NZ615513B2 - Pharmaceutical compositions comprising sorbitan esters - Google Patents

Abstract

Disclosed is an injectable pharmaceutical composition comprising: (a) aripiprazole lauroxil of formula A-7; (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle, for treating disorders of the central nervous system, including anxiety or depression, bipolar disorder, autism-related irritability, schizophrenia or schizophreniform diseases. ritability, schizophrenia or schizophreniform diseases.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING SORBITAN ESTERS RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 61/454,008, Attorney Docket No. 513352, titled "Formulations Having Improved Site Reactions", filed on March 18, 2011. The contents of any patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entireties.

TECHNICAL FIELD The present invention relates to an able, pharmaceutical composition comprising sorbitan esters of carboxylic acids that are useful for the delivery of antipsychotic drugs.

BACKGROUND OF THE INVENTION U.S. patent Nos. 4,734,416 and 5,006,528 discloses razole, 7-{4-[4-(2,3- dichlorophenyl)piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone or 7-{4-[4-(2,3- rophenyl)piperazinyl]butoxy}-3,4-dihydro tyril, as an atypical antipsychotic agent useful in the treatment of schizophrenia, bipolar disease, depression and other CNS disorders. Aripiprazole has the following chemical structure: Aripiprazole is sold under the tradename Abilify®. It acts as a dopamine D2 partial agonist, serotonin 5-HT1A receptor agonist and is an antagonist of the serotonin 5-HT2A receptor. Abilify® is currently administered orall y on a once-a-day dosing schedule as Abilify® (aripiprazole) Tablets, Abilify Discmelt® (aripiprazole) Orally Disintegrating Tablets and Abilify® (aripiprazole) Oral Solution. In one embodiment, Abilify® ion for intramuscular use is a rapid-acting solution t for treating agitation associated with phrenia and bipolar disease. Poor and variable patient compliance with a -day dosing schedule of psychiatric drugs has been reported.

Efforts have been made to provide drug dosage forms that may increase the compliance of patients and thereby lower the rate of relapse in the treatment of schizophrenia. US. Patent No. 7,807,680 and US. Publication No. 2005/0032811 describe long-acting aripiprazole sterile injectable formulations. s on aripiprazole free base injections showed a prolonged pharmacokinetic profile, but incidents of unacceptable (moderate to severe) tissue irritation following IM and SC injection were also reported.

US. Patent No. 7,115,587 discloses an injectable ation that delivers an aripiprazole solution complexed with a substituted B-cyclodextn'n to the muscular site with diminished irritation as compared to injectable suspensions containing uncomplexed aripiprazole. The Abilify® ion for intramuscular use is a single- dose, ready to use vial consisting of 9.75 mg1.3ml of razole and 150 mg/ml of sulfobutylether B-cyclodextrin. Formulation challenges due to drug loading and poor lity of aripiprazole in B-cyclodextrin at neutral pH have been reported. pine (l ,2-methyl(4—methyl-l-piperazinyl)-10H—thieno[2,3-b][1,5]be- nzodiazepine) is a second generation ychotic drug marketed as Zyprexa®. It is useful for the treatment of disorders such as schizophrenia, r disorder, psychotic depression and Tourette syndrome. This active pharmaceutical ingredient acts as an antagonist on 5-HT; serotonin receptors as well as the Dl/Dz dopamine receptors, while also exhibiting olinergic and antimuscarinic properties. Olanzapine belongs to the benzodiazepine family, and has the following structure: This compound is disclosed, for example, in US. Patent Nos. 5,229,382 and 6,169,084. An ed release uscular injection product containing the water- insoluble salt Olanzapine pamoate monohydrate is approved for use in schizophrenia.

Like aripiprazole, Olanzapine can cause adverse site reactions when injected into a subject.

SUMMARY OF THE INVENTION There exists a need for improved ceutical compositions of aripiprazole, olanzapine, prodrugs thereof, and other anti-psychotic , for extended release use, thereby improving patient compliance and optimizing the pharmacological profile of the ‘ active agent.

Provided herein are pharmaceutical compositions comprising (a) a water- insoluble antipsychotic agent, and (b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms. In a particular embodiment, the sorbitan ester is sorbitan laurate (SML). In an embodiment, the composition can be in the form of an aqueous, flocculated, injectable suspension. The composition can se additional components, such as a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the ylic acid comprises 8-14 carbon atoms (e.g., polysorbate 20). The pharmaceutical composition can be injectable.

These pharmaceutical compositions can take a variety of forms. Such forms include, but are not limited to, completely dispersed and flocculated systems.

As described below, the ceutical compositions described herein have a number of advantages. For example, the compositions can be-easily resuspended'by the user, e.g., through handshaking, in a short time prior. to administration. In r example, the pharmaceutical compositions, e.g., ated systems, can be used to improve the local tissue reaction of antipsychotic drugs in extended e formulations. By mitigating the e results associated with the injection of these drugs, drug compliance will be greatly improved.

Water insoluble antipsychotic agents that can be used in the pharmaceutical compositions described herein include aripiprazole, as well as prodrugs thereof, and olanzapine, as well as gs thereof. Particular prodrugs of aripiprazole include compounds of the formula (I) or‘ a (11), e.g., compounds of the formula (1'), e.g., compounds A—4 and A-7: (I) (”l (l') Particular prodrugs of olanzapine include compounds of the formula (III) or (IV):' (III) (IV) In another aspect, ed herein is a pharmaceutical composition sing: (a) a water-insoluble antipsychotic agent; (b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8- 14 carbon atoms; (c) a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms; and (d) an aqueous vehicle; wherein the composition ioms an aqueous, flocculated, injectable suspension.

The composition comprising components (a) — (d) can have ents at varying ratios. For example, in one embodiment of the composition comprising components (a) — (d), the composition comprises components (b) and (c) at a ratio that. s in flocs sing component (a), wherein the flocs settle to a predetermined sediment bed height, such that components (a), (b) and (c) can be resuspended for injection. In an embodiment, the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non-flocculated suspension after 24 hours of undisturbed sitting, and, in another embodiment, components (a), (b) and (c) can be resuspended for injection within 1-60 seconds of handshaking. In another ment, the ratio of components (b) to (c) is such that the composition can be injected using a 20 to 25 gauge needle.

In a particular embodiment, the ratio of ents (b) to (c) is approximately 5 to 2, by weight.

When component (b) is an laurate, the composition can comprise about 0.2 -1 weight percent, about 0.4 – 0.7 weight percent or about 0.5 weight percent sorbitan laurate.

When component (c) is polysorbate 20, the composition can se about 0.05 – 0.8 weight percent polysorbate 20, about 0.1 – 0.3 weight percent polysorbate 20, or about 0.2 weight percent polysorbate 20.

In an embodiment, the flocs of the pharmaceutical composition have the following sizes: Dv[10]: , Dv[50]: 10-30μm, and : less than 80 μm (e.g., approximately 65 um). In another embodiment, the flocs are Dv[10]: 1-10μm, Dv[50]: 5- 30μm, and Dv[90]: less than 65 μm.

The compositions can have varying amounts of antipsychotic agent in the pharmaceutical composition. For example, the composition can be comprised of 15-35 weight percent, e.g., 20-30 weight percent, e.g., 20 - 26 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V (lurasidone).

In another aspect, provided herein is an aqueous injectable suspension sing: (a) aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, pharmaceutically acceptable salts, hydrates, or es f, wherein component (a) is in a weight ratio of approximately 15 – 35%; (b) sorbitan laurate in a weight ratio of approximately 0.2 – 1% (c) polysorbate 20 in a weight ratio of approximately 0.05 – 0.8%; and (d) an aqueous carrier.

In another , provided herein is a ceutical composition comprising: (a) compound A-7: (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle.

