Therapeutic formulations and uses thereof

Abstract

To provide a solid dispersion of BNC210 and a formulation containing the solid dispersion.SOLUTION: The present invention provides a solid dispersion comprising BNC210 or a salt or prodrug thereof, being dispersed, within a polymer matrix formed by at least one pharmaceutically acceptable polymer, together with one or more pharmaceutically acceptable surfactants; and a tablet comprising the solid dispersion together with one or more pharmaceutically acceptable excipients.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates generally to therapeutic formulations comprising therapeutic compounds that exhibit non-sedating anxiolytic activity, the manufacture of said formulations, and methods and uses of said formulations in the treatment of anxiety and related disorders of the central nervous system. [Background technology]

[0002] Formulation science is the complex yet crucial aspect of creating physiologically effective pharmaceutical products that ensure that active pharmaceutical ingredients (APIs) are delivered to the required site in the body at the correct concentration and rate to enable an effective therapeutic response while avoiding any undesirable side effects. There are literally thousands of excipients / ingredients that formulators can choose from to promote the desired effect, and this choice depends to a large extent on the physical properties of the API and the desired pharmacokinetics (PK).

[0003] In addition to the above, the particular form of the formulation, whether oral (e.g., capsules, tablets, etc.), parenteral (e.g., intravenous, subcutaneous, intramuscular, etc.), or topical (e.g., transdermal, ointments, etc.), is also an important factor to consider when formulating a particular API.

[0004] For example, for oral delivery, whether capsule or tablet, preformulation studies are essential to better understand the physical, chemical and mechanical properties of the API. Such formulation studies consider factors such as pH, solubility, particle size, polymorphism, etc., that ultimately affect the bioavailability and therefore activity of the API when formulated.

[0005] Another factor to consider with respect to bioavailability is the effect of administering the formulation to a patient in a fasted or non-fasted state. Thus, when a formulation is administered immediately after a meal (fed conditions), a food effect study or food effect bioavailability (BA) study is usually performed to evaluate the effect of food on the rate and extent of absorption of a formulation containing an API compared to administration under fasted conditions. Summary of the Invention

[0006] The present invention seeks to ameliorate some of the shortcomings of known formulations of non-sedating anxiolytic APIs. In one embodiment, the present invention provides a compound of formula (I):

[0007] [ka]

[0008] or a salt or prodrug thereof. The present invention also provides solid dosage formulations, particularly tablet formulations, comprising said solid dispersions. The present invention also provides solid dosage formulations, particularly tablet formulations, comprising said solid dispersions, prepared by dry granulation and compression.

[0009] In certain embodiments, the at least one pharma- ceutical acceptable polymer is at least one crystallization inhibitor polymer. In a further embodiment, the solid dispersion comprises an effective amount of (i) a compound of formula (I) or a salt or prodrug thereof, and (ii) an amount of at least one crystallization inhibitor polymer, wherein the ratio of (i):(ii) is from about 10:90 to about 80:20 (wt / wt %).

[0010] During the preformulation studies, the inventors observed that the compound of formula (I) has a high melting point, a low in vitro solubility of the crystalline form of compound I (a thermodynamically stable form, observed when the amorphous form of compound I is exposed to water / humidity), and a low oral exposure that increases with the addition of 0.5% HPMC to the suspension formulation and depends on the fed / fasted state of the subject. In this regard, it was identified that an alternative formulation needs to be developed, for further development focused on preventing (or at least substantially minimizing) the formation of poorly soluble crystalline forms, reducing the food effect, and increasing oral exposure. Solid dispersion techniques, such as hot melt extrusion (HME) and spray drying, lipid formulation, and nanosizing were considered as approaches to overcome the deficiencies of these formulations. Considering the target dose of the compound and its good solubility in a mixture of dichloromethane (DCM) and methanol, it was recognized by the inventors that the compound of formula (1) may be suitable for spray drying. For example, it has been shown that when certain crystallization inhibitor polymers are used in spray-dried amorphous solid dispersions of a drug (a compound of formula (I)), which can be used in the preparation of tablets, undesirable drug / drug interactions that lead to crystallization are avoided (see Figure 1). Preferred ratios of compound of formula (I):polymer are discussed below and can result in advantageously high loadings of API in the subsequent tablet formulation. These resulting tablet formulations have been shown to have good in vivo solubility and to avoid or at least minimize any adverse food effects.

[0011] In a further aspect, the present invention provides a compound of formula (I):

[0012] [ka]

[0013] or a salt or prodrug thereof. In a further aspect, the present invention provides a method for producing a method for the treatment of a cancer (i) 5 mg to 500 mg of a compound of formula (I):

[0014] [ka]

[0015] or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, The ratio of (i):(ii) is about 10:90 to about 80:20 (wt / wt%); Provide tablets.

[0016] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) A compound of formula (I):

[0017] [ka]

[0018] or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, The ratio of (i):(ii) is about 10:90 to about 80:20 (wt / wt%); A solid dispersion is provided.

[0019] In a further aspect, the present invention provides a method of treating a disease of the central nervous system, comprising administering to a subject in need thereof a substantially amorphous form of a compound of formula (I):

[0020] [ka]

[0021] or a salt or prodrug thereof. The present invention provides a method for treating a disease of the central nervous system, comprising the step of: In another aspect, the present invention provides a method of treating a disease of the central nervous system, comprising administering to a subject in need thereof: (i) 5 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I):

[0022] [ka]

[0023] or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, A method for treating a disease of the central nervous system is provided, comprising the step of administering an effective amount of a tablet having a ratio of (i):(ii) of about 10:90 to about 80:20 (wt / wt%).

[0024] In a further aspect, the present invention provides a compound of formula (I) in substantially non-crystalline form dispersed in a polymer matrix formed by a pharma- ceutically acceptable polymer:

[0025] [ka]

[0026] or a salt or prodrug thereof The present invention provides a use of a tablet prepared from a solid dispersion comprising:

[0027] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) 5 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I):

[0028] [ka]

[0029] or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, The present invention provides a use of a tablet having a ratio of (i):(ii) of about 10:90 to about 80:20 (wt / wt%) for treating a disease of the central nervous system.

[0030] In yet another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) 5 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I):

[0031] [ka]

[0032] or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, The present invention provides a use of a solid dispersion formulation having a ratio of (i):(ii) of about 10:90 to about 80:20 (wt / wt%) in the manufacture of a medicament in tablet form for treating a disease of the central nervous system. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 is a graph depicting a three-dimensional representation of the interaction between HPMCAS-M and a compound of formula (I) ("BNC210") versus drug loading. [Figure 2a] FIG. 2a is a graph depicting the mDSC (reversing heat flow versus temperature) of a spray dried composition of the present invention. [Figure 2b] FIG. 2b is a graph depicting the mDSC (reversing heat flow versus temperature) of a spray dried composition of the present invention. [Figure 2c] FIG. 2c is a graph depicting the mDSC (reversing heat flow versus temperature) of a spray dried composition of the present invention. [Figure 3a] FIG. 3a is a graph depicting the XRPD characterization (intensity (cps) versus 2 theta (degrees)) of a spray dried composition of the present invention. [Figure 3b] FIG. 3b is a graph depicting the XRPD characterization (intensity (cps) versus 2 theta (degrees)) of a spray dried composition of the present invention. [Figure 3c] FIG. 3c is a graph depicting XRPD characterization (intensity (cps) versus 2 theta (degrees)) of a spray dried composition of the present invention. [Figure 4a] FIG. 4a is a graph depicting the results of dissolution time testing of spray dried dispersions (API (BNC210) (μgA / mL) versus time (min)). [Figure 4b] FIG. 4b is a graph depicting the results of dissolution time testing of spray dried dispersions (API (BNC210) (μgA / mL) versus time (min)). [Figure 4c] FIG. 4c is a graph depicting the results of dissolution time testing of spray dried dispersions (API (BNC210) (μgA / mL) versus time (min)). [Figure 4d] FIG. 4d is a graph depicting the results of dissolution time testing of the hot melt extrudates (API (BNC210) (μgA / mL) versus time (min)). [Figure 4e] FIG. 4e is a graph depicting the results of dissolution time testing of the hot melt extrudates (API (BNC210) (μgA / mL) versus time (min)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For purposes of the present invention, the following terms are defined below.

