cyclobenzaprine free base should also improve tolerability, including reduced temporary numbness of the tongue during sublingual administration of the tablet, improving sublingual absorption.

In certain embodiments, the invention provides a eutectic pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein mannitol is in its β polymorphic form. In certain embodiments, the invention provides a eutectic pharmaceutical composition comprising cyclobenzaprine HCl and mannitol, wherein mannitol is in its delta polymorphic form. In certain embodiments, the pharmaceutical composition comprising beta polymorphic form of mannitol is a sublingual composition. In certain embodiments, the pharmaceutical composition comprising beta polymorphic form of mannitol is an oral composition. In certain embodiments, the pharmaceutical composition comprising delta polymorphic form of mannitol is a sublingual composition. In certain embodiments, the pharmaceutical composition comprising delta polymorphic form of mannitol is an oral composition. In particular embodiments where the composition is an oral composition, the oral composition is bioequivalent to 5mg cyclobenzaprine HCl oral tablet (e.g., 5mg of frerelil). In particular embodiments where the composition is an oral composition, the oral composition is bioequivalent to 10mg cyclobenzaprine HCl oral tablet (e.g., 10mg of freirel). The Freund's tablet is composed of hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, starch, and titanium dioxide. In the case of 10mg t.i.d. dosing in normal healthy volunteers, steady state AUC (4 days after dosing) was 177ng.hr/mL (range 80-319 ng.hr/mL) and Cmax was 25.9ng/mL (range 12.8-46.1 ng/mL). Additional pharmacokinetic properties of cyclobenzaprine administered orally 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 certain embodiments, the invention provides compositions comprising a eutectic of mannitol and cyclobenzaprine HCl. Those skilled in the art will appreciate that these compositions may be adapted for administration in a variety of ways, such as those described herein. For example, the composition may be suitable for oral administration (administration, wherein cyclobenzaprine is absorbed in the gastrointestinal tract), or transmucosal absorption (e.g., sublingual, buccal, or intranasal absorption, or by inhalation).

In certain embodiments, the present invention provides compositions that are particulate compositions. In certain embodiments, the granule is a granule comprising cyclobenzaprine HCl and mannitol. In particular embodiments, the granule comprises an excess of mannitol. In more particular embodiments, the granule comprises beta mannitol, delta mannitol, or both. Granules containing an excess of mannitol may contain, inter alia, beta mannitol and delta mannitol. For example, granules produced by a process such as fluid bed drying may comprise an inner layer of beta mannitol and an outer layer of delta mannitol-cyclobenzaprine eutectic.

Method for preparing eutectic mixture composition

Those skilled in the art will appreciate that the eutectic composition of the present invention can be prepared according to any of a number of known methods. In certain embodiments, the present invention provides a method of producing a eutectic composition of the present invention, comprising milling an API (cyclobenzaprine HCl) and mannitol, mixing the API (cyclobenzaprine HCl) and mannitol, or a combination thereof. For example, the API and mannitol can be ground in an agate mortar or mixed in a high shear granulator. High shear mixing the ingredients were mixed uniformly with a high speed impeller and chopper blade to combine the dry powders. Some particle size reduction is possible due to shear forces and high speeds of the mixing blades. APIs and mannitol can also be used in, for example Grinding and mixing in a shaker-stirrer. In certain embodiments, the API and mannitol can be mixed via compression, e.g., via roller compaction. Compaction forces the fine powder into between two counter-rotating rollers and extrudes the feedstock into a dense solid or sheet (called a flake). The flakes are reduced in size until they reach the desired particle 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).

In certain embodiments, the present invention provides a method of producing a eutectic composition of the present invention, comprising spray drying a solution of API (cyclobenzaprine HCl) and mannitol. Those skilled in the art will appreciate that spray drying is conventional and that the parameters of spray drying can be determined without undue experimentation. For example, spray drying can be performed under any of the following conditions:

tset (c): 120-150

T outlet (°c): 73-90

Feed rate (ml/min): 4-6

Flow rate (L/h): 600-800

Inhalation (100%): 100

Delta pressure (mbar): 2-20

These conditions can also be scaled up or adjusted to provide higher throughput production.

In certain embodiments, a composition comprising a eutectic of delta mannitol cyclobenzaprine HCl and mannitol is prepared by mixing mannitol and cyclobenzaprine HCl. The mixing can be, for example, wet granulation, including high shear wet granulation. Fig. 1 shows an exemplary Differential Scanning Calorimetry (DSC) with small peaks corresponding to delta mannitol eutectic (melting point 139.75 ℃) formed by wet granulation with cyclobenzaprine HCl, mannitol, and water. Wet granulation can then be fluidized bed dried, and optionally ground, to produce the composition. Without being limited by theory, it is possible that during wet granulation, cyclobenzaprine and mannitol (starting in their β form) become metastable, and then some or all of the wetted edges of the β mannitol crystals in the paste formed by wet granulation crystallize into a β and/or δ mannitol eutectic with cyclobenzaprine HCl. This may occur as the solvent evaporates, the process of interpenetration and recrystallization of the crystals into a eutectic occurs during the mixing or drying stage, either directly or through a modified metastable amorphous intermediate and subsequent nucleation with the beta and/or delta mannitol eutectic. In certain embodiments, wet granulation and drying can be cycled continuously to stimulate or enhance delta mannitol eutectic formation. Without being limited by theory, circulating wet granulation and drying may enhance delta mannitol eutectic formation, as a single cycle may produce a portion of the total possible delta mannitol eutectic, while each cycle promotes additional delta mannitol formation.