In another , provided herein is an injectable pharmaceutical composition comprising: (a) compound A-7: or pharmaceutically able salts, hydrates, or solvates thereof, wherein component (a) is in a weight ratio of approximately 15 – 35%; (b) sorbitan laurate in a weight ratio of approximately 0.2 – 1% (c) polysorbate 20 in a weight ratio of approximately 0.05 – 0.8%; and (d) an aqueous carrier.

In r aspect, provided herein is an injectable composition comprising: (a) compound A-7: (b) sorbitan laurate; (c) polysorbate 20: and (d) an aqueous vehicle.

In another aspect, provided herein is a pharmaceutical ition comprising: (a) 24 – 30 weight percent compound A-7: - 5A - Cl N Cl N O O A-7 ; (b) 0.2 – 1 weight percent sorbitan laurate; (c) 0.1 – 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle.

In one embodiment of the s injectable suspension, the components are as follows: - 5B - (a) aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V in a weight ratio of approximately 20-26%; (b) sorbitan laurate in a weight ratio of approximately 0.5%; (c) polysorbate 20 in a weight ratio of approximately 0.2%; and (d) an aqueous r.

In one embodiment, the pharmaceutical composition is formulated for use in delivering a water-insoluble antipsychotic agent into a host. In a red embodiment, the host is human. The composition can be intended for parenteral (e.g., intramuscular, ermal or subcutaneous) administration. In certain embodiments, the composition is ated for delivery through a needle into a host. Accordingly, the composition may be formulated for delivery for injection through a syringe equipped with a needle, where the end-user resuspends the composition prior to use.

In an embodiment, the antipsychotic agent (e.g., aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or .V) can be ated for ting tissue reaction associated with the delivery of a water-insoluble antipsychotic agent. The pharmaceutical composition having reduced injection site reaction can comprise (a) an ychotic agent, and (b) sorbitan esters of a carboxylic acid, n the carboxylic acid comprises 8-14 carbon atoms. In a particular embodiment, the an ester is sorbitan laurate. In an embodiment, the compdsition for injection site modulation can comprise onal components, such as a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid ses 8-14 carbon atoms (e.g. , polysorbate 20).

In another embodiment, the modulation of the tissue reaction is a ion in the irritation at the site of injection. In another embodiment, the modulation of the tissue reaction is a reduction in the irritation following IM or SC injection. In certain embodiments, the tissue reaction is reduced by at least about 20 percent by weight. In other embodiments, the tissue reaction is reduced by at least about 10 percent by weight.

In one embodiment, the antipsychotic agent is selected from the group consisting of razole, or olanzapine, or a compound of formula I, II, III, IV or V and pharmacologically active salts, hydrates or solvates thereof In certain embodiments, the pharmaceutical composition for ion site reaction modulation further comprises a buffer. The buffer may be selected from a phosphate, citrate, tartrate or acetate buffer. In a particular embodiment, the buffer is a phosphate buffer.

In a particular embodiment of the preceding compositions, the composition comprises a water-insoluble antipsychotic agent, about 0.1-2% percent of sorbitan laurate, about 0.05-1% percent of polysorbate 20 and phosphate buffer. In a particular embodiment, the phosphate buffer comprises ic saline with 5-50 mM phosphate buffer at pH 5.0 — 7.5.

In another aspect, ed herein is an injectable composition comprising sorbitan e, polysorbate 20, phosphate buffer and'aripiprazole, or pharmacologically active salts, hydrates, solvates or prodrugs thereof.

In yet another aspect, provided herein is an able ition comprising sorbitan laurate, polysorbate 20, phosphate buffer and olanzapine, or pharmacologically active salts, hydrates, es or prodrugs thereof.

In yet another aspect, provided herein is an injectable composition sing sorbitan laurate, polysorbate 20, phosphate buffer and Compound A-7, or pharmacologically active salts, hydrates, solvates or prodrugs thereof.

Also provided herein is a method for ng disorders of the central nervous system, comprising administering an effective amount of any of the preceding compositions to an individual in need of such treatment.

In one embodiment, the disorder is anxiety or depression. In another embodiment, the disorder is bipolar disorder. In still another embodiment, the disorder is autism-related irritability. In yet another embodiment, the er is a psychotic condition. The psychotic condition may be phrenia or schizophrenifonn diseases.

Alternatively, the psychotic condition may be acute mania.

In still another aspect, provided herein is a method of modulating tissue reaction associated with delivering a water-insoluble antipsychotic agent h a needle into a host, comprising a water-insoluble ychotic agent and sorbitan laurate. In one embodiment of the , the composition is administered parenterally. In certain embodiments, the composition is administered intraderrnally, subcutaneously or intramuscularly. In another embodiment of the method, the modulation of the tissue reaction is a reduction in the irritation and the subsequent granuloma formation at the site of ion. In a certain embodiments, the tissue reaction is reduced by at least about 20 t. In other embodiments, the tissue on is reduced by at least about t. In still r embodiment of the method, the composition comprises a water-insoluble antipsyehotic agent, about 0.1-2% percent of sorbitan laurate, about 0.05-1% t ofpolysorbate 20 and phosphate buffer.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows results from the settled bed height assessments described in the experimental section. The data indicate that pharmaceutical compositions containing sorbitan laurate and rbate 20 have significantly higher settled bed heights than compositions without sorbitan laurate.

IO Figure 2 shows sorbitan laurate's positive effect on settled bed height in pharmaceutical compositions of antipsyehotic drugs.

Figure 3 shows an example raph illustrating the sediment height measurement on a vial for the pharmaceutical compositions described herein.

Figure 4 shows microscopy images of three suspensions made with pharmaceutical compositions containing polysorbate 20 and increasing amounts of sorbitan laurate. It is visually clear that flocculation is ocbuning as SML content in the vehicle increases.

Figure 5 shows vials containing ceutical compositions after ‘ sedimentation with sediment height calculations.

Figure 6 shows plots of pharmaceutical composition re-suspension time vs. drug particle size. Larger measured stispension particle sizes, caused by flocculation, facilitate faster re-suspension than smaller ones.

Figure 7 is a contour plot showing amounts of polysorbate 20 and sorbitan laurate necessary for adequate wetting and re-suspendability. s 8A and 8B demonstrate the reduction of tissue on associated with antipsyehotic drugs when the drugs are formulated with an laurate.

Figure 9 demonstrates the results of solubility studies comprising varying ratios of active agent, component (b), and component (c).

DETAILED DESCRIPTION OF INVENTION ceutical Compositions Provided herein is an injectable pharmaceutical composition sing an antipsyehotic agent and a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 (e.g., 11-13) carbon atoms. A preferred sorbitan ester is sorbitan laurate.

This composition is particularly useful for the forrnulationof a insoluble antipsychotic agent into an injectable pharmaceutical composition. In addition to a sorbitan ester of a carboxylic acid, the pharmaceutical composition can further comprise a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms. In an embodiment, the polyoxyethylene derivative is polysorbate 20. The pharmaceutical composition can further comprise and aqueous e, such as phosphate buffered saline, as well as any of the pharmaceutical components described herein.

The compositions described herein possess a number of advantages. For example, the compositions'offer minimized excipient levels while co-optimizing both rc— suspcndability and acceptable injectability, and in good chemical attributes of the ychotic agent. As described in the experimental section, these properties were discovered based on comparisons of vehicle performance based on settled bed height and qualitative ease of resuspension. Briefly, the ersibility of the pharmaceutical compositions were assessed by preparing a number of ent ations (antipsychotic agent with a variety of excipients), and comparing the relative height of the settled beds. In l, higher settled bed heights are indicative of flocculated, or loosely aggregated, particles. These suspensions settle faster initially, but their loosely aggregated statc allows for casicr redispersion and better physical stability as the particles cannot pack as tightly as fully dispersed suspensions, thereby g to reduced resuspension times using, for example, hand shaking. In one embodiment, the pharmaceutical compositions, e.g., a pharmaceutical composition of components (a) and (b), or (a), (b) and (c), can be resuspended for injection within 1-60 seconds of handshaking.