[0035] "BNC210" refers to the compound of formula (I) shown below.

[0036] [ka]

[0037] This compound and its salts may be prepared as described in PCT / AU2007 / 001566 (WO2008 / 046135), the entire contents of which are incorporated herein by reference.

[0038] An "excipient" is a pharma- ceutically inactive substance that serves as a vehicle or medium for a drug or other active substance, and the "crystallization inhibitor polymers" described herein are distinct from the use of the term "excipient" as used herein. Thus, the present invention, in certain embodiments, contemplates compositions having BNC210, at least one crystallization inhibitor polymer, and one or more excipients.

[0039] "HPMC" is the excipient hydroxypropyl methylcellulose, also known as hypromellose. It is a semi-synthetic, inert, viscoelastic polymer. It is a non-ionic, hydrophilic derivative of cellulose ether and is stable over the pH range of 3 to 11. A preferred example is HPMC E15LV, a low viscosity grade of premium polymer of about 15 cP (sold by Dupont as METHOCEL™ E15 Industrial LV).

[0040] "HPMCAS" is the excipient hydroxypropyl methylcellulose acetate succinate (i.e., hypermellose acetate succinate), which has various contents of acetyl and succinoyl groups in the polymer and is primarily used as an enteric coating material for both standard enteric coatings and sustained release formulations. There are several HPMCAS that dissolve at various pH levels. Type L HPMCAS are polymers with a high ratio of succinoyl substitution to acetyl substitution (S / A ratio), Type H are polymers with a low S / A ratio, and Type M are intermediate S / A ratio polymers with higher S / A ratios. Type L HPMCAS dissolves at a lower pH (≧5.5) compared to Type M at pH≧6.0 and Type H at pH≧6.8.

[0041] "Cellulose-microcrystalline" is an excipient, often called refined wood pulp, and is often used as a texturizing agent, anticaking agent, suspending agent, and adsorbent. As microcrystalline cellulose, it is often sold under the trade name Avicel PH-105.

[0042] "Croscarmellose sodium" or "sodium croscarmellose" is the sodium salt of an internally bonded carboxymethylcellulose and is used as a superdisintegrant. It is sold, among others, by FMC Biopolymer under the trade name Ac-Di-Sol SD711.

[0043] "Colloidal silica" (also called silicon dioxide or colloidal silicon dioxide) is used in tablet formulations as an anti-caking agent, adsorbent, disintegrant or glidant to allow for improved flowability when the tablet is processed. It is sold, among others, by Cabot under the trade name Cab-O-Sil MP.

[0044] "Sodium stearyl fumarate" (also known as sodium monostearyl fumarate or sodium monooctadecyl fumarate) Fumurate is a water-soluble lubricant that aids in tablet compression. It is sold inter alia by JRS Pharma under the trade name Pruv SSF.

[0045] "PVP-VA" (also PVP / VA copolymer or poly(l-vinylpyrrolidone-co-vinyl) acetate or copovidone or PVP VA64) is a random linear vinylpyrrolidone-vinyl acetate copolymer (vinyl acetate-vinylpyrrolidone copolymer) produced by free radical polymerization of monomers with ratios of vinyl acetate to vinylpyrrolidone ranging from 70:30 to 30:70. It is also known by the trade names Polectron 845 and Luviskol VA281, Kolima 10, 35, Ganhon S860, or Ganex E313, to name a few.

[0046] "CAP" (also known as cellulose acetate, ceracephate, cellulose acetate, 1,2-benzenedicarboxylate) is a cellulose acetate phthalate polymer that is insoluble in water, alcohol, hydrocarbons, and chlorinated hydrocarbons. It is often used as an enteric coating material.

[0047] "Eudragit" is a common trade name for copolymers derived from esters of acrylic and methacrylic acid containing methacrylic acid, methacrylic acid esters, and methacrylate monomers, such as dimethylaminomethyl methacrylate, in ratios ranging from two to three.

[0048] Soluplus™ is a polyvinylcaprolactam-polyvinylacetate polyethylene glycol graft copolymer (PCL-PVAc-PEG) available from BASF. It is a water-soluble copolymer with an average molecular weight ranging from 90,000 to 140,000 g / mol and is capable of solubilizing poorly water-soluble drugs.

[0049] In the formulations of the present invention, the primary active ingredient is a compound of formula (I), or a salt or prodrug thereof. The amount of the compound of formula (I) contained in the formulation is an amount effective to provide a therapeutic plasma concentration in a subject for up to 24 hours. In one embodiment, the formulation, when provided as a tablet, contains between about 10 mg and about 400 mg of active ingredient. In one embodiment, the formulation, when provided as a tablet, contains between about 30 mg and about 300 mg of active ingredient. In one embodiment, the formulation, when provided as a tablet, contains between about 50 mg and about 200 mg of active ingredient. In another embodiment, the tablet formulation contains between about 50 mg and 175 mg of active ingredient. In another embodiment, the tablet formulation contains between about 50 mg and 150 mg of active ingredient. In another embodiment, the tablet formulation contains between about 50 mg and 125 mg of active ingredient. In another embodiment, the tablet formulation contains between about 50 mg and 100 mg of active ingredient. In another embodiment, the tablet formulation contains between about 50 mg and 70 mg of active ingredient.

[0050] It is understood that the solid dispersion formulation disclosed herein comprises only the compound of formula (I) and at least one pharma- ceutically acceptable polymer or at least one crystallization inhibitor polymer. This solid dispersion will ultimately be mixed with additional excipients prior to tablet formation, and such a formulation (i.e., solid dispersion and added excipients) is referred to herein as a pre-tabletting formulation.

[0051] For example, a 1 gram tablet provided by the present invention may contain 50% solid dispersion and 50% other excipients (%wt / %wt basis), which are further described herein. Of course, for a 1 gram tablet containing 150 mg of compound of formula (I), 50% of the tablet would be calculated to be composed of a 50%wt / 50%wt solid dispersion / excipients mixture, with the solid dispersion having 30%wt of compound (I).

[0052] Therefore, the tablet formulation of the present invention also includes a combination of formulation excipients that allows immediate release of active ingredient throughout the gastrointestinal tract. This can be achieved by swelling under the influence of the medium and erosion of the matrix to release the active ingredient through a rapid release controlled process. In certain embodiments, the formulation disclosed herein is an immediate release formulation, for example, showing about 70% dissolution in the first 15 minutes.

[0053] The solid dispersions, pre-tablet formulations and tablet formulations described herein comprise an effective amount of the compound of formula (I) dispersed within a polymer matrix formed by at least one pharma- ceutically acceptable polymer or crystallization inhibitor polymer (used interchangeably) to ensure maintenance of the compound of formula (I) in a substantially amorphous form.