In certain embodiments, the composition comprising a eutectic of delta mannitol cyclobenzaprine HCl and mannitol is produced by fluid bed drying (also known as fluid bed drying). Without being limited by theory, fluidized bed drying may have advantages over other eutectic mixture forming methods in that it provides controlled, gentle, and uniform wet solids drying. The intensive heat/mass exchange of the fluidized bed product makes the process particularly efficient and time-saving. The technique is also suitable for spray granulation with very low residual moisture or post-drying of extruded products.

In certain embodiments, fluid bed drying can be used to form cyclobenzaprine pharmaceutical products. The drying process using fluidized bed drying can reduce the drying time in the drying oven by about 20 times relative to other methods. Furthermore, fluid bed drying provides controlled and uniform drying conditions compared to possible non-uniform drying in the tray. In addition, fluid bed drying can improve the homogeneous distribution of the active pharmaceutical ingredient over the surface of one or more excipients.

In the case of spraying a liquid solution containing a solvated drug substance (e.g. cyclobenzaprine HCl) onto the surface of excipient particles, a fluid bed drying technique can be used. In this way, the spray solution at the surface of the excipient particles constitutes a positive interaction between the solution and the solid particles. During the drying step under a stream of hot air, water is removed from the surface so that the active pharmaceutical ingredient is attached to the excipient particles. In certain embodiments, a cyclobenzaprine HCl solution (e.g., cyclobenzaprine HCl and water) is sprayed onto mannitol to form a eutectic between cyclobenzaprine and mannitol. Without being limited by theory, where a solution of the active pharmaceutical ingredient (e.g., cyclobenzaprine HCl) spreads out over a surface through a nozzle and forms a eutectic mixture, the eutectic mixture particles may physically interact with particles comprising one or more excipients, constituting granules of the desired size.

A further advantage of fluidized bed drying is that drying occurs in thermodynamic equilibrium. The inlet air temperature is chosen such that the water evaporated from the particle surface is only equivalent to those transported from the interior of the particle to the surface by capillary tubes. During this moisture migration, the active pharmaceutical ingredient can be linked to the substance on which it has been sprayed. For example, in the case of spraying cyclobenzaprine HCl onto mannitol, the cyclobenzaprine HCl and mannitol are mixed in the correct ratio to form a eutectic, although there is an excess of mannitol that is not required for eutectic formation. Even more surprisingly, this process resulted in a eutectic of cyclobenzaprine and delta mannitol, although the cyclobenzaprine HCl spray and mannitol thereon was beta mannitol. With proper use, fluid bed drying provides an effective solution that constitutes a proper particle size for good tabletting, has a uniform active pharmaceutical ingredient distributed throughout the tablet and does not undesirably flake off.

In certain embodiments, the alcohol is used to stimulate or enhance the formation of delta mannitol eutectic. Exemplary alcohols 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 delta mannitol eutectic (see figure 10 differential scanning calorimetry data and figure 11X-ray powder diffraction data, which compare ethanol and water spray drying alone). For example, a 1:1 ethanol:1 water mixture containing 5% (w/w) cyclobenzaprine and mannitol mixture can be introduced during spray drying to constitute the delta mannitol eutectic. In an alternative embodiment, ethanol is used in combination with wet granulation to stimulate or enhance the formation of delta mannitol eutectic. In other embodiments, ethanol is used in combination with lyophilization to stimulate or enhance the formation of delta mannitol eutectic. In other embodiments, ethanol is used in combination with flash evaporation to stimulate or enhance the formation of delta mannitol eutectic. In additional embodiments, ethanol is used in combination with fluid bed drying to stimulate or enhance the formation of delta mannitol eutectic. In certain embodiments, methanol is used in combination with spray drying to stimulate or enhance the formation of delta mannitol eutectic. In an alternative embodiment, a combination of methanol and wet granulation is used to stimulate or enhance the formation of delta mannitol eutectic. In other embodiments, methanol is used in combination with lyophilization to stimulate or enhance the formation of delta mannitol eutectic. In other embodiments, methanol in combination with flash evaporation is used to stimulate or enhance the formation of delta mannitol eutectic. In additional embodiments, methanol is used in combination with fluid bed drying to stimulate or enhance the formation of delta mannitol eutectic. An exemplary protocol for spray drying to obtain a delta mannitol eutectic mixture via spray drying with ethanol is as follows:

The device comprises: buchi Mini Spry Dryer SD B290 and 290

Ethanol to water solvent at a ratio of 1:1v/v

Cyclobenzaprine: concentration of mannitol mixture (ratio e.g. 65:35) in solution: 5% w/w