As used , the term lation" refers to the formation of a loose aggregation of discrete particles held together in a k—like structure by physical adsorption Of macromolecules, bridging during al interaction (precipitation), or when the longer range van der Waals forces of attraction exceed the shorter range forces of attraction. (See Pharmaceutical dosage forms: Disperse systems Volume 2. Edited by Herbert A. Lieberman, Martin M. Rieger, and Gilbert S. Banker. (1996) Pg. 18). The "loose aggregation of discrete particles" can be referred to herein as "flocs." 2012/029625 As shown in Figure 1, pharmaceutical compositions containing component (b) (e.g., sorbitan laurate) and component (c) (e.g., polysorbate 20) have significantly higher settled bed heights than compositions without component (b), regardless of the presence of onal additives (e.g., rs) or salts (e.g., ate buffer, saline).

Additionally, the flocculation d is unique to component (b) / component (c), as evidenced by comparison to compositions containing sorbitan lmitate, docusate sodium, or polysorbate 20 alone. As bed below, the flocculation phenomenon is uniquely attributed to the additional influence of component (b), e.g., sorbitan laurate.

Accordingly, in one embodiment, provided herein is a composition comprising components (a), (b) and (c) at a ratio that results in flocs, wherein the flocs settle to greater than a predetermined nt bed , such that ents (a), (b) and (c) can be resuspended for injection. The flocs can be comprised of component (3), components (a) and (b), or components (a), (b) and (c). A predetermined sediment bed height refers to a bed height thatis higher than the bed height of a comparative pharmaceutical composition that has none of component (b), or none of components (b) or (c). In one ment, the bed height is comprised of at least a 10, 20, 30, 40, 50, 60, 70 or 80% increase in sediment height compared to a non ated pharmaceutical composition afier 24 hours ofundisturbed sitting. In another embodiment, the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non flocculated ceutical composition after 24 hours of undisturbed sitting.

The formed flocs can be any number of sizes. Non—limiting examples of sizes include Dv[10]: 2-10um, Dv[50]: 10-30um, and Dv[90]: less than 80 um (e.g., approximately 65 um). In r embodiment, the flocs are Dv[10]: 1-10um, Dv[50]: -30um, and Dv[90]: less than 65 um.

In addition to the re-suspendability and injectability advantages described above, the pharmaceutical compositions provided herein result in reduced tissue reactions.

Typically, flocculated pharmaceutical suspensions have an increased viscosity and reduced flow properties, which i'rnpact the ability to inject or administer the product to the patient. This in turn may negatively impact the local tissue response; therefore it is surprising that the formulations described herein result in improved tissue response.

Accordingly, in one embodiment, provided herein is a method ofmodulating tissue reactions associated with delivering a water-insoluble antipsyehotic agent into a host, comprising the water-insoluble antipsyehotic agent and component (b), e.g., sorbitan e. In another embodiment, the antipsychotic agent/component (b) composition is delivered to the host through a needle. singly, it has been discovered that the composition provided herein results in a sed tissue reaction normally associated with antipsychotic agents, such as aripiprazole, olanzapine, derivatives thereof, prodrugs thereof, and salts thereof. As demonstrated in the experimental section, an injectable composition comprising an antipsychotic agent and a sorbitan ester of a ylic acid, wherein the ylic acid comprises 8-14 carbon atoms (e.g., sorbitan laurate), demonstrated an unexpected improvement in tissue reaction compared to a similar compositions comprising a sorbitan ester of a carboxylic acid falling outside of this range (e.g., sorbitan monopalmitate). Without being bound by theory, it is believed that a favorable surface interaction between the sorbitan ester ofa carboxylic acid (e.g., sorbitan laurate) and the antipsychotic drug (e.g., aripiprazole or olanzapine) reduces tissue reaction.

Moreover, due to the maximized interaction between, these components, the injectable composition provided herein can be formulated and maintained in suspension with ease. Surprisingly, it was found that it was easier to formulate the antipsychotic drugs described herein using a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms (e.g., sorbitan laurate) compared with other an esters falling outside of this range (e.g., sorbitan monopalmitate). This was also unexpected. t being bound by theory, it is believed that the sorbitan ester component of the injectable composition provided herein es the hilicity of the drug h surface interactions of the various components. It is additionally noted that formulation es containing sorbitan laurate and rbate 20 formed e emulsions with no oiling out of either surfactant. In contrast, formulations containing sorbitan palmitate, did not form consistent emulsions, even with the addition of a second non-ionic surfactant, with visible undissolved material at the bottom of the al.

As used , the term “tissue reaction” (TR) refers to foreign body responses to a drug t (active agent and/or vehicle used for administration). For example, local tissue reaction to drug product results in the influx of immune cells, the subsequent encapsulation of the drug product and usually the development of a fluid filled central cavity. The presence of fibroblasts, neutrophils, macrophages and giant cells are often observed via histological examination. The term “undue TR” or “unacceptable TR” refers to moderate to severe TR which is unacceptable to the patient and thereby impacts unfavorably on patient comfort and ance. The term “reduced TR” refers to generally minimal to mild TR which is acceptable to the patient and therefore does not engender an e event related nor impact unfavorably on patient compliance. As such, the injectable composition provided herein is characterized by a decreased undue TR and a more able TR following injection of drug product. As used herein, "tissue reaction" can also be referred to as "injection site reaction." The modulation of tissue response following SC administration is described by the reduction of the ion site weight (comprising the drug depot and surrounding tissue) which provides a quantitative assessment of the ty of the response. The modulation of the tissue response following IM administration is described by the spreadability of the drug and resulting depot morphology; ing of the drug along the fascial planes le is desirable rather than the formation of a concentrated mass of drug in a small area.

Depot morphology resulting from IM injection of aripiprazole and aripiprazole prodrugs has been described. Injections of eleasing formulations of drugs, including aripiprazole commonly result in the formation of “cyst-like structures”, characterized by a vascularized capsule of roughly spherical shape and comprising various cell types, with or without and a central serous fluid compartment. Tissue responses to slow-releasing formulations occur as the body mounts an immune response to clear the material from the injection site; this reaction is commonly referred to as a foreign body response. The spherical nature of these ons can result in localized discomfort and pain, as the FBR increases in size compressing on nerve fibers innervating muscle tissue and with the e of pro-inflammatory cytokines fiom the site.

In a particular embodiment, the tion of the tissue reaction is the reduction in tissue reaction at the site of injection. In one embodiment, the injection site reaction is reduced by a particular amount, e.g., about 90%, 80%, 70%, 60%, 50%, 40%, 30%, %, 10%, 5%, etc.

When the antipsychotic agent/sorbitan ester ition is to be used as an injectable composition, including but not limited to injection through a needle or needle— 1ess injection, it can be formulated into a conventional injectable carrier. Suitable carriers include biocompatible and ceutically acceptable solutions.

Provided below are representative drawings of the sorbitan esters used in the pharmaceutical compositions described herein. Sorbitan laurate can also be ed to as "sorbitan monolaurate": HO OH 0' ‘ O 4 O oJIM n n OH Sorbitan Ester n = 6-12 Sorbitan Laurate (n = 10) As described above, the pharmaceutical composition comprising components (a) and (b) can r comprise ent (c): a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8—14 carbon atoms. In a particular embodiment, component (c) is polysorbate 20, sold under the trademark TWEEN ®. The polysorbate can be added in an amount that reduces surface tension of a drug product or aids in suspension stability of the drug product.