[0054] In certain embodiments, the ratio of (i):(ii) is about 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, and about 80:20 wt / wt%.

[0055] In certain embodiments, the crystallization inhibitor polymer is a polymer excipient selected from the group consisting of HPMCAS-M, HPMCAS-L, HPMCAS-H, PVP-VA, HPMC (e.g., HPMC EI5LV), and Soluplus.

[0056] In certain embodiments, the crystallization inhibitor polymer is HPMCAS-H. In certain embodiments, the crystallization inhibitor polymer is HPMCAS-M. In certain embodiments, the crystallization inhibitor polymer is HPMC E15LV.

[0057] In one particular embodiment, the crystallization inhibitor polymer is HPMCAS-L. In certain embodiments, the crystallization inhibitor polymer is PVP-VA. In one embodiment, the solid dispersion formulations disclosed herein are produced by spray drying. In one embodiment, the total weight of solids in the solution to be spray dried (wt% total solids) is between 2-15% wt, for example, between about 2-10% wt.

[0058] In certain embodiments, the spray drying solvent comprises dichloromethane. In certain embodiments, the spray drying solvent comprises dichloromethane and methanol. In certain embodiments, the spray drying solvent comprises dichloromethane and methanol in a weight / weight ratio of about 90:10 to 60:10, for example, about 85:15, 80:20, 75:25, 70:30, and about 65:35 wt / wt %.

[0059] In certain embodiments, the yield of the spray dried dispersion is about 50-100%. In one embodiment, the solid dispersion formulations disclosed herein are produced by hot melt extrusion (HME). In certain embodiments, the extrudate is produced at a temperature of about 160-190° C.

[0060] The pre-tabletting and tablet formulations may also include microcrystalline cellulose, which is known in the art to be a purified, partially depolymerized cellulose prepared by treating α-cellulose obtained as a pulp from plant material with mineral acid. In one embodiment, the tablet formulation or pre-tabletting formulation includes between about 30% and about 60% (% wt / wt, based on the total weight of the tablet) microcrystalline cellulose. In another embodiment, the tablet formulation or pre-tabletting formulation includes between about 35% and about 55% (% wt / wt) microcrystalline cellulose. In another embodiment, the pre-tabletting and tablet formulation includes between about 40% and about 50% (% wt / wt) microcrystalline cellulose.

[0061] In one embodiment, the pre-tabletting and tablet formulations contain between about 0.2% and about 2% (% wt / wt, based on the total weight of the tablet) sodium stearyl fumarate (SSF). In another embodiment, the pre-tabletting and tablet formulations contain between about 0.3% and 1.5% (% wt / wt) SSF. In another embodiment, the pre-tabletting and tablet formulations contain between about 0.5% and 1% (% wt / wt) SSF. In another embodiment, the formulations contain between about 0.5% and 0.8% (% wt / wt) SSF.

[0062] In another embodiment, the pre-tabletting and tablet formulations contain about 0.8%-2.5% (% wt / wt) croscarmellose sodium, based on the total tablet weight. In another embodiment, the pre-tabletting and tablet formulations contain about 1%-2% (% wt / wt) croscarmellose sodium. In another embodiment, the pre-tabletting and tablet formulations contain about 1.2%-1.8% (% wt / wt) croscarmellose sodium.

[0063] In another embodiment, the pre-tabletting and tablet formulations contain between about 0.5% and about 2% (% wt / wt, based on the total weight of ferrous sulfate) colloidal silica. In another embodiment, the pre-tabletting and tablet formulations contain between about 0.7% and about 1.5% (% wt / wt) colloidal silica. In another embodiment, the formulations contain between about 0.9% and about 1.3% (% wt / wt) colloidal silica.

[0064] In certain embodiments, the tablet formulation comprises a coated tablet.Accordingly, the coating components can comprise polymers, plasticizers and pigments, which are mixed and finely dispersed as a film covering the tablet to protect the tablet, maintain the tablet shape, aid in swallowing, and provide a glossy appearance.The above formulation uses a poly(vinyl alcohol) (PVA)-based coating formulation.

[0065] In another embodiment, to further aid in solubility, the formulation also includes a surfactant selected from SLS (sodium lauryl sulfate) or a sorbate, which, when added, is present in an amount of less than 5% (wt / wt of the total formulation), for example, about 4%, about 3%, about 2%, about 1% or less than about 1%.

[0066] The surfactant can be added either at the solid dispersion stage or at the tabletting stage. Tabletting Process In certain embodiments, the excipients and solid dispersion (comprising the compound of formula (I)) of the pre-tabletting formulation may be advantageously combined and processed by a dry granulation process which may consist of intragranular blending, roller compaction, de-lumping and extragranular blending. This has been found to be advantageous as it further aids in maintaining the compound of formula (I) in an amorphous state. Moreover, such a process has been found to produce flowable granules suitable for compression in a tablet press. The granules may be compressed at a compression pressure ranging from 80 to 200 MPa.

[0067] Thus, in another aspect, the present invention comprises: (i) A compound of formula (I) in substantially non-crystalline form:

[0068] [ka]

[0069] or a salt or prodrug thereof, by dispersing said compound of formula (I) in a polymer matrix formed by at least one pharma- ceutically acceptable polymer; (ii) mixing the solid dispersion of step (i) with at least one pharma- ceutically acceptable excipient; (iii) subjecting the mixture obtained in step (ii) to dry granulation; and (iv) tableting the dry granulation mixture of step (iii) by compression. The present invention provides a method for preparing a pre-tablet pharmaceutical composition, comprising: Treatment The present disclosure also contemplates the treatment or prevention of diseases of the central nervous system, such as mood disorders (e.g., depression), anxiety disorders, and neurodegenerative diseases. The term neurodegenerative disease encompasses pathologies that lead to progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases contemplated herein include AIDS dementia complex, adrenoleukodystrophy, Alexander disease, Alpers disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, brainstem and cerebellar atrophy, Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familial insomnia, Friedreich's ataxia, familial spastic paraparesis, frontotemporal lobar degeneration, Huntington's disease, These include infantile Refsum disease, Kennedy disease, Krabbe disease, Lyme disease, Machado-Joseph disease, monolimbic muscular atrophy, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, neurodegenerative diseases with cerebral iron deposition, opsoclonus-myoclonus, Parkinson's disease, Pick's disease, primary lateral sclerosis, progranulin, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, protein aggregation, Refsum disease, Sandhoff disease, diffuse myelinoclastic sclerosis, Shy-Drager syndrome, spinocerebellar ataxia, spinal muscular atrophy, spinal-bulbar muscular atrophy, subacute combined spinal degeneration, laryngeal spinal cord, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, and Wobbly hedgehog syndrome.

[0070] In certain embodiments, tablets containing Compound (I) can be used to treat, ameliorate, prevent or delay the onset or progression of a CNS disease, disorder or condition.

[0071] Thus, the present invention provides a pharmaceutical composition for treating and / or preventing a central nervous system disorder, such as a mood disorder (e.g., depression), an anxiety disorder, or a neurodegenerative disease, in a subject in need thereof. The use of tablet formulations containing Compound (I) in manufacture is taught herein.

[0072] Also provided herein is a method for treating and / or preventing a central nervous system disorder, such as a mood disorder (e.g., depression), an anxiety disorder, or a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a tablet comprising Compound (I).