Spray drying conditions:

inlet temperature=150℃

Outlet temperature=90℃

Solution flow rate = about 6mL/min

Delay time (required for complete recrystallization of the powder distributed on the device) before removal of the powder from the device = 1-2 hours

In certain embodiments, the flash evaporation process is used to stimulate or enhance the formation of delta mannitol eutectic. Flash evaporation refers to the step of mixing 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 flash evaporation of the solvent, e.g., by hot air over the solution. Cyclobenzaprine HCl, mannitol, and water can be mixed to form a paste (e.g., wet granulation) or can be mixed to form a solution. For example, 65% cyclobenzaprine: 35% mannitol (w/w) mixture in methanol: the water 1:1 mixture (final concentration of cyclobenzaprine/mannitol mixture 5% to 20%) evaporated rapidly, forming a delta mannitol eutectic after about 30 minutes of drying (see fig. 9). See also fig. 2-4, wherein the delta mannitol eutectic mixture is formed as follows: cyclobenzaprine and mannitol were dissolved in a mixture of methanol and water followed by rapid evaporation.

In certain embodiments, lyophilization is used to stimulate or enhance the formation of delta mannitol eutectic. In certain embodiments, lyophilization is performed without annealing. See fig. 5 and 6, which show X-ray powder diffraction data and phase diagrams, respectively, of the delta mannitol eutectic formed by lyophilization but not annealing. Although these traces show low crystallinity in the initial composition, delta mannitol eutectic crystals form more clearly after a period of crystallization. In an alternative embodiment, lyophilization and annealing is performed. See fig. 7 and 8, which show X-ray powder diffraction data and phase diagrams, respectively, of the delta mannitol eutectic formed by lyophilization and annealing. Although these traces show low crystallinity in the initial composition, delta mannitol eutectic crystals form more clearly after a period of crystallization.

Method for detecting eutectic mixture composition

Methods for detecting eutectic mixture compositions are well known. Those skilled in the art will appreciate that the eutectic composition can be detected by any of these methods. For example, rapid differential scanning calorimetry ("DSC") can be used to detect eutectic melting points: the heat recorded from the eutectic melting was evaluated and compared to the heat of fusion of the eutectic composition. During the slow scan of the DSC, the increased temperature in the crucible promotes the formation of a eutectic mixture even where the two components (such as mannitol and cyclobenzaprine HCl) may not be mixed before the start of the experiment. In contrast, fast DSC scanning reduces the time that the eutectic composition can form in the crucible, as the temperature inside the crucible increases rapidly during analysis and reaches the value of mannitol melting rapidly. Yet another useful method is to measure the compaction force vs. In this process, the mixture is prepared in known ratios and then subjected to a well-defined compaction force. DSC analysis was then performed, and the thermal vs force of the eutectic melt was recorded and plotted. These values are compared to those obtained with the eutectic ratio, providing the percentage of eutectic in the formulation.

An additional method that can be used to detect the amount of eutectic in a composition is to compare the tensile strength and compressive force. In this method, tablets were prepared with only mannitol and API, using different compression forces. For each tablet prepared, the tensile strength of the formed percent vs tablet of the eutectic mixture was corrected. There is a proportional linear correlation between tensile strength and intimate contact area. The associated slope provides a percentage of the eutectic mixture formed.

There is a linear correlation between the percentage of eutectic composition in the formulation and the porosity of the powder in the composition. In this method, the standard curve can be generated as follows: samples were prepared with different ratios of components, where at least one of the components had various particle sizes, specific surface areas and porosity of the powder were measured, and porosity was plotted against the percentage of eutectic mixture. Because there is a linear correlation between the two parameters, the slope of the correlation provides the percentage of eutectic mixture formed by recording the eutectic mixture.

The dissolution rate can also be used to detect the percentage of eutectic mixture, as the eutectic mixture can have higher solubility and higher bioavailability. In this method, the intrinsic dissolution rate of the individual components (with a disc sample holder in a defined and appropriate medium) is calculated, followed by calculation of the dissolution rate of the eutectic mixture. Based on thermodynamic parameters (entropy), the eutectic mixture should have a faster dissolution rate than the other mixtures. From these analyses, it is also possible to obtain information about the efficacy of the tablet in terms of bioavailability. This approach also enabled evaluation of higher bioavailability of the mixture of individual components of the eutectic vs.

Scanning Electron Microscopy (SEM) can be used to scan EM for each of the pure components, eutectic mixtures and mixtures, and observe different crystal morphologies by pointing out the differently shaped particles.

Method of administering a eutectic composition

The appropriate method of administering a pharmaceutical composition of the invention to a subject will depend on, for example, the age of the subject, the activity or inactivity of the subject at the time of administration, the symptoms of whether the subject is experiencing a disease or condition at the time of administration, the extent of the symptoms, and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the API. In certain embodiments, the pharmaceutical composition is administered for oral or transmucosal absorption.

Methods of administering compositions for oral absorption are well known in the art. For example, the composition may be administered orally in the form of a tablet, capsule, pill or powder. In these embodiments, the composition is absorbed through the gastrointestinal tract after swallowing. In certain embodiments, the composition lacks a film or membrane (e.g., a semipermeable membrane).