Provided below are representative gs of the polyoxyethylene derivative of a sorbitan ester of a carboxylic acid used in the ceutical compositions: Polyoxyethylene Derivative of a Sorbitan Ester Polysorbate 20 w+x+y+z = 20 z = 20 n = 6—1 2 n = 10 For compositions comprising components (a), (b), and (c), or (a), (b), (c) and (d), the ratios of (b) and (c) can vary. In one embodiment, the ratio of components (b) to (c) is approximately 10 to 0.5, e.g., 10 to 1, e.g., 8 to 1, e.g., 5:2, by weight. In r embodiment, the ratio of components (b) to (c) is approximately 5 to 2, by weight. In still another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, n the ratio of sorbitan laurate and polysorbate 20 is approximately 5 to 2, by weight. In still another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, n the ratio of sorbitan laurate and polysorbate 20 is approximately 3 to l, by . In another ment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate and polysorbate 20 is approximately 2 to l, by weight. In yet another embodiment, the composition ses component (a), sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate and; polysorbate 20 is within the range of approximately 3 to l — 2 to. 1, by weight.

As described in Table 3, the sorbitan laurate/polysorbate 20 ratio can be approximately 0.625, 1, 1.25, 2, 2.5, or 5, representing a range of 0.625 — 5.

For compositions comprising components (a) and (b), (a), (b), and (c), or (a), (b), (c) and (d), the weight percent of (b) and (c) can vary. In one embodiment, the composition comprises about 0.2 — 1 weight percent component (b), e.g., an laurate. In another embodiment, the composition comprises about 0.4 — 0.7 weight pcrccnt component (b), e.g., sorbitan laurate. In still another embodiment, the composition comprises about 0.5 weight percent component (b), e.g., sorbitan laurate.

In another embodiment, the composition comprises about 0.05 —- 0.8 weight percent component (c), e.g., polysorbate 20. In yet another embodiment, the composition comprises about 0.1 — 0.3 weight percent component (c), e.g., polysorbate . In still another embodiment, the composition comprises about 0.2 weight t polysorbate 20.

In an embodiment, the ratio of components (b) to (c) is such that the composition can be injected using a 20-25 gauge needle. For example, the needle can be a 20, 21, or 23.5 gauge needle.

The compositions provided herein can also have varying amounts of antipsychosis agent. The antipsychosis agent can be aripiprazole, or pine, salts of these nds, hydrates of these compounds, and/or gs of these compounds.

In one embodiment, the composition comprises approximately 15 — 35 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V (lurasidone), or ceutically acceptable salts, hydrates, or solvates thereof. In another embodiment, the composition comprises approximately 20 — 30 weight percent razole, or olanzapine, or a compound of formula I, II, III, IV or V, or ceutically acceptable salts, es, or solvates thereof. In still another embodiment, the composition comprises imately 20 — 26 weight percent aripiprazole, aripiprazole, or olanzapine, or a compound of a I, II, III, IV or V, or ceutically acceptable salts, hydrates, or solvates thereof. In another embodiment, the ition comprises approximately 24-26 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

The aqueous vehicle of the pharmaceutical compositions provided herein can be a buffer. The buffer may be selected from a phosphate, citrate, tartrate or acetate buffer.

In a ular embodiment, the buffer is a phosphate .

The pharmaceutical compositions ed herein can further comprise additional components. For example, the use of additional wetting agents or surfactants in a pharmaceutical composition may promote one or more of the following: (1) Surface n reduction, which may aid in g, since a ‘1ower e tension’ liquid will wet surfaces or particles more readily than a ‘high surface tension’ liquid. Lowering the surface tension of a liquid may also decrease the incidence of g. The surface tension of a liquid will be lower as more surfactant is added; (2) Formation of micelles (i.e., spherical or non-spherical surfactant structures in on that have the capability to ve non-soluble components); and/or (3) Increase of suspension physical ity.

The pharmaceutical compositions can also contain an aqueous vehicle, which is a vehicle that dilutes and suspends the drug. The diluent of interest herein is one which is pharmacehtically acceptable (safe and nontoxic for administration to a human) and is useful for the preparation of a reconstituted ation. Exemplary diluents include sterile water, sterile water for injection (WFI), bacteriostatic water for injection (BWFI), a pH ed solution (e.g., phosphate-buffered saline), sterile saline on, Ringer's solution or dextrose solution. The buffer can be phosphate, citrate, tartrate or acetate. In a particular embodiment, the diluent is phosphate-buffered saline, which is a water- based salt solution containing either sodium chloride or potassium chloride, and sodium ate or potassium phosphate. In one embodiment, the phosphate buffer comprises isotonic saline with 5-50 mM phosphate buffer at pH 4.0 — 9.0, e.g., 5.0 — 8.0, e.g., 5.0 — 7.5.

The pharmaceutical compositions can further contain an additional surfactant that preferentially adsorbs to an interface between two immiscible , such as the interface between water and an organic r solution, a water/air interface or organic solvent/air interface. Suitable surfactants include but are not limited to fatty alcohols such as polyethylene glycols (PEGs) and cety] alcohol.

Optionally, the pharmaceutical compositions can further comprise a dispersant, such as, for example, carboxymethyl cellulose (CMC), carboxymethyl cellulose sodium, linked sodium carboxymethyl cellulose, calcium ymethyl cellulose, and low substituted hydroxypropyl cellulose magnesium aluminum te, or a mixture thereof.

In a particular embodiment, the pharmaceutical ition ses carboxymethyl cellulose.

The pharmaceutical compositions may also optionally comprise an antioxidant to inhibit the oxidation of ingredients. Some examples of antioxidants e, but are not limited to, ascorbic acid, ascorbyl ate, ted yanisole, a mixture of 2 and 3 tertiary-butylhydroxyanisole, butylated hydroxytoluene, sodium iso-ascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alpha— tocopherol, and propylgallate.

The pharmaceutical compositions can further include a lipid, e.g., a neutral lipid.

Neutral lipids include any lipid that remains neutrally charged at a pH between about 4 and 9. Neutral lipids include, without limitation, cholesterol, other sterols and derivatives thereof, phospholipids, and combinations f and other l lipids.

The phospholipids include any one phospholipid or combination ofphospholipids capable of forming liposomes. They include phosphatidylcholines, phosphatidylethanolamines, in and fractions thereof, phosphatidic acid, phosphatidylglycerols, phosphatidylinositols, phosphatidylserines, plasmalogens and sphingomyelins. The phosphatidylcholines. include, without limitation, those obtained from egg, soy beans or other plant sources or those that are partially or wholly synthetic or of variable lipid chain length and unsaturation, POPC, OPPC, l or hydrogenated soy bean PC, natural or hydrogenated egg PC, DMPC, DPPC, DSPC, DOPC and derivatives thereof. In one embodiment, phosphatidylcholines are POPC, non- hydrogenated soy bean PC and non-hydrogenated egg PC. Phosphatidylethanolamines include, without tion, DOPE, DMPE and DPPE and tives thereof.

Phosphatidylglycerols include, without limitation, DMPG, DLPG, DPPG, and DSPG.

Phosphatidic acids include, without limitation, DSPA, DMPA, DLPA and DPPA.

The pharmaceutical compositions can also advantageously employ a density enhancing agent, such as a sugar, e.g., mannitol, or sorbitol and/or a tonicity adjusting agent, such as sodium chloride or glycerol.

Other pharmaceutical carriers that could be used in the ceutical compositions provided herein also include water, aqueous methylcellulose solutions, , dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The ceutical carrier may also contain preservatives, and buffers as are known in the art.

The term "pharmaceutical composition", "formulation", "injectable composition," etc. are used synonymously throughout the application.