[0073] As used herein, mood disorders are widely recognized and well-defined by applicable DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revised) criteria. Thus, there is a group of depressive disorders, the best known and most studied of which are major depressive disorder (MDD, commonly referred to as clinical depression or major depression), and bipolar disorder (BD, formerly known as manic depression, characterized by intermittent episodes of mania or hypomania, usually combined with multiple depressive episodes). Other depressive disorders include atypical depression, melancholic depression, psychotic major depression, catatonic depression, postpartum depression, seasonal affective disorder, dysthymia, depressive disorder not otherwise specified (DD-NOS) (e.g., recurrent brief depression, minor depressive disorder), substance-induced mood disorder (e.g., alcohol-induced mood disorder, benzodiazepine-induced mood disorder, interferon-alpha-induced mood disorder).

[0074] Those skilled in the art are familiar with the lag period of conventional antidepressant drugs and the increased anxiety caused by new generation antidepressants, including SSRIs, SNRIs and NRIs, in the early stages of treatment (within 2-4 weeks) before antidepressant effects are observed. Thus, in certain embodiments, the compounds described herein can be administered to a subject in need thereof as a substitute or replacement for a conventional antidepressant drug. In another embodiment, the compounds described herein can be administered to a subject in need thereof as a supplement to a conventional antidepressant drug. In another embodiment, a method of treating or preventing depression in a subject is provided, comprising administering to the subject a tablet described herein without adjunctive antidepressant therapy.

[0075] Substituting the tablet of the present invention for conventional antidepressant drugs may be advantageous, especially when conventional drug therapy is accompanied by one or more adverse effects (e.g., anxiety, nausea, headache, erectile dysfunction, early-onset suicidality, etc.). Examples of conventional antidepressant drugs are known to those skilled in the art and include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), serotonin / noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and other mood stabilizers, atypical antidepressants, and hormones such as estrogen or progestogens.

[0076] In another embodiment, the tablet of the present invention can be administered to a subject in need thereof together with a conventional antidepressant for about 2-4 weeks to address symptoms of depression, with the option of discontinuing treatment with the compound of the present invention while continuing the conventional treatment. In another embodiment, the subject is treated with both the tablet of the present invention and one or more conventional antidepressant drugs (administered sequentially or in combination) for the treatment period. Such combination therapy can be particularly useful, for example, when the combination of the tablet formulation of the present invention with one or more conventional antidepressant drugs provides relief from depression in the acute phase with a delayed effect during the treatment period, and / or when an additive or synergistic antidepressant therapeutic effect is desired.

[0077] Relapse of depression can also occur in patients treated with conventional antidepressant drugs. Many such compounds are administered for months to years and often show reduced efficacy with such extended use, leading to significant ongoing depression and functional impairment. Depression may be sudden in some patients, and in others, it may manifest as a gradual decline in mood and function, which may decline over time as the patient approaches a state of relapse. Thus, the tablet formulation of the present invention can compensate for the diminishing effect of conventional antidepressant treatment, so that patients who experience sudden onset of depression relapse or gradual depression relapse will benefit from the methods disclosed herein. Thus, the use of the tablet formulation of the present invention can prevent or partially alleviate the relapse of depression commonly observed in patients taking conventional antidepressant drugs.

[0078] Thus, in certain embodiments, provided herein is a method of treating or preventing relapse in a subject receiving antidepressant therapy, comprising administering to the subject a tablet comprising Compound (I) as described herein.

[0079] Conventional antidepressant treatments related to possible depression recurrence in subjects will be known to those skilled in the art.Examples include but are not limited to: increased dosage, alternative SSRI or SNRI, and non-SSRI antidepressants, such as noradrenaline reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and other mood stabilizers, atypical antidepressants, and hormones such as estrogen and progestogen, which are also referred to herein as "second antidepressant compound".

[0080] The desired therapeutic activity or therapeutic effect will usually depend on the pathology being treated.For example, if a subject is treated for depression, therapeutic effect can be the reduction of at least one clinical symptom of depression, including but not limited to cognitive impairment, anorexia, depression and / or inactivity.

[0081] In certain embodiments, the tablet formulations described herein are administered to the subject sequentially (i.e., before or after) or in combination with a second antidepressant compound (e.g., with an existing antidepressant treatment).

[0082] In certain embodiments, the tablet formulations disclosed herein have the added benefit of being more than conventional treatments in that they reduce sedative side effects that can adversely affect a subject's quality of life. In certain embodiments, the tablet formulations disclosed herein are free of measurable sedative side effects.

[0083] Abrupt cessation of antidepressant medications can result in withdrawal symptoms due to physical dependence on the drug. Compounds can be evaluated for physical dependence in a simple animal model in which the test drug is discontinued after a period of continuous use (e.g., 14-20 days) and food intake, weight, and temperature are measured over the next 5 days. Symptoms of abrupt cessation of the drug are manifested as a marked decrease in appetite, weight loss, and a drop in body temperature. This model is suitable for detecting effects across a wide range of drug classes, including opiates, antidepressants, and benzodiazepines. The compounds described herein, or pharmaceutical compositions thereof, may also be used as combination therapy, e.g., to administer the treatment in combination with other antidepressants, e.g., benzodiazepines (e.g., alprazolam, diazepam, lorazepam, clonezepam), selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, zimelidine, vilaxodone), serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran), monoamine agonists (e.g., benzodiazepines, They may also be used in combination with acetylcholine oxidase inhibitors (e.g., phenelzine, moclobemide), tricyclic antidepressants (e.g., trimipramine, imipramine), tetracyclic antidepressants (e.g., mertazepine, maprotiline), mood stabilizers (e.g., lithium, sodium valproate, valproic acid), atypical antidepressants (e.g., bupropion), acetylcholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine), atypical antipsychotics (e.g., risperidone, aripiprizole, quetiapine, olanzapine), and hormones such as estrogens and progestogens.

[0084] It will therefore be appreciated that the tablet formulations described herein can be used in the treatment and / or prevention of any disease state, disorder or condition that can be ameliorated by enhancing neurite outgrowth.

[0085] In certain embodiments, the disease responsive to neurite outgrowth is a neurodegenerative disease.In certain embodiments, the neurodegenerative disease is multiple sclerosis or Parkinson's disease-like related disorder.In further embodiments, the neurodegenerative disease is multiple sclerosis.In further embodiments, the disease may include conditions involving nerve damage, such as wound healing, spinal cord injury, peripheral neuropathy, etc.

[0086] Subthreshold diseases, pathologies, conditions, disorders, or trauma are also contemplated herein. In one embodiment, a disease, pathology, condition, disorder, or trauma is defined by its symptoms. Thus, the tablet formulations described herein may be useful for improving symptoms of a disease, pathology, condition, disorder, or trauma of the CNS. "Trauma" includes stroke, cerebral hemorrhage, or another condition or event of the systemic vasculature that affects the CNS. Symptoms of a disease, pathology, condition, disorder, or trauma of the CNS will be familiar to those skilled in the art. Examples of such symptoms include mood disorders such as depression. Thus, in certain embodiments, the tablet formulations described herein are used to treat depression caused by (or associated with) a neurodegenerative disease in a subject.

[0087] The tablet formulations described herein can also be used as therapeutics, for example, by combining the treatment with other neurodegenerative treatments, such as acetylcholinesterase inhibitors (e.g., Aricept, Exelon), and multiple sclerosis treatments (e.g., Avonex, Betaseron, Copaxone, Tysabri, Gilenya).

[0088] Of course, the tablet formulations described herein can be used to treat anxiety or anxiety-related pathologies / disease states such as irritable bowel syndrome and fibromyalgia.