Methods of administering compositions for transmucosal absorption are well known in the art. For example, the composition may be administered for buccal absorption by buccal tablets, troches, buccal powders, and buccal spray solutions. The composition may be administered for sublingual absorption by sublingual tablets, sublingual films, liquids, sublingual powders and sublingual spray solutions. In certain embodiments, the composition lacks a film or membrane (e.g., a semipermeable membrane). The composition may be administered for intranasal absorption by nasal spray. The composition may be administered for pulmonary absorption by aerosolizing the composition and inhalable dry powder. Since mannitol powder is an inhalation product of U.S. (trade name: Pharmaxis ltd.) inhalants may be particularly advantageous forms of administration. When administered via a spray or nebulized composition, the composition may be prepared as a solution in saline, with benzyl alcohol or other suitable preservatives, or include absorption promoters to enhance bioavailability, fluorocarbons, and/or other solvating or dispersing agents.

Dosages and dosing schedules can be determined by one skilled in the art according to the needs of the subject to be treated. Factors that can be considered by those skilled in the art are, for example, the age or weight of the subject, the severity of the disease or condition to be treated, and the subject's response to treatment. The compositions of the invention can be administered, for example, on demand or daily. In certain embodiments, the composition can be administered immediately prior to sleep or hours prior to sleep. Administration prior to sleep may be beneficial in that it provides a therapeutic effect prior to onset of symptoms of the disease or disorder being treated. Dosing may occur over varying time intervals. For example, a dosing regimen 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 certain embodiments, the dosing regimen will last 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 longer.

Therapeutic use

The pharmaceutical compositions of the invention may be used to treat or prevent the development of fibromyalgia syndrome, also known as fibrositis (see, e.g., moldofsky et al, J Rheumatoid 38 (12): 2653-2663 (2011) and Thomas, J Rheumatoid 38 (12): 2499-2500 (2011)). Fibromyalgia is a chronic, non-inflammatory, rheumatic disease. The American College of Rheumatology (ACR) in 1990 discloses a grading standard for fibromyalgia (Wolfe, F., et al Arthritis and Rheumatism 33:160-172 (1990)). Subsequently, modifications to the ACR standard are disclosed (Wolfe et al, J Rheumatol38 (6): 1113-22 (2011)). Diagnostic criteria are also published by the International Business group network, called "Outcome Measures in Rheumatology" clinical trial or OMERACT (Mease P, et al J Rheumatol 2009;36 (10): 2318-29.). Fibromyalgia is traditionally characterized as stiff or diffuse pain, myalgia, sleep disorder, or fatigue. Pain is generally extensive and sometimes focused on specific "points of weakness" which can lead to extensive pain and muscle cramps when touched. Other symptoms include mental and emotional disorders such as inattention and irritability, neuropsychiatric symptoms such as depression and anxiety, joint swelling, headache, numbness. Fibromyalgia is associated with unrecognized sleep, tiredness, drowsiness, reflux, confusion, and cognitive impairment, including difficulty in multitasking. Fibromyalgia is also often co-morbid with sleep disorders, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the present invention can be used to treat any of the above conditions, as well as any combination thereof.

Some practitioners further classify fibromyalgia into two categories-primary fibromyalgia or secondary-concomitant fibromyalgia. In general, primary fibromyalgia syndrome can be considered fibromyalgia occurring in the absence of yet another significant condition, while secondary-concomitant fibromyalgia can be considered fibromyalgia occurring in the presence of yet another significant medical disorder, which may be caused by or related to patient fibromyalgia alone. Secondary or concomitant fibromyalgia can include fibromyalgia in a patient suffering from classical or explicit rheumatoid arthritis, knee or hand osteoarthritis, lumbago syndrome, cervicodynia syndrome, cancer pain syndrome, temporomandibular joint disorder, migraine, menopause, post-traumatic stress disorder, and interstitial cystitis or painful bladder syndrome (or a combination thereof).

The compositions of the invention may also be used to treat or prevent the development (onset, actual change or perpetuation) of PTSD symptoms following a traumatic event. Traumatic events are defined as direct personal experiences that involve real or threatening death or serious injury, or other threat to the integrity of an individual, or that see events involving death, injury, or threat to the physical integrity of others; or awareness of unexpected or violent death, serious injury, or death threat or injury experienced by family members or other related intimate persons. Directly experienced traumatic events include, but are not limited to, military combat, violent personal attacks (sexual attacks, physical attacks, robbers), kidnapped, hijacked to humanbody, terrorist attacks, affliction, banked to war or concentrated camp prisoners, natural or man-made disasters, serious car accidents, or diagnosed life threatening diseases. For children, an traumatic event may include developing undue sexual experience without threat or actual violence or injury. Events that are seen include, but are not limited to, observing serious injury or non-natural death of others due to a violent attack, accident, war or disaster, or unexpectedly seeing a cadaver or body part. Events known to be experienced by others may include, but are not limited to, a violent personal attack, a serious accident, or a serious injury experienced by a family member or close friend, a sudden unexpected death known to a family member or close friend, or a disease known to have life threatening to a child. If the stressor is of a human origin (e.g., affliction or rape), the disorder may be particularly severe or long lasting. Initiation of PTSD symptoms generally occurs immediately after a traumatic event, during which the PTSD symptoms appear and become increasingly severe. One theory on how PTSD develops is that there is a "learning" or strengthening process during which the wound memory is well-held in mind. As these memories become more fixed (a process called real-time), symptoms such as flashback and nightmares increase in severity and frequency. Intervention during this critical time period may prevent some patients from developing well-developed PTSDs. The actual change in PTSD symptoms generally occurs during weeks and months following a traumatic event. The memory of a person about an event becomes consolidated into a highly vivid and firm memory that again experiences with increasing frequency such as flashback or nightmare. During this time, the symptoms of hypersusceptibility and avoidance behavior can become increasingly severe and incapacitating. Permanent persistence of PTSD symptoms occurs once traumatic memory consolidation, and the symptoms (flashback and nightmare) and hypersomnia experienced again become persistent and remain at levels that functionally disable the patient.