The pharmaceutical compositions described herein may also be in the form of an emulsion. The term “emulsion” as used in this specification denotes a two-phase system in which one phase is finely dispersed in the other phase. An emulsifier can be used in the pharmaceutical compositions to form the emulsion. The term emulsifier, as used by this invention, denotes an agent that can reduce and/or eliminate the surface and the interfacial tension in-a two-phase system. Such an agent possesses both hydrOphilic and lipophilic groups in the fier' agent.

The ceutical compositions described herein may also be in the form of a dispersion. As used herein, the term “dispersion” is to be understood as a mixture in which fine particles of one substance (e.g., a drug) are scattered throughout r substance (e.g,, a liquid). Dispersions e suspensions, and colloids.

The methods of the ion include administering the compositions described , thereby obtaining an extended release or sustained e profile in the patient. ded—release” or “sustained-release” includes dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish eutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. An extended release profile includes deliveries that achieve a therapeutically effective amount of the antipsychotic agent, e.g., aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, is present in the plasma of the individual for at least about 7 days, preferably at least about 14 days, or more preferably at least about 21 days alternatively for at least 2, 3, 4, 6 or 8 weeks or as much as three months.

In one embodiment, the pharmaceutical itions can be administered as a single or sole (undivided) dose. However, the composition is also useful for those duals that require constant or chronic therapy, such as those that receive repeated doses over several hours, days, weeks, months, or more. In such dosing regimens, the method can comprise a first administration of a first extended release composition and a second administration of a second extended release compOSition. The second composition can be the same, substantially the same or different as the first and can include the same active agent or a different active agent. For example, the second composition can be administered at about 7 days, or more, such as at least about 14 days, or at least about 17 days, after the first administration, where the first administration results in the release t for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more.

The able, pharmaceutical compositions described herein can be injected into a patient in any number of ways. The term “injectable” as used herein refers to a ition that is le to be delivered to an individual in an injection, such as with an injection , including one that employs a syringe or a cartridge, which may be housed in a manual injection device or an auto-injection device, for example.

Specifically, the injectable composition is le for parenteral administration. As used herein, the term “parenteral administration” refers to administration‘through injection or infusion. Parenteral administration includes, but is not limited to, intravenous administration, intradermal administration, subcutaneous administration or uscular administration. The term “intravenous administration” means stration into a vein. “Intradermal stration” is injection into the upper layer ‘of skin (i.e., the ), just beneath the epidermis. “Subcutaneous administration” refers to administration just below the skin. “Intramuscular administration” is the injection directly into a muscle.

Antigsychotic Agents As discussed above, the pharmaceutical compositions provided herein are useful for the stration of antipsychotic drugs to a subject. As used herein the term “antipsychotic” refers all drugs used to treat psychosis. Common conditions for which antipsychotics are prescribed include phrenia, mania and delusional disorder, although antipsychotics are also used to counter psychosis associated with a wide range of other diagnoses. Antipsychoties also act as mood stabilizers making them suitable for the treatment of bipolar disordef"(even when no symptoms of psychosis are present).

The pharmaceutical compositions provided herein are particularly useful for formulating a water-insoluble antipsychotic into an injectable composition. 2012/029625 The pharmaceutical compositions described herein are usefiil for administration ofwater-insoluble ychotic agents. As used herein, a water-insoluble antipsychotic agent is one that dissolves in a quantity of water to an extent of less than 100%. The term "water-insoluble" does not necessarily refer to complete or 100% water- insolubility. In certain embodiments, the water-insoluble material ves to an extent of less than 50%. In other embodiments, the water-insoluble material dissolves to an extent of less than 10%. In a particular embodiment, the water-insoluble material dissolves to an extent of less than 1%. The term "water-insoluble" can refer to lity as prescribed in the United States Pharmacopoeia. .10 In one embodiment, the antipsychotic drug of the pharmaceutical composition is aripiprazole. The razole drug substance can comprise, consist essentially of, or consist of razole (in a crystalline, non—crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including ethanolates and hydrates), or other aripiprazole polymorphs. Preferred salts include those salts insoluble in an aqueous vehicle. Pharmaceutical salts such as the hydrochloride and various pharrnaceutically acceptable ylate salts are suitable.

The aripiprazole drug substance can also include aripiprazole prodrugs. The term “prodrug” is art-recognized and is ed to encOmpass compounds which, under physiological conditions, are converted into active compounds, e.g., those described herein. A common method for making a prodrug is to select moieties which are hydrolyzed or otherwise cleaved under physiological conditions to provide the desired nd; In other ments, the prodrug is converted by an enzymatic activity of the host animal.

Preferred razole prodrugs that can be used in the pharmaceutical compositions include the prodrugs described in US. Publication No. 2011/0003828, which is incorporated herein by reference in its entirety.

In a particular embodiment, the aripiprazole prodrug is a compound of formula (I) or formula (II): (I) (ll) wherein R” is absent, and R" is —CH20C(O)R',—CH20C(O)OR1,—CH20C(O)N(R')2 or — C(O)R'; Rb is absent, and R” is —CH20C(O)R', —CH20C(O)OR_‘, —CH20C(O)N(R1)2 or — C(0)R'; R° is -CH20C(O)R‘, —CH20C(O)OR', —CH20C(O)N(R')2 or —C(O)R'; wherein each RI is independently selected from the group consisting ofhydrogen, substituted or unsubstituted aliphatic, and substituted or tituted aryl; and wherein each R2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein Y 9 is a pharrnaceutically acceptable rion; and wherein represents a single or double bond. le counterions include, e.g., de, bromide, iodide, sulfate, phosphate, acetate, benzoate, tartratc, citrate, propionatc, gluconate, lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate, e, conjugate bases of organic carboxylic acids, and the like.

In one embodiment of formula (I), the razole prodrug.is a compound of formula (1'): Cl {\NWO 0') wherein R8 is CH20C(O)Rl and wherein Rl is selected from substituted or unsubstituted aliphatic.

In a particular embodiment of formula (I'), R] is -—CH20C(O)-(CH2)4CH3 (Compound A-4). In r particular ment of formula (1'), R1 is —CH20C(O)- (CH2)10CH3 (Compound A-7). nds A-4 and A—7 are depicted below: In another embodiment, the ychotic drug of the pharmaceutical composition is olanzapine. The olanzapine drug substance can comprise, consist S essentially of, or consist of olanzapine (in a lline, ystalline or amorphous form), an pine salt, an pine solvate (including for example ethanolates and hydrates), or other olanzapine polymorphs. A preferred olanzapine salt is olanzapine pamoate. The antipsychotic drug can also be an olznapine prodrug.

The olanzapine drug substance can also e pine prodrugs of Formula (III), or (IV): (III) (IV) wherein R3 is—CH20C(O)R', —CH20C(O)OR’, —CH20C(O)N(R1)2 or —C(O)Rl; R4 is—CH20C(O)R', —CH20C(O)OR‘, —CH20C(O)N(R‘)2 dr -C(O)R‘; wherein each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or tituted aryl; wherein Y e is a pharmaceutically acceptable counterion.

Suitable counterions include, e.g., chloride, bromide, iodide, sulfate, phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate, lactate, maleate, fumarate, camsylate, glucepate, mesylate, napsylate, pamoate, conjugate bases of organic ' carboxylic acids, and the like. 2012/029625 In r embodiment, the antipsychotic drug of the pharmaceutical compositions is done. Lurasidone is an atypical antipsychotic that is useful for the treatment of a variety of psychiatric disorders, including schizophrenia and bipolar disorder. This compound is described in, e.g., US. Patent No. 372, which is incorporated herein by reference. Lurasidone is the c name of the compound (3 aR,4S,7R,7aS)-2—[((1R,2R) {[4—( 1 ,2-benzisothiazol-3 -yl)-piperazin yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione: Thelurasidone drug substance can comprise, consist essentially of, or consist of lurasidone free base (in a lline, non-crystalline or ous form), a lurasidone salt, a lurasidone solvate (including for example ethanolates and hydrates), or other lurasidone polymorphs. The lurasidone drug substance can also include lurasidone prodrugs.