[0089] In certain embodiments, the anxiety disorder is classified as one of the following: Panic disorder, Anxiety associated with autism, Obsessive-compulsive disorder (OCD), Post-traumatic stress disorder (PTSD), Social phobia (or social anxiety disorder - (SAD)), ·Specific phobia, Generalized Anxiety Disorder (GAD), Substance-induced anxiety disorder, and Acute Stress Disorder (ASD).

[0090] In certain embodiments, the tablet formulations described herein may be used to treat panic disorder. In certain embodiments, the tablet formulations described herein are used to treat autism. obtain.

[0091] In certain embodiments, the tablet formulations described herein may be used for the treatment of obsessive-compulsive disorder (OCD). In certain embodiments, the tablet formulations described herein may be used to treat restlessness, for example in the elderly.

[0092] In certain embodiments, the tablet formulations described herein may be used for the treatment of post-traumatic stress disorder (PTSD). In one embodiment, the tablet formulations described herein may be used to treat social phobia (or social anxiety disorder - SAD).

[0093] In certain embodiments, the tablet formulations described herein may be used to treat specific phobias. In certain embodiments, the tablet formulations described herein may be used for agoraphobia, or agoraphobia without a history of panic disorder.

[0094] In certain embodiments, the tablet formulations described herein may be used for animal phobia. In certain embodiments, the tablet formulations described herein may be used for the treatment of substance-induced anxiety disorder.

[0095] In certain embodiments, the tablet formulations described herein may be used for the treatment of acute stress disorder (ASD). In certain embodiments, the tablet formulations described herein may be used for the treatment of generalized anxiety disorder (GAD).

[0096] Criteria for generalized anxiety disorder include: (i) "Excessive anxiety and worry" for at least six months about various events and situations. In general, "excessive" can be interpreted as greater than would be expected for a particular situation or event. Most people become anxious about certain things, but the intensity of the anxiety usually corresponds to the situation.

[0097] (ii) Having significant difficulty controlling anxiety and worry. This requirement applies if the person has significant difficulty regaining control, releasing tension, or dealing with anxiety and worry.

[0098] (iii) Presence of three or more of the following symptoms (only one in children) on most days over the past six months: 1. Feeling agitated, nervous, or uneasy 2. Fatigue or exhaustion easily 3. Lack of concentration 4.Irritation 5. Significant muscle tension 6. Difficulty sleeping (iv) The symptoms are not part of another mental disorder.

[0099] (v) The symptoms cause "clinically significant distress" or problems functioning in daily life. "Clinically significant" depends in part on the perspective of the person providing the treatment. Some people can.

[0100] (vi) The condition is not due to a substance or medical problem. In certain embodiments, the tablet formulations described herein may be identified by one or more of the above criteria for generalized anxiety disorder.

[0101] In certain embodiments, the tablet formulations described herein may be used to treat or prevent one or more symptoms associated with an anxiety disorder. Although each anxiety disorder has different symptoms, all symptoms center around excessive and irrational fear and terror.

[0102] In another embodiment, the tablet formulations described herein may be used to treat depression, e.g., major depressive disorder. Criteria for major depressive disorder include:

[0103] (i) At least five of the following symptoms are present during the same 2-week period and represent a change from previous functioning, and at least one of the symptoms is: 1) Depressed mood, or 2) Loss of interest or pleasure Either:

[0104] (ii) A depressed mood most of the day, almost every day, as noted either by subjective report (e.g., feeling sad or empty) or by observations made by others (e.g., appearing to be about to cry).

[0105] (iii) A marked diminution of interest or pleasure in all or almost all activities for most of the day, on most days, as noted either by subjective description or by observations made by others.

[0106] (iv) Significant weight loss or weight gain in the absence of dietary restriction (e.g., weight change of more than 5% in one month) or decreased or increased appetite on most days. (v) Insomnia or hypersomnia almost every day.

[0107] (vi) Psychomotor agitation or psychomotor retardation almost daily (observable by others as well as a subjective feeling of restlessness or slowness). (vii) Fatigue or loss of energy almost every day.

[0108] (viii) Almost daily feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) (not just remorse or guilt about being ill). (ix) Diminished ability to think or concentrate, or difficulty making decisions, almost every day (either by subjective description or as observed by others).

[0109] (x) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan to commit suicide. (xi) The symptoms do not meet the criteria for a mixed episode.

[0110] (xii) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (xiii) The symptoms are not attributable to the direct physiological effects of a substance (e.g., a drug of abuse, medication) or to a systemic medical condition (e.g., hypothyroidism).

[0111] (xiv) Symptoms are not better explained by bereavement, i.e., symptoms persist for more than two months after the loss of a loved one or are characterized by significant functional impairment, preoccupation with feelings of worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

[0112] The above criteria are adapted from the American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revised), Washington DC: American Psychiatric Association.

[0113] In certain embodiments, the tablet formulations described herein may be identified by one or more of the above criteria for major depressive disorder. In another embodiment, the tablet formulations described herein may be used to treat or prevent one or more symptoms associated with depression.

[0114] Further disorders for which the tablet formulations described herein may be beneficial include pain and nociception; emesis, e.g., acute, delayed and anticipatory emesis, particularly chemotherapy or radiation induced emesis, as well as motion sickness and postoperative nausea and vomiting; eating disorders, including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasms or muscle spasms, e.g., in paraplegic subjects; hearing impairment, including tinnitus and age-related hearing loss; urinary incontinence; and effects of substance abuse or dependence, including alcohol withdrawal, neuroses, convulsions, migraines, depressive disorders, bipolar disorders, psychotic disorders, neurodegeneration resulting from cerebral ischemia, attention deficit hyperactivity disorder, Tourette's syndrome, speech disorders, circadian rhythm disorders, single episode or recurrent major depressive disorder, dysthymic disorder, bipolar I or bipolar II mania, cyclothymic disorder, schizophrenia, and stuttering.

[0115] In one embodiment, the tablet formulations described herein can be used to treat cerebral ischemia. In certain embodiments, the tablet formulations described herein can be used to treat neurodegeneration resulting from cerebral ischemia.

[0116] In one embodiment, the tablet formulations described herein may be used to treat circadian rhythm disorders. In one embodiment, the tablet formulations described herein may be used for the treatment of pain and nociception.

[0117] In one embodiment, the tablet formulations described herein may be used in the treatment of Alzheimer's disease. Of course, the tablet formulations described herein can be administered to a subject in a treatment-effective amount. In some embodiments, the treatment-effective amount is a therapeutically or prophylactically effective amount. The term "therapeutically effective amount" as used herein means an amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, body, animal or human that is sought by a researcher, veterinarian, physician or other clinician. The therapeutically effective amount of a compound to be administered will be governed by such considerations and is the minimum amount necessary to improve, cure or treat a disease or disorder or one or more of its symptoms. The term "prophylactically effective amount" refers to an amount effective to prevent or substantially reduce the chance of contracting a disease or disorder, or to reduce the severity of a disease or disorder before it is contracted, or to reduce the severity of one or more of the symptoms of a disease or disorder before the symptoms of the disease or disorder develop. Roughly speaking, preventive measures are divided into primary prevention (to prevent the development of a disease or condition) and secondary prevention (whereby the subject is protected from the worsening of the process even if the disease or condition has already developed).