The compositions of the present invention may be used to treat PTSD progression at various stages at various time intervals following a traumatic event. For example, the initial phase of treatment of PTSD may require rapid administration of the present compositions following a traumatic event, such as within the first week, within the second week, within the third week, or within the fourth week or later. By contrast, in treating the actual change phase of PTSD, one skilled in the art would be able to administer the compositions of the present invention later after a traumatic event and later during symptom development, for example, during the first month, during the second month, or during the third month or later. The permanent stage of PTSD may be treated with the compositions of the present invention, administered 3 months or more after a traumatic event, e.g., within the third month, within the fourth month, within the fifth month or later. The PTSD symptoms will be ameliorated or eliminated as a result of initial, actual or permanent stage treatment.

The compositions of the invention can also be used to treat Traumatic Brain Injury (TBI). TBI is associated with sleep disorders, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the invention can also be used to treat any of the above conditions, either in combination with or independent of treatment of TBI.

The compositions of the present invention can also be used for Chronic Traumatic Encephalopathy (CTE). CTE is associated with sleep disorders, 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 independent of the therapeutic CTE.

The compositions and methods of the invention may be used to treat sleep disorders or sleep disturbances. "sleep disorder" can be any 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). One class of primary sleep disorders comprises sleep disorders that are not caused by yet another mental disorder, substance, or general medical condition. They include, but are not limited to, primary insomnia, primary hypersomnia, narcolepsy, circadian rhythm sleep disorders, nightmare disorders, nocturnal convulsions, nocturnal migration disorders, REM sleep behavioural disorders, sleep paralysis, day/night reversal and other related disorders; substance-induced sleep disorders; and sleep disorders caused by general medical conditions. Primary insomnia non-restorative sleep is described by DSM-IV-TR as a type of primary insomnia, where the main problem is lack of mental or mental unrecoverable arousal sensation. The second category includes those sleep disorders attributable to substances, including drugs and drug abuse. The third category comprises sleep disorders resulting from the effects of general medical conditions on the sleep/wake system. A fourth category of sleep disorders comprises those resulting from identifiable psychotic disorders such as mood or anxiety disorders. A fifth category of sleep disorders includes those described as non-restorative sleep. One definition of non-restorative sleep in DSM-IV-TR is the primary insomnia type (A1.3), where the main problem is lack of mental or mental unresponsive arousal sensation. Symptoms of each class of sleep disorders are known in the art. The "sleep disorder" may be a lesion of restorative sleep. The above clinical diagnosis may be made based on the patient's own fatigue feeling when describing wakefulness or the patient reporting poor sleep quality. The blockage of good sleep quality may be described as light sleep or frequent wakefulness, which may be associated with periodic alternating pattern (CAP) A2 or A3 rates or period durations or normalized CAPA2+A3 increases depending on CAP (A2+A3)/CAP (A1+A2+A3) of 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 rhythmic pollution in non-REM sleep, or lack of delta waves during deeper body restorative sleep. The "sleep disorder" may or may not rise to the "sleep disorder" level as defined in DSM-IV, but they may share one or more common symptoms. Symptoms of sleep disorders are known in the art. Among the known symptoms are disorientation, tiredness, a weakening sensation and difficulty concentrating during the awake time. Sleep-related disorders that can be treated with the methods and compositions of the invention are, inter alia, sleep disorders (e.g., intrinsic sleep disorders such as subjective sensory insomnia, psychophysiological insomnia, spontaneous insomnia, obstructive sleep apnea syndrome, central alveolar hypoventilation syndrome, restless leg syndrome, and periodic limb movement disorders; external sleep disorders such as environmental sleep disorders, regulatory sleep disorders, restricted sleep disorders, stimulant-dependent sleep disorders, alcohol-dependent sleep disorders, toxin-induced sleep disorders, disorders related to onset of sleep, hypnotic-dependent sleep disorders, inappropriate sleep hygiene, altitude insomnia, insufficient sleep syndrome, nocturnal eating syndrome, and alcohol intake syndrome; and circadian rhythm sleep disorders such as jet lag syndrome, delayed sleep stage syndrome, late sleep stage syndrome, shift sleep disorders, non-24 hour sleep arousal disorders, and irregular sleep modes), parasomnias (e.g., arousal disorders, mental arousal, and sleep disordered transition disorders such as sleep onset and sleep dyskinesia, sleep-and sleep-wake pattern), sleep disorders and sleep-related disorders or sleep disorders, sleep-related disorders or sleep-related disorders. The compositions of the present invention can also be used to treat muscle spasms. Muscle spasms can be associated with muscle pain, such as back pain. The compositions and methods of the invention can also be used to treat any of the above conditions, in combination with or independent of the treatment of muscle spasms.