Accordingly, razole, or olanzapine, or a compound of formula I, II, III, IV, or V can be referred to as an "antipsychotic agent" or "water~insoluble antipsychotic agent. " An “aliphatic group” or “aliphatic” is non-aromatic moiety that may be saturated (e.g. single bond) or n one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.

An aliphatic group, when used as a linker, preferably contains between about 1 and about 24 atoms, more preferably between about 4 to about 24 atoms, more preferably n about 4 to about 12 atoms, more typically between about 4 and about 8 atoms. An aliphatic group, wlien used as a substituent, preferably contains between about 1 and about 30 atoms, more preferably between about 4 to about 19 atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is tood that aliphatic groups may include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted l groups described herein.

In certain embodiments, the tic groups of the present invention are alkyl chains containing from 5 to 11 carbon atoms. In other embodiments, the aliphatic groups are alkyl chains containing from 15 to 19 carbon atoms.

The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and yl. In an embodiment, aryl is unsubstituted or independently substituted one or more times with halogen, CH; alkyl, or O- CH, alkyl.

The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyn'dyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4I-I-1,2,4-triazolyl, ,3-triazolyl, '2H-1,2,3-triaz'olyl, etc.) tetrazolyl (e. g. IH-tetrazolyl, 2H-tetrazolyl, etc), etc.; unsaturated condensed cyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, nolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6—membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to ered heteromonocyclic group containing 1 to 2 oxygen atoms and l to 3 en atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group ning 1 to 2 oxygen atoms" and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); rated 3 to 6—membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4— thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc. ; unsaturated condensed heterocyclyl 2012/029625 group containing 1 to 2 sulfur atoms and l to 3 nitrogen atoms (e. g., hiazolyl, benzothiadiazolyl, etc.) and the like.

The term "substituted” refers to the replacement of one or more en radicals in a given ure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, io, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, xy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, inoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, yl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent may be further substituted.

For simplicity, chemical moieties that are defined and ed to throughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.) or alent moieties under the appropriate structural stances clear to those skilled in the art. For example, an "alkyl" moiety can be ed to a monovalent radical (e.g. CH3-CH2-), or in other instances, a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." Similarly, in circumstances in which divalent moieties are required and are stated as being “alkoxy3) ,3 £$ , “alkylamino , aryloxy”, “alkylthio”, "aryl", “heteroaryl”, “heterocyclic” ‘fl 3) 66 , alkyl” yl”, “alkynyl , aliphatic”, or “cycloalkyl”, those skilled in the art will understand that the terms alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, "'aryl", “heteroaryl”, “heterocyclic”, “alkyl”, “alkenyl”, yl”, “aliphatic”, or “cycloalky ” refer to the corresponding nt moiety.

The term “compound” is defined herein to include'pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds having a formula as set forth herein.

Methods of Treatment The pharmaceutical compositions provided herein can be used for treatment of a variety of disorders in a subject in need thereof. For example, the disclosed compositions may be used to treat conditions selected from: disorders such as cerebral deficit subsequent to cardiac bypass surgery and grafiing, stroke, cerebral ischernia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, ia (including AIDS-induced dementia), Alzheimer’s e, Huntington's Chorea, amyotrophic l sclerosis, ocular , retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine (including ne headache), urinary incontinence, nce tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, ***e, ves, hypnotics, etc.), sis, phrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD)), attention deficit disorder (ADD), ion deficit hyperactivity disorder (ADI-ID), mood ers (including depression, mania, bipolar disorders), circadian rhythm ers (including jet lag and shift work), trigeminal gia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder. _20 In another embodiment, the present invention provides a method of treating cardiac and cardiovascular disorders such as angina, arrhythmia, and hypertension, in a patient in need thereof. The method comprises administering to the subject a therapeutically ive amount of a composition of the invention or a pharmaceutically acceptable salt thereof.

The invention further s to the ent of fever, diabetes, allergy, asthma, infection, inflammation, and ulcers in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of the invention or a pharmaceutically acceptable salt thereof.

The invention further relates to the treatment of sleep modulation comprising administration of a composition of the invention. Sleep modulation includes decreasing the time to sleep onset, increasing the average sleep bout length, and sing the, maximum sleep bout length.

In a particular ment, the pharmaceutical compositions described herein can be used to treat anxiety, depression, bipolar disorder, autism—related irritability, and psychotic conditions including acute mania, schizophrenia and schizophreniform diseases in a subject.

The term “treated,” “treating” or “treatment” includes the diminishment or alleviation of at least one symptom associated with sis or a related CNS disorder.

The term “treated,” “treating” or “treatment” as used in reference to a disease or condition shall mean to intervene in such disease or condition so as to prevent or slow the development of, t or slow the progression of, halt the progression of, or eliminate the disease or condition.

As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological ty, especially a biological ty associated with an injection site on.

The term “subject” is intended to include animals, which are capable of suffering from or afflicted with iaassociated with sis or a related CNS disorder, including, without limitation, psychotic conditions including acute mania, schizophrenia and schizophreniform disorders, r disorder, anxiety and depression. Examples of subjects include mammals, e.g., , dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from any of the diseases described herein.

The term “about” or “approximately” usually means within 20%, more preferably within 10%, and most preferably still within 5% of a given value or range.

Alternatively, especially in biological systems, the term “about” means within about a log (i.e., an order of magnitude), preferably within a factor of two of a given value.

In one embodiment, a therapeutically effective amount of the agent is given to a subject using the ceutical compositions provided herein. The term “therapeutically effective amount” is further meant to define an amount resulting in the improvement of any parameters 6r" clinical symptoms. The actual dose may vary with each patient and does not necessarily indicate a total elimination of all disease symptoms. In the case of antipsychotics, the management of exacerbations and maintenance of remission of psychiatric ms are main goals of therapy, and selection of the appropriate drug and dosage in a particular disease balances these goals with the minimization of adverse events attributable to the drug.

A therapeutically effective amount of the compound used in the treatment described herein can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous stances. In determining the therapeutically effective dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the ilability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

Preferred suitable dosages for the compounds used in the treatment described herein are on the order of about 1 mg to about 600 mg, preferably about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580 to about 600 mgs total of active agent. Dosing schedules may be adjusted to provide the optimal therapeutic response. For e, administration can be one to three times daily for a time course of one day to l days, weeks, months, and even years, and may even be for the life 'of the patient. Practically speaking, a unit dose of any given composition used in the treatment described herein can be administered in a variety of dosing schedules, depending on the judgment of the clinician, needs of the patient, and so forth. The specific dosing le will be known by those of ordinary skill in the art or can be determined mentally using e s. Exemplary dosing schedules e, without limitation, administration five times a day, four times a day,' three times a day, twice daily, once daily, every other day, three times , twice , once weekly, twice monthly, once monthly, and so forth. Unit dose preparations provided herein can contain aripiprazole, a compound of Formula I or a compound of Formula II in the range of about 20 to about 900, e.g., 60 to about 800, mgs (aripiprazole base equivalents). Unit dose preparations provided herein can contain olanzapine, a compound of Formula III, or a compound of Formula IV in the range of 40 to about 500 mgs (olanzapine base equivalents). Unit dose ations provided herein WO 29156 can contain a compound of Formula V in the range of 160 to about 1000 mgs (lurasidone base equivalents).

Preferred amounts according to the selected mode of administration are able to be determined by one skilled in the art. Pharmaceutical itions can be manufactured utilizing techniques known in the art. Typically the therapeutically effective amount of the compound will be admixed with a pharmaceutically acceptable carrier.

EXEMPLIFICATION OF THE INVENTION The invention is further illustrated by the ing examples. The examples should not be construed as r limiting.