[0118] As used herein, the term "effective amount" refers to an amount of tablet formulation that, when administered according to a desired dosing regimen, results in a desired therapeutic activity. Dosing may occur minutes, hours, days, weeks, months, or years apart, or continuously over any one of these periods. A suitable dosage is in the range of about 0.1 ng / kg body weight to 1 g / kg body weight per dose. Dosage may range from 1 μg to 1 g / kg body weight per dose, such as from 1 mg to 1 g / kg body weight per dose. In one embodiment, dosage may range from 1 mg to 500 mg / kg body weight per dose. In another embodiment, dosage may range from 1 mg to 250 mg / kg body weight per dose. In yet another embodiment, dosage may range from 1 mg to 100 mg / kg body weight per dose, such as up to 50 mg / kg body weight per dose.

[0119] In certain embodiments, the methods provided include administering to a subject in need of administration of the tablet formulation of the present invention in a dosage amount that provides an in vivo effective amount that enhances neurite outgrowth (neurogenesis), including but not limited to acute treatment (e.g., within 1, 2, 3, or 4 weeks of initiation of treatment). In one embodiment, the in vivo effective amount has an in vitro equivalent concentration sufficient to increase neurite outgrowth by at least 5%, at least 10%, at least 20%, or at least 50% in a neurite outgrowth assay, such as the neurite outgrowth assays described herein. Methods for determining the in vitro equivalent concentration of the compounds of the present invention will be familiar to those of skill in the art. For example, at about 10 minutes to about 60 minutes after administration of the compounds of the present invention to the subject, blood samples are taken and assayed by HPLC, ELISA, gas chromatography, or other suitable assays to determine concentration per ml of blood. The equivalent effective concentration can then be used in the in vitro assay, taking into account factors such as the subject's body weight, the subject's appropriate blood volume, and the appropriate diffusion rate of the compounds of the present invention across the blood-brain barrier. In another embodiment, once the tablet formulation of the present invention is found in vitro to stimulate neurite outgrowth (compared to a control), an approximate in vivo effective amount can be determined for a subject by extrapolating the in vitro concentration to an in vivo equivalent amount.Factors such as the subject's body weight, the subject's appropriate blood volume, and the appropriate diffusion rate of the compound of the present invention across the blood-brain barrier may be used to extrapolate the in vivo effective amount, and therefore the appropriate dosage that produces said in vivo effective amount.

[0120] Then, the treatment with the tablet formulation may be continued throughout the treatment period, or may be discontinued, or may be replaced by conventional therapeutic compounds.The method of determining the effective amount of tablet formulation required to enhance neurite outgrowth (neurogenesis) in vivo will be familiar to those skilled in the art.For example, enhancement of neurogenesis can be determined by measuring the symptoms of CNS disorders, including but not limited to cognitive impairment, the degree and frequency of seizures or tremors, motor dysfunction, headache, and mood (e.g., happiness).

[0121] The terms "administer," "administering," or "administration," in the context of a compound, composition, or formulation of the invention, refer to the introduction of the compound into the body of an animal in need of treatment. When the compounds of the invention are provided in combination with one or more other active agents, "administration" and variations thereof are understood to include simultaneous and / or sequential introduction of the compound and the other active agents, respectively.

[0122] In certain embodiments, an effective amount of a tablet formulation for administration once or multiple times per day to a 70 kg adult human may contain from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0123] In certain embodiments, tablet formulations may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and from about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0124] Suitable dosage and administration schedule can be determined by the attending physician and can depend on the specific pathology to be treated, the severity of the pathology, and the age, health condition and weight of the general subject.Of course, the dosage range described herein is the guidance for administering the provided pharmaceutical composition to adults.For example, the amount administered to children or adolescents can be determined by a physician or person skilled in the art and can be less than or the same as the amount administered to adults.

[0125] The tablet formulation described herein can be used for combination therapy with one or more additional therapeutic agents.When combined treatment with more than one active agent, where the active agent is a separate dosage formulation, the active agent can be administered separately or together.In addition, the administration of one element can be before, simultaneously with, or after the administration of the other agent.

[0126] When co-administered with other drugs, for example, co-administered with another antianxiety or antidepressant drug, the "effective amount" of the second drug will depend on the type of drug used.Suitable dosages are known for approved drugs and can be adjusted by those skilled in the art according to the target condition, the type of condition to be treated, and the amount of compound described herein used.If no amount is explicitly stated, an effective amount should be assumed.

[0127] When "combination therapy" is used, an effective amount may be achieved using a first amount of the tablet formulation, and a second amount of an additional suitable therapeutic agent. In certain embodiments, the tablet formulations described herein and the additional therapeutic agent are each administered in an effective amount (i.e., an amount that is therapeutically effective when each is administered alone). In another embodiment, the tablet formulations described herein and the additional therapeutic agent are each administered in an amount that does not provide a therapeutic effect alone (a sub-therapeutic dose). In yet other embodiments, the tablet formulations described herein can be administered in an effective amount and the additional therapeutic agent is administered in a sub-therapeutic dose. In yet other embodiments, the tablet formulations described herein can be administered in a sub-therapeutic dose and the additional therapeutic agent is administered in an effective amount.

[0128] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). The use of these terms does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0129] The combined administration includes essentially simultaneous administration of the first and second amounts of the compound in a single pharmaceutical composition (e.g., a tablet having a fixed ratio of the first and second amounts), e.g., in a tablet, each in a separate multiple tablet. In addition, such combined administration also includes sequential use of each compound in any order. When combined administration includes separate administration of a first amount of the tablet formulation described herein and a second amount of an additional therapeutic agent, the compounds are administered close enough in time to have a desired therapeutic effect. For example, the time between each administration that can produce a desired therapeutic effect can range from a few minutes to a few hours, and can be determined by considering the properties of each compound, e.g., potency, solubility, bioavailability, plasma half-life, and pharmacokinetic profile. For example, the tablet formulation described herein and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

[0130] More particularly, the first treatment (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the second treatment to the subject.

[0131] Examples of therapeutic agents that may be combined with the present tablet formulations, either administered separately or in the same pharmaceutical composition, include, but are not limited to, muscle relaxants, anticonvulsants, hypnotics, anesthetics, analgesics, cholinergic agonists, antidepressants, mood stabilizers, and anti-anxiety agents.

[0132] In certain embodiments, the second therapeutic agent is one of the following: citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital), dapoxetine (Priligy), escitalopram (Lexapro, Cipralex, Seroplex, Esertia), fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin(EUR), Fluox(NZ), An SSRI selected from Depress (UZB), Lovan (AUS), Prodep (IND)), fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox), paroxetine (Paxil, Seroxat, Serupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc), sertraline (Zoloft, Lustral, Serlain, Asentra), and vilazodone (Viibryd).

[0133] In certain embodiments, the second therapeutic agent is a tetracyclic antidepressant (TeCA) selected from the group consisting of amoxapine (Amokisan, Asendin, Asendis, Defanyl, Demolox, Moxadil), maprotiline (Deprilept, Ludiomil, Psymion), mazindol (Mazanor, Sanorex), mianserin (Bolvidon, Depnon, Norval, Tolvon), mirtazapine (Remeron, Avanza, Zispin, Miro), and setiptiline (Tecipul).

[0134] In certain embodiments, the second therapeutic agent is a serotonin-norepinephrine reuptake inhibitor (SNRI) selected from the group consisting of desvenlafaxine (Pristiq), duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela), milnacipran (Ixel, Savella, Dalcipran, Toledomin), and venlafaxine (Effexor, Efexor).

[0135] In certain embodiments, the second therapeutic agent is a noradrenaline reuptake inhibitor (NRI) selected from the group consisting of atomoxetine (Tomoxetine, Strattera, Attentin), mazindol (Mazanor, Sanorex), reboxetine (Edronax, Norebox, Prolift, Solvex, Davedax, Vestra), and viloxazine (Vivalan, Emovit, Vivarint, Vicilan).