Alkalizing agent

The compositions of the present invention may include an alkalizing agent. As used herein, "basifying agent" refers to increasing the dissolution of cyclobenzaprine HCl-containing compoundsAgents for pH of the liquor (e.g. substances which increase the local pH of the liquor containing cyclobenzaprine HCl, including monopotassium phosphate (monopotassium phosphate, monobasic potassium phosphate, KH) ₂ PO ₄ ) Dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K) ₂ HPO ₄ ) Tripotassium phosphate (K) ₃ PO ₄ ) Sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, naH) ₂ PO ₄ ) Disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, na) ₂ HPO ₄ ) Trisodium phosphate (Na ₃ PO ₄ ) Trisodium citrate anhydrous, bicarbonate or carbonate salts, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugate bases of certain organic acids (including bicarbonate salts), and sulfides. Without being limited by theory, the alkalizing agent provides beneficial pharmacokinetics due to the pharmaceutical composition comprising cyclobenzaprine HCl, but it may also destabilize the cyclobenzaprine HCl due to interactions between HCl and the alkalizing agent. Thus, the eutectic mixture composition as described herein may be particularly useful for compositions comprising an alkalizing agent.

Excipient

In certain embodiments, the compositions of the present invention are useful as medicaments. In certain embodiments, the invention provides the use of a composition of the invention in the manufacture of a medicament. In certain embodiments, one or more excipients may be advantageously included in the compositions of the present invention. One skilled in the art will appreciate that the selection of any excipient may affect the selection of any other excipient. For example, selection of a particular excipient may prevent use of one or more additional excipients, as the combination of excipients may produce undesirable effects. Those skilled in the art will be able to empirically determine what additional excipients (if desired) to include in the formulations of the present invention. For example, cyclobenzaprine HCl can be combined with at least one pharmaceutically acceptable carrier, such as a solvent, filler, binder, humectant, disintegrant, dissolution inhibitor, disintegrant, glidant, absorption accelerator, wetting agent, solubilizing agent, lubricant, sweetener, or flavoring agent. By "pharmaceutically acceptable carrier" is meant any diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutically acceptable carrier can be selected according to standard pharmaceutical practice based on the desired route of administration.

Filler (B)

In certain embodiments, it may be beneficial to include a filler in the compositions of the present invention. Fillers are commonly used in pharmaceutical compositions to provide an additive volume of the composition. Fillers are well known in the art. Accordingly, the fillers described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary fillers that may be used in the compositions and methods of the present invention.

Exemplary fillers may include carbohydrates, sugar alcohols, amino acids, and sugar acids. Fillers include, but are not limited to, one, two or more carbohydrates, starch, aldose, ketose, aminosugars, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, galactose, glucose, hexose, idose, mannose, talose, heptose, glucose, fructose, methyl a-D-glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, gulose, idose, talose, erythrose, ribulose, xylulose, allose, tagatose, glucosamine, galactosamine, arabinan, levan, fucan, polygalacturonic acid, dextran, mannans, xylans, inulin, levans, fucoidans, carrageenans, galactose canola (pectin), amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, stone-like elements, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, xanthine gum, sucrose, trehalose, dextran, lactose, alditol, inositol, sorbitol, mannitol, glycine, aldonic acid, uronic acid, aldonic acid, gluconic acid, isovitamin C, vitamin C, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, neuraminic acid, pectic acid, corn starch, and alginic acid.

Disintegrating agent

In certain embodiments, it may be beneficial to include a disintegrant in the compositions of the present invention. Disintegrants facilitate the breaking of solid compositions, allowing for the delivery of active pharmaceutical compositions. Disintegrants are well known in the art. Some disintegrants have been referred to as superdisintegrants because they have fast properties and can be used as disintegrants in the context of the present invention. Accordingly, the disintegrants described herein are not intended to constitute an exhaustive list, but merely provide exemplary disintegrants that may be used in the compositions and methods of the invention. Exemplary disintegrants include crospovidone, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, sodium starch glycolate, sodium calcium carboxymethylcellulose, polyvinylpyrrolidone, lower alkyl-substituted hydroxypropyl cellulose, indion 414, starch, pregelatinized starch, calcium carbonate, gums, sodium alginate and PearlitolPearlitol/>(Roquette) is a mannitol-cornstarch disintegrant specifically designed for an Orally Dispersible Tablet (ODT). Some disintegrants have effervescent qualities.

Glidant

In certain embodiments, it may be beneficial to include a glidant in the compositions of the present invention. Glidants promote the ability of powders to flow freely. Glidants are well known in the art. Accordingly, the glidants described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary glidants that may be used in the compositions and methods of the present invention. Exemplary glidants include colloidal silicon dioxide (silicon dioxide), magnesium stearate, starch, talc, glycerol behenate, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate.