EXAMPLE I - ation Optimization of Antipsychotic Drug Product This study describes the formulation development of the Compound A-7 drug product for use in further studies. Development was focused on improving the wettability and redispersibility characteristics of the injection vehicle, with the ultimate intent of increasing the physical stability of the suspension. The zation experiments identified a formulation comprising Compound A-7 recrystallized bulk drug substance (256 mg/mL) suspended in an 10 mM phosphate buffer injection vehicle containing sorbitan laurate (0.5 wt%), polysorbate 20 (0.2 wt%), and sodium chloride, (0.8 wt%).

While the early clinical formulation was deemed acceptable for term study, there was a desire to improve the physical ties of the drug product suspension (namely ease facturing, and resuspendability with increased drug loads) for long term use. Optimization of ’properties would also improve the likelihood of success in a prefilled syringe, in the event such a system becomes a desired container closure configuration. The gy for ation development consisted of a two-tiered approach designed to screen a wide array of injection vehicles and identify promising candidates for further optimization. The first round of experiments assessed wettability characteristics, specifically free energy of immersion and spreading ient, of various vehicles with Compound A-7. Immersion of a solid in a liquid (wetting) begins with displacement of the solid-air interface with a solid-liquid interface. The immersional free energy in this solid/liquid/air system describes how thermodynamically favorable (or unfavorable) exchange of these aces is. The ing coefficient ts whether this exchange will occur spontaneously, or will require additional energy input. Thus, these parameters were selected for study since they would be good indicators of the favorability of the vehicles to wet the hydrophobic drug substance, and the relative difficulty of doing so. The excipients screened were primarily limited to materials that have been used in approved drug products (although not necessarily limited to parenteral routes of stration) with acceptable safety profiles [Rowe, Raymond C., Paul J. Sheskey, and Paul J Weller. ok of Pharmaceutical Excipients, 4th Ed. New York, Pharmaceutical Press. 2003]. The excipients screened represent a number of functionalities in the formulation of stable suspensions, including suspending agents, surfactants/wetting agents, viscosity modifiers, vents and flocculants. ‘The ion vehicles that were found to have favorable wetting characteristics with Compound A-7 were then advanced to the second tier of experiments.

Description of Excipients Utilized MATERIAL ABBREVIATION gmlé MANUFACTURER Sodium carboxymethyl CMC N/A Spectrum ‘ cellulose Poloxamer 188 P188 Pluronic® F68 _--Polyvinylpyrrolidone PVP, Povidone Plasdone® K- ---IPolyvinylpyrrolidone N/A' ‘ Plasdone® K- Sigma USP Polyethylene glycol PEG3350 -tN/A ' Polyethylene glycol 300 PEG 300 Emerald Bio Polysorbate 20 Ps 20 Tween® 20 m Polysorbate 80 PS 80 Tween® 80 an monolaurate SML Span® 20, Sigma-Aldrich Montane® 20 Sorbitan monopalmitate Span® 40 Sigma-Aldrich ---Monobasic sodium N/A N/A ---Dibasic sodium N/A N/A . _--Phosphate buffered PBS N/A *One tablet dissolved in 200 mL of zed water yields 0.01 M phosphate buffer, 0.0027 M potassium chloride and 0.137 M sodium de, pH 7.4, at 25 °C. .2 METHODS .2.2 Injection Vehicle Formulation Injection vehicles were made by weighing the appropriate mass of cxcipient into a metered volume of water for injection (WFI) to give the desired weight percentage by volume. Since the cxcipient quantities were typically low (<1%), the volume change from addition was considered negligible. In the cases where multiple surfactants were added, the more water-soluble surfactant was added first to aid in dispersion of the less soluble surfactant. The vehicle formulations were then stirred with a magnetic stir plate until all solids were dissolved and the vehicle appeared visually homogeneous. .2.3 Compound A-7 Drug Product Compounding The suspension was formed by adding recrystallized Compound A—7 to the formulated injection e with mixing to e the target drug concentration. At the bench scale, this was done on a vial-by-vial basis. The appropriate mass of Compound A-7 was d into a 5 mL nized glass vial and the appropriate volume of vehicle was added to achieve the desired suspension tration. The vial was then stoppered/sealed and mixed by alternating between a vortex mixer and a 60 second sonication bath. This procedure was typically repeated 7 times (total of 7 minutes). Afier compounding, the absence of aggregates or unincorporated powder was visually confirmed. .2.5 Wettability terization A surface energy measurement methodology was developed that would allow for facile screening of formulation candidates with minimal use of drug substance. These experiments utilize the surface tension of the injection-vehicle and surface energy of the solid to predict the immersional free energy and spreading coefficient between the liquid and the solid. .2. 6 Liquid Surface Tension Analysis A force-balance tensiometer (Attension Sigma® 701) with a platinum Wilhelmy plate was used to measure the surface energy (tension) of the vehicle of st. This was done using a 30 mL sample of the vehicle of interest and taking 8 individual surface tension measurements. The first 3 measurements were discarded as being non- representative of equilibrium conditions, and the remaining measurements were averaged to give the surface tension value. The vehicle sample contained a small- (approx. 10 mm) stir bar and the magnetic stir plate in the meter was turned to the lowest setting to allow for mixing without significant disruption of the measurement. All measurements were taken at ambient ions. To then obtain the polar and non-polar (dispersive) components of the surface tension, a polytetrafluoroethylene (PTFE) contact angle rd(Rame-Hart) was‘affixed to the meter and the dynamic contact angle was measured. Since the desired ement was the static contact angle, a very slow measurement speed was used (0.001 m/min) which allowed for approximation of the t —> oo (infinite time) condition. This was done using a 30 mL sample of the vehicle of interest and taking the average of 3 individual contact angle measurements. The e sample contained a small (approx. 10 mm) stir bar and the magnetic stir plate in the tensiometer was turned to the lowest setting to allow for mixing without significant disruption of the measurement. All measurements were taken at ambient conditions.

With the total surface tension of the liquid, and the contact angle of the liquid on a non-polar surface with known surface energy attributes, the polar and dispersive ents of the surface n were calculated. .2.7 Solid Surface Energy Analysis A force balance meter (Kruss K100) with a Washbum-type powder measurement apparatus (Kruss FL12) was used to obtain the polar and dispersive e energy components of the'Compound A-7 sample. This was done by using probe liquids with precisely terized surface tensions (diiodomethane and ethylene glycol) and measuring the rate at which the probe s wick up into a packed, 125 mg bed of the powder by capillary action. The contact angle experiments were performed on the samples according to the m method for the determination of contact angles for liquids wetting porous materials. The contact angle data with methane and ethylene glycol were used along with the Fowkes theory to obtain the surface energy data. .2.8 Redispersibilily/Settled Bed Height Characterization The redispersibility of the drug products were assessed by creating low concentration suspensions and comparing the relative height of the settled beds. Higher d bed heights are indicative of flocculated, or loosely aggregated, particles. These suspensions settle faster initially, but their loosely aggregated state allows for easier redispersion and better al stability as the particles cannot pack as tightly as fiilly dispersed suspensions.

The experiments were made using a concentration of 220i22 mg of Compound A—7 in 3 mL ofthe vehicle of interest (73.3 mg/mL). The lower concentration was used to allow for easier rank ordering of Settled bed heights as well as for material conservation. A key assumption was that this rank ordering would be the same at full concentration. This suspension was nded in a 5 mL vial, drawn into a 3 mL BD c syringe using an 186 needle, capped, placed upright and allowed to settle. Early ments showed that suspensions were fully settled after approximately 10 hours, and that uent time did not result in any discemable amount of further bed packing.

As such, all sions tested were allowed to settle for a minimum of 16 h and a maximum of 48 h prior to being characterized.