[0136] In certain embodiments, the second therapeutic agent is benmoxine (Nerusil, Neuralex), hydralazine (Apresoline), iproclozide (Sursum), iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), isocarboxazid (Marplan), isoniazid (Laniazid, Nydrazid), mebanazine (Actomol), nialamide (Niamid), octamoxine (Ximaol, Nimaol), phenelzine (Nardil, Nardelzine), pheniprazine (Catron), phenoxypropazine (Drazine), pivalylbenzhydrazine (Tersavid), procarbazine (Matulane, Natulan, Indicarb), camocycline (Camocycline), cyclosporine (Cyclosporin ... A monoamine oxidase inhibitor (MAOI) selected from the group consisting of loxazone (Surodil, Timostenil), echinopsidine (Adepren), furazolidone (Furoxone, Dependal-M), linezolid (Zyvox, Zyvoxam, Zyvoxid), tranylcypromine (Parnate, Jatrosom), brofaromine (Consonar), metralindole (Inkazan), minaprine (Cantor), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), toloxatone (Humoryl), lazabemide (Pakio, Tempium), pargyline (Eutonyl), rasagiline (Azilect), and selegiline (Deprenyl, Eldepryl, Emsam).

[0137] In certain embodiments, the second therapeutic agent is amitriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Sarotex, Lentizol), butriptyline (Evadene, Evadyne, Evasidol, Centrolese), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dosulepin (Prothiaden, Dothep, Thaden, and Dopress), doxepin (Aponal, Adapine, Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, Silenor), imipramine (Anti A tricyclic antidepressant (TCA) selected from the group consisting of deprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil), lofepramine (Gamanil, Tymelyt, Lomont), nortriptyline (Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren, Nortrilen), protriptyline (Vivactil), and trimipramine (Surmontil, Rhotrimine, Stangyl).

[0138] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, severity of side effects or disorders, identity of the particular compound, mode of administration, etc. The desired dosage can be delivered three times a day, twice a day, once a day, once every two days, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 or more administrations).

[0139] The reference in this specification to any prior publication (or information derived therefrom), or to any known matter, is not, and should not be taken as, an acknowledgement or admission in any way of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavor to which this specification pertains.

[0140] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step, or group of integers or steps, but not the exclusion of any other integer or step, or group of integers or steps.

[0141] Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of," and variations such as "consists essentially of," will be understood to indicate that the recited elements are essential, i.e., required elements of the invention. This phrase allows for the presence of other unrecited elements that do not materially affect the characteristics of the invention, but excludes additional unspecified elements that would affect the basic and novel characteristics of the defined method.

[0142] Throughout this specification, it has been the intention to describe preferred embodiments of the invention, without limiting the invention to any one embodiment or particular set of features. Thus, those skilled in the art will appreciate in light of this disclosure that various modifications and changes can be made in the specific embodiments exemplified without departing from the scope of the invention. All such modifications and changes are intended to be included within the scope of the appended claims.

[0143] Further features of the present invention are described in more detail in the following non-limiting examples. EXAMPLES

[0144] Example 1 (Ex1): Preparation of a representative spray-dried dispersion (SDD) composition of the present invention Approximately 150 g of compound (I), also known as "BNC210", was dissolved in 4 kg of a mixture of dichloromethane and methanol (80:20% w / w). An appropriate amount of polymer (Table 1) was added to the solution and the mixture was stirred to obtain a homogenous solution. Alternatively, additional excipients, such as SLS (sodium lauryl sulfate), were added. The solution was spray dried using a Buchi B290 spray dryer equipped with a two-fluid nozzle. Representative compositions of the spray-dried dispersion powders and their physical appearance are listed in Table 1.

[0145] [ka]

[0146] Example 2 (Ex2): Preparation of a representative hot melt extrusion (HME) dispersion composition of the present invention Approximately 6 g of compound (I), also known as "BNC210", and HPMCAS-H polymer were blended using a Turbula Blender, the blend was de-lumped through a 25 mesh and blended again. The blended mixture was fed at 165°C, 175°C or 180°C into a HAAKE Mini CTW Extruder in a reverse screw rotation configuration at a screw speed of 200 rpm and extruded through a die. Optionally, the roll was cooled with dry ice to quench the extrudate. The extrudate was crushed through a 60 mesh size screen.

[0147] Representative compositions of the hot melt extrudates and their physical appearance are given in Table 2.

[0148] [Table 1-1]

[0149] [Table 1-2]

[0150] [Table 2]

[0151] Determination of thermal properties and crystallinity Modulated Differential Scanning Calorimetry (mDSC) was used to characterize the compositions of the present invention, both spray dried and HME-based compositions. Solid samples were placed in aluminum pans, sealed and pinhole-proofed. A TA instruments (New Castle, Del., USA) Model Q2000 with an RCS90 chiller was used to apply a modulation amplitude within ±1.0°C for 60 seconds to samples heated at 2°C / min under a dry nitrogen purge. As described in Table 3 and shown in Figures 2a, 2b and 2c, the compositions of the present invention exhibit a single glass transition (T g ) indicates temperature.

[0152] [Table 3]

[0153] Crystallinity of the spray dried and hot melt extruded dispersion compositions of the present invention was determined by powder X-ray diffraction (PXRD) using a Rigaku Miniflex 6G benchtop X-ray diffractometer. Recommended parameters for recording PXRD are listed in Table 4.

[0154] [Table 4]

[0155] The spray dried and hot melt extruded dispersion compositions of the present invention exhibit very broad peaks in XRPD (Figures 3a, 3b and 3c), indicating that these compositions are amorphous in nature. Dissolution Test Compound I is a poorly soluble compound with moderate permeability, so its systemic absorption will depend heavily on the dissolution rate and precipitation from the small intestine. Therefore, biologically relevant dissolution experiments (solubility / precipitation) were performed by suspending the dispersion powder in SGF (0.1N HCl, pH=1) medium, then transferring the solution to SIF (simulated intestinal fluid: 2.24 mg / mL FaSSIF in 100 mM PBS). An appropriate amount (equivalent to 2.0 mg / mL Compound I) of the composition of the present invention was added to 50 mL of 0.1N HCl and stirred. Aliquots of the mixture were removed at 10 and 25 minutes, vortexed for 10 seconds, and the amount dissolved was measured by analytical HPLC using an external reference standard at a wavelength of 240 nm. After 30 min, the entire amount of sample from the SGF incubation was transferred to 50 mL of SIF medium with stirring and the amount dissolved was measured at 35, 50, 75, 120 and 210 min. A control experiment was performed using the micronized powder of compound I "as is". The results are shown in Table 5 and Figures 4a, 4b, 4c, 4d and 4e. In SGF medium, all spray-dried compositions released a higher amount of compound I compared to the micronized powder of compound I "as is". Spray-dried compositions based on HPMCAS-H and HPMC E15LV polymers released significantly more dissolved compound I compared to compositions based on HPMCAS-M, HPMCAS-M, CAP and Eudragit polymers. Due to the rapid increase in pH that occurred when the medium was changed from SGF to SIF, compound I rapidly decreased in solubility and precipitated. Unexpectedly, for compositions based on HPMCAS-H, HPMCAS-M, HPMCAS-L and HPMC E15LV, the amount of dissolved compound I was not reduced to the same extent as for compositions based on PVP-VA, CAP and Eudragit polymers or "neat" compound I. In addition, compositions based on HPMCAS-H, HPMCAS-M and HPMC E15LV exhibited a parachute effect where the polymers helped the compound maintain solubility in the SIF medium for longer, and therefore compound I did not precipitate as quickly.