Lubricant

In certain embodiments, it may be beneficial to include a lubricant in the compositions of the present invention. The lubricant helps to keep the composition components from agglomerating. Lubricants are well known in the art. Accordingly, the lubricants described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary lubricants that may be used in the compositions and methods of the present invention. Exemplary lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, vegetable-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, ethyl laurate.

Sweetener composition

In certain embodiments, it may be beneficial to include a sweetener in the compositions of the present invention. Sweeteners help improve the palatability of the composition by imparting sweetness to the composition. Sweeteners are well known in the art. Accordingly, the sweeteners described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary sweeteners that may be used in the compositions and methods of the invention. Exemplary sweeteners include, but are not limited to, compounds selected from the group consisting of: saccharides 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 and calcium salts; cyclorac and salts thereof; dipeptide sweetener; chlorinated sugar derivatives such as sucralose and dihydrochalcones; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and the like, and combinations thereof. Potassium, calcium and sodium salts of hydrogenated starch hydrolysates and 3, 6-dihydro-6-methyl-1, 2, 3-oxathiazin-4-one-2, 2-dioxide are also used in many cases.

Spice

In certain embodiments, it may be beneficial to include a fragrance in the compositions of the present invention. The fragrance helps improve the palatability of the composition by imparting a desired taste to the composition. Perfumes are well known in the art. Accordingly, the perfumes described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary perfumes that may be used in the compositions and methods of the present invention. Exemplary flavors include, but are not limited to, natural and/or synthetic (i.e., artificial) compounds such as peppermint, spearmint, winter green, menthol, fennel, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, lime, mixed fruits, passion fruit, pomegranate, chocolate (e.g., white chocolate, milk chocolate, dark chocolate), vanilla, caramel, coffee, hazelnut, cinnamon, combinations thereof, and the like.

Coloring agent

Colorants can be used to color code the composition, for example to indicate the type and dosage of therapeutic agent. Colorants are well known in the art. Accordingly, the colorants described herein are not intended to constitute an exhaustive list, but are merely provided as exemplary colorants that may be used in the compositions and methods of the present invention. Exemplary colorants include, but are not limited to, natural and/or artificial compounds such as FD & C colorants, natural juice concentrates, pigments such as titanium oxide, silicon 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, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, and anxiety disorder. Any of the described methods of treatment may also be combined with psychotherapeutic interventions that improve the outcome of treatment. Exemplary psychotherapeutic interventions aim to modify or reduce emotional response to traumatic memory, including psychological grooming, cognitive behavioral therapy and ocular movement desensitization and retreatment, systemic desensitization, relaxation training, biofeedback, cognitive treatment therapies, stress infusion training, firmness training, exposure therapy, combined stress infusion training and exposure therapy, combined exposure therapy and relaxation training and cognitive therapy. In each case, the intervention objective involves modifying or reducing the emotional response to the traumatic memory. The desired outcome is generally an improvement in PTSD symptoms or a reduction in the occurrence of symptoms that manifest in physiological responses, anxiety, depression, and a sense of distraction.

In certain embodiments of the invention, the composition is combined with a medicament that can further alleviate PTSD symptoms, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, or anxiety disorder. The drugs include alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants, selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine-norepinephrine reuptake inhibitors, and analgesics. Exemplary anticonvulsants include carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate and valproate. An exemplary alpha-1 adrenergic receptor antagonist is prazosin. Exemplary selective 5-hydroxytryptamine reuptake inhibitors or 5-hydroxytryptamine-norepinephrine reuptake inhibitors include bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, escitalopram, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, and venlafaxine. Exemplary analgesics include pregabalin, gabapentin, acetaminophen, tramadol, and non-steroidal anti-inflammatory drugs (e.g., ibuprofen and naproxen sodium). Additional drugs that can be used in combination with the compositions of the present invention include sodium hydroxybutyrate, zolpidem, pramipexole, modafinil, temazepam, zaleplon, and armodafinil (armodafinil).

It is to be understood that the embodiments of the invention that have been described are merely illustrative of certain applications of the principles of the present invention. Many modifications may be made by one of ordinary skill in the art based on the teachings herein without departing from the true spirit and scope of the invention.

The following examples are provided to represent the invention. These examples are not to be construed as limiting the scope of the invention as these and other equivalent embodiments are apparent upon reference to the disclosure, drawings and appended claims of this application.

Examples

Example 1: wet granulation

In order to produce a delta mannitol eutectic with cyclobenzaprine HCl, the following protocol was used:

1. 52.830% cyclobenzaprine HCl (w/w) (e.g., 368.4 g) and 47.170% mannitol (w/w) (e.g., 328.9 g) were loaded into a high shear granulator.