[0156] [Table 5]

[0157] Tablet Processing A demonstration batch of tablets (300 g blend, approximately 200 tablets) was produced by dry granulation using a roller compactor followed by tabletting using a rotary tablet press (B12-705-29). The dry granulation process consists of intragranular blending, roller compaction, delumping, and extragranular blending to produce flowable granules suitable for compression on a Riva Piccola rotary tablet press. The compositions of the intragranular and extragranular blends are listed in Table 6.

[0158] [Table 6]

[0159] Step 1: Intragranular blending a) Weigh out the desired amount of Avicel PH-105 and add to a 5 L container. Blend for 1 minute at 20 rpm to coat the blender shell.

[0160] b) Weigh out the desired amount of Test No. 1: HPMCAS-M SDD, Cab-O-Sil, Ac-Di-Sol, Pruv SSF and add to container. Blend for 10 minutes at 20 rpm.

[0161] c) De-lump the blend using Comil (Quadro U5) using the following settings: d) Screen=032R, impeller=1612 and RPM=3000.

[0162] e) Return the de-lumped ingredients to the container and blend for 10 minutes at 20 rpm. Step 2: Roller compaction and granulation a) The intragranular blend from step 1 was placed in a Vector TFC-Lab Micro roller compactor and compressed into ribbons using the roller compactor at the following settings: roll speed = 3.0 rpm, screw speed = 50 rpm, and roll pressure = 10 MPa.

[0163] b) The ribbons were granulated with TFC Micro which was granulated using an 18 mesh screen. Step 3: Extragranular blending and granulation a) The granulated blend from step 2 was added to a 5.0 L vessel and appropriate amounts of Avicel PH-200, Ac-Di-Sol and Pruv SSF were added (de-lump using 40 mesh before adding to vessel).

[0164] b) The materials are blended for 10 minutes at 20 rpm and the physical parameters are measured. The bulk / tap density, Carr index and Hausner ratio of the final blends are listed in Table 7.

[0165] [Table 7]

[0166] Step 4: Tableting The granulated blend from step 3 was then compressed into tablets using a Piva Piccola rotary tablet press. The process parameters and properties of the resulting tablets are listed in Table 8.

[0167] [Table 8]

Claims

1. A compound of formula (I) or a salt or prodrug thereof dispersed in a polymeric matrix formed by at least one pharma- ceutically acceptable polymer, together with one or more optionally pharma- ceutically acceptable surfactants; 【Chemistry 1】 A solid dispersion comprising:

2. 13. A tablet comprising the solid dispersion of claim 1 together with one or more pharma- ceutically acceptable excipients.

3. (i) 50 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I): 【Chemistry 2】 or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, the ratio of (i):(ii) is from about 10:90 to about 80:20 (wt / wt%); tablet.

4. (i) A compound of formula (I) in substantially non-crystalline form: 【Chemistry 3】 or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, the ratio of (i):(ii) is from about 10:90 to about 80:20 (wt / wt%); Solid dispersion formulations.

5. 1. A method for treating a disease of the central nervous system, comprising administering to a subject in need thereof: (i) 50 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I): 【Chemistry 4】 or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, administering an effective amount of a tablet having a ratio of (i):(ii) of about 10:90 to about 80:20 (wt / wt %).

6. (i) 50 mg to 500 mg of a substantially non-crystalline form of a compound of formula (I): 【Chemistry 5】 or a salt or prodrug thereof, and (ii) Crystallization inhibitor polymer Including, Use of a solid dispersion formulation having a ratio of (i):(ii) of about 10:90 to about 80:20 (wt / wt %) in the manufacture of a medicament in tablet form for treating a disease of the central nervous system.

7. 5. The solid dispersion of claim 1 or claim 4, wherein the polymer or crystallization inhibitor polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate, copovidone, hydroxypropyl methylcellulose, seracephate, Soluplus® and amino methacrylate copolymers.

8. 8. The solid dispersion of claim 7, wherein the polymer or crystallization inhibitor polymer is HPMC E15LV.

9. 8. The solid dispersion of claim 7, wherein the polymer or crystallization inhibitor polymer is HPMCAS.

10. 8. The solid dispersion of claim 7, wherein the polymer or crystallization inhibitor polymer is HPMCAS selected from one of the various grades, namely L, M and H.

11. 11. The solid dispersion of claim 10, wherein the polymer or crystallization inhibitor polymer is HPMCAS-H.

12. 11. The solid dispersion of claim 10, wherein the polymer or crystallization inhibitor polymer is HPMCAS-M.

13. 12. The solid dispersion of claims 7 to 11, having an added surfactant such as SLS or a sorbate.

14. 14. The solid dispersion of any one of claims 7 to 13, wherein the weight ratio of compound of formula (I) to polymer ((i):(ii)) is from about 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25 or about 80:20 (wt% / wt%).

15. 15. The solid dispersion of claim 14, wherein the weight ratio of compound of formula (I) to polymer ((i):(ii)) is from about 10:90 to about 60:

40.

16. 15. The solid dispersion of claim 14, wherein the weight ratio of compound of formula (I) to polymer ((i):(ii)) is from about 20:80 to about 60:40 (wt% / wt%).

17. 15. The solid dispersion of claim 14, wherein the weight ratio of compound of formula (I) to polymer ((i):(ii)) is from about 30:70 to about 70:30 (wt% / wt%).

18. 15. The solid dispersion of claim 14, wherein the weight ratio of compound of formula (I) to polymer ((i):(ii)) is about 30:70 (wt% / wt%).

19. The solid dispersion of any one of claims 7 to 18, which is produced by spray drying.

20. 20. The solid dispersion of claim 19, wherein the total weight of solids in the solution to be spray dried (wt % total solids) is between 2-15% wt, preferably about 2-10% wt.

21. 21. The solid dispersion of claim 19 or 20, wherein the spray drying solvent comprises dichloromethane, or comprises dichloromethane and methanol, or comprises dichloromethane and methanol in a weight / weight ratio of about 90:10 to 60:10, such as about 85:15, 80:20, 75:25, 70:30, or about 65:35 wt / wt %.

22. 22. The solid dispersion of claim 19, 20 or 21, wherein the yield of the spray dried dispersion is about 50-100%.

23. 19. The solid dispersion of any one of claims 7 to 18, which is produced by hot melt extrusion (HME).

24. A pre-tabletting pharmaceutical composition comprising the solid dispersion according to any one of claims 1, 4 and claims 7 to 23 together with at least one pharma- ceutically acceptable excipient.

25. 25. The pharmaceutical composition of claim 24, comprising about 1% to about 75% w / w of said solid dispersion.

26. 26. The pharmaceutical composition of claim 24 or 25, comprising one or more of a diluent, a disintegrant, a glidant, a lubricant, and any combination thereof.

27. (i) A compound of formula (I) in substantially non-crystalline form: 【Chemistry 6】 or a salt or prodrug thereof, by dispersing said compound of formula (I) in a polymer matrix formed by at least one pharma- ceutically acceptable polymer; (ii) mixing said solid dispersion of step (i) with at least one pharma- ceutically acceptable excipient; (iii) subjecting the mixture obtained in step (ii) to dry granulation; and (iv) tableting the dry granulation mixture of step (iii) by compression. A method for preparing a pre-tablet pharmaceutical composition comprising:

28. 28. The method of claim 27, prepared under any one or more of the conditions according to claims 19 to 23.

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