2. Optionally, cyclobenzaprine HCl and mannitol were mixed for 5 minutes with a paddle speed of 500 rpm.

3. Mix for 1 min under the following conditions: stirring paddle speed, 200rpm; cutter speed, 2000rpm; time, 2 minutes.

4. While mixing was continued, water (10% w/w) was sprayed onto the powder blend.

5. Mix for an additional 1 minute.

6. Drying in a fluid bed dryer to a loss of drying (LOD) of Not More Than (NMT) 2.0% under the following conditions: air flow, 100m ³ /h; wetting temperature: 65 ℃; LOD:0.31%.

7. Samples were collected.

As an example, a cyclobenzaprine HCl-mannitol delta eutectic can be prepared as follows: wet granulation was performed by mixing 368.4g cyclobenzaprine HCl,328.9g Pearlitol 100SD and 55.8g water. Those amounts were used to make a net yield of 662.2g of dry granules, for a total of 95% yield.

The eutectic mixture formed by the above method is then blended with other excipients as follows:

cyclobenzaprine eutectic: 232.4g

Dye D & C yellow #10Lake:0.667g

Pearlitol Flash：1144g

crospovidone-Kollidon CL:87.7g

Anhydrous potassium phosphate monobasic: 52.7g

Natural and artificial spearmint fragrances: 83.3g

Colloidal silica: 22.0g

Sodium stearyl fumarate (PRUV): 43.8

Exemplary compression parameters for tableting include: compression at 30rpm, pressure 5.0kN, optionally precompressed (3.0 kN) to form a tablet with less than 2% weight change, disintegration time of about 40-50 seconds, and hardness of about 3kp. Alternative exemplary compression parameters include: compression at 40rpm (5.5 kN pressure, 3.0kN pre-compression) formed tablets with less than 2% weight change, disintegration time of about 90 seconds, and hardness of 3.0-3.5kp.

Example 2: fluidized bed drying

For the formation of tablets containing cyclobenzaprine by fluid bed drying, the following protocol was used:

beta mannitol having a particle size of less than 20 microns is deposited in a basin at the bottom of the fluidized bed dryer. The warmed air flow is then induced to induce a strong turbulence inside the chamber. After all the substances in the chamber are in a controlled and steady turbulent flow, the aqueous solution containing cyclobenzaprine is connected to a nozzle in the center of the apparatus. In bottom-to-filter turbulence, the liquid spreads out over the mannitol particles by a peristaltic pump, and small, nearly atomized droplets wet the mannitol particle surface. The liquid phase present on the mannitol surface induces partial solvation of the mannitol particle surface. The eutectic mixture forms on the particle surface, starting from the metastable phase and then crystallizing, by the process of hot air removal of the moisture. Preliminary analysis of the granules by thermal analysis (differential scanning calorimetry) and X-ray powder diffraction (XRPD) confirmed the presence of eutectic components in the mixture and the homogenous distribution of cyclobenzaprine HCl throughout the matrix. Without being limited by theory, this interaction of cyclobenzaprine with mannitol by spray induction to form a eutectic can promote more chemically stable drug substances than simple mechanical mixtures. Interestingly, this process resulted in granules with a beta mannitol core and delta mannitol-cyclobenzaprine eutectic outer surface. These granules have improved tabletting properties relative to eutectic mixtures formed by other methods.

Claims (19)

1. A pharmaceutical composition comprising a eutectic of mannitol and cyclobenzaprine HCl, wherein the eutectic comprises 65% ± 2% cyclobenzaprine HCl and 35% ± 2% delta mannitol by weight, and wherein the eutectic is incorporated into a granule characterized by an inner layer comprising beta mannitol and an outer layer comprising a eutectic of delta mannitol and cyclobenzaprine HCl.

2. The pharmaceutical composition of claim 1, wherein the cyclobenzaprine HCl is micronized cyclobenzaprine HCl.

3. A process for preparing the pharmaceutical composition of claim 1 or 2 comprising mixing cyclobenzaprine HCl and mannitol in the presence of a solvent.

4. The method of claim 3, wherein the mixing is wet granulation mixing.

5. The method of claim 3, wherein the mannitol is β mannitol.

6. The method of claim 5, wherein the beta mannitol is converted to delta mannitol.

7. The method of claim 3, wherein the solvent is water, an alcohol, or a mixture thereof.

8. The method of claim 7, wherein the alcohol is methanol.

9. The method of claim 7, wherein the alcohol is ethanol.

10. The method of claim 4, further comprising drying the mixture after the wet granulation.

11. The method of claim 10, wherein the drying is fluid bed drying.

12. The method of claim 10, wherein the wet granulation and drying are repeated one or more times.

13. The process of claim 4, further comprising crystallizing the cyclobenzaprine HCl-mannitol mixture after the wet granulation.

14. The method of claim 13, wherein the wet granulation and crystallization are repeated one or more times.

15. A process for preparing the pharmaceutical composition of claim 1 or 2 comprising fluid bed drying a mixture of cyclobenzaprine HCl, mannitol, and a solvent.

16. The method of claim 15, wherein the solvent is water, an alcohol, or a mixture thereof.

17. The method of claim 16, wherein the alcohol is methanol.

18. The method of claim 16, wherein the alcohol is ethanol.

19. The method of claim 15, wherein the solution of cyclobenzaprine HCl is sprayed onto the β mannitol particles in a fluidized bed dryer.