‘Settled bed heights were assessed by qualitatively recording the height of the undisturbed bed and total height of the liquid using the graduations on the 3 mL syringes. Formulations that looked promising (highest bed heights) at lower concentrations were also screened at full concentration (810 mg in 3 mL — equivalent to 270 mg per mL vehicle) to qualitatively assess rcdispersibility. 6.0 SAND SION Table 1: Frce Energy of Immersion and Spreading Coefficient of Compound A-7 in Various Formulations FREE SPREADING FORMULATION ENERGY OF COEFFICIENT IMMERSION (mN/m) (mN/m) 2% CMC - 0.2% PS 20 2% PEG3’350 - 0.2% PS 20 - 2% Eth -- 0.2% Docusate Sodium 4% PEG3350 - 0.8% SML - 0.5% PS 20 0.8% SML- 0.5% ps 20 4% PEG 3350 - 0.2% Ps 20 (2% PEG 3350 - 0.2% PS 20 2% PEG3350 - 0.2% Ps 20 - 1% Eth 2% CMC - 0.2% PS 20 - PBS - (SAD) 6% PEG3350 — 0.2% PS 20 _“ 2% CMC - 0.2% PS 80 -6.7 1% CMC — 0.8% SML - 05% PS 20 2% CMC - 0.5% PS 20 40% PEG 300 4% PEG 3350 2% PEG 3350 2% CMC - 0.2% Poloxamer 188 0.8% SMP- 0.5% Ps 20 - 1% CMC - 0.8% SMP- 0.5% PS 20 2% PVP K30 As shown in Table l, the free energy of immersion for all formulations tested against all tallized Compound A-7 samples was found to be negative, with the exception of pure water. Free energy of immersion describes the energy gained or lost when displacing the air-solid interface with a liquid-solid interface. If the sign is negative, the -solid interface (created by wetting) is more energetically favorable, and if the sign is positive, the lid interface is more energetically favorable.

Examination of the data shows that formulations containing sorbitan laurate, polysorbate and rbate 80 are the most favored (most negative free energy of ion While all vehicle formulations tested have thermodynamically favorable immersional free energies, the data in Table 1 illustrate that formulations are differentiated by their spreading coefficients. The value of spreading coefficient indicates whether the replacement of the air-solid interface by the liquid-solid interface will occur spontaneously. The results show that vehicle formulations containing docusate sodium and an e/polysorbate 20 combinations have positive spreading coefficients, which means they will replace the solid-air ace with the solid-liquid interface without the addition of work (i.e. spreading occurs spontaneously).

A positive spreading coefficient is desirable because of an increased likelihood of complete deaggregation/wetting of the powder during suspension compounding leading to an overall ease of processing.

In summary, while analysis of the wetting data show that practically all formulations are predicted to wet, with the most favored formulations containing a surfactant such as polysorbate 20, polysorbate 80, sorbitan laurate or docusate sodium, review of the spreading coefficient data identified formulations that are neously wetting. The latter has ve ations for processing ease and robustness. As such, these materials were selected as the area of focus in the subsequent ersibility studies discussed in Section 6.4. 6.4 Redispersibility/Settled Bed Height The results from the settled bed height assessments are presented in Figure l.

The data te that formulations containing sorbitan laurate and polysorbate 20 have significantly higher settled bed heights than formulations without sorbitan laurate, regardless of the presence of additional polymers (CMC, PEG 3350) or salts (phosphate buffer, saline). onally, the flocculation induced is unique to sorbitan laurate/polysorbate 20, as evidenced by comparison to formulations containing sorbitan monopalmitate, docusate sodium, or polysorbate 20 alone. ments were also performed to assess whether the induced flocculation could be uniquely attributed to the presence of sorbitan laurate, or whether it was the result of an se in total surfactant load. sions were made with an equivalent mass load of polysorbate 20 and polysorbate 80 (1.3 wt%) and an lent molar content load of rbate 20 (3.1 wt%) to the total surfactant load of a 0.5% sorbitan laurate/0.2% polysorbate 20 suspension. The suspensions with increased polysorbate 20 were found to have similar settled bed heights to 0.2 wt% polysorbate formulations, showing the flocculation phenomenon to be uniquely attributed to the additional influence of sorbitan laurate.

Compared with other formulations, the sorbitan laurate/polysorbate 20 formulations resuspend more easily afier ng, and as such these suspensions were made at the full concentration of 21 wt%. At full concentration d bed heights could not be measured as the flocculated bed filled the entirety of the syringe volume. ative assessment of redispersibility showed the settled bed to be easily ted with moderate hand shaking of the vials.

In an effort to ze the ratio between sorbitan laurate and polysorbate 20, suspensions were made in 0.2% polysorbate 20 with phosphate buffered saline and the amount of sorbitan laurate variedbetween 0.2% and 0.6% (representing sorbitan laurate: polysorbate 20 ratios from 1:1 to 3:1). The results are shown in Figure 2. The settled bed height increases to a maximum at a 2:1 ratio, after which, increasing sorbitan laurate concentration has no further effect on bed height. In order to select a formulation in a robust formulation space, the 10 mM phosphate buffer injection vehicle ning sorbitan laurate (0.5 wt%), polysorbate 20 (0.2 wt%), and sodium chloride, (0.8 wt%) was selected as the lead candidate and advanced into further studies. 7. 0 Example 1 Conclusion The optimized Compound A-7 drug product (Compound A-7 recrystallized bulk drug substance suspended in an 10 mM phosphate buffer injection e containing an laurate (0.5 wt%), polysorbate 20 (0.2 wt%), and sodium chloride, (0.8 wt%)) was found to meet all target criteria and exhibits improved physical attributes (redispersibility, ease of wetting) when compared to the Compound A-7 recrystallized bulk drug substance (21 wt%) suspended in an 5 mM phosphate buffer injection vehicle 2012/029625 containing sodium carboxymethyl cellulose (2 wt%)_, polysorbate 20 (0.2 wt%), and sodium de, (0.7 wt%). The Optimized ation is physically and chemically stable when nded as a 21 wt% suspension (approximately 221 mg/mL) and as a .6 wt% suspension (approximately 270 mg/mL).

EXAMPLE II - Evaluation of Performance of Compound A-7 Suspensions Containing Varied Amounts of Sorbitan Laurate and Polysorbate 20: zation of Excipient Concentrations and Sorbitan Laurate to Polysorbate 20 Ratio The objective of this study was to evaluate formulation performance of Compound A-7 suspensions containing varied amounts and ratios of sorbitan laurate and polysorbate 20 in an effort to establish a robust region for the drug product which meets all target t attributes.

An array of vehicle formulations were evaluated and a lead drug t candidate consisting of Compound A-7 bulk recrystallized drug nce (25.6 wt%) suspended in an 10 mM phosphate buffer injection vehicle containing sorbitan laurate (0.5 wt%), rbate 20 (0.2 wt%), and sodium chloride, (0.8 wt%) was identified.

During development, settled bed height and qualitative ease of re-suspension were assessed and utilized to identify a lead formulation. Increases in these properties are associated with flocculation, a common mechanism used to increase physical stability of pharmaceutical suspensions [Akers, M., Fites, A. and Robison, R.

Formulation Design and Development of Parenteral Suspensions. Journal of Parenteral Science and Technology Vol. 41, No.3 (pp. 88-96), 1987; and man, Herbert A., Martin M. Reiger and Gilbert S. Banker.

Pharmaceutical Dosage Forms: Disperse Systems Volume 2. (pp 18—22, 285-301) 2nd Ed. New York: Marcel Dekker, 1996.]. Flocculation refers to the formation of loose aggregates held together by interparticular forces. The sediment layer in a flocculated suspension is loosely packed and more easily redispersed compared to non-flocculated formulations in which a dense cake can form. Further ments to quantify flocculation and formulation performance with vehicles containing varied amounts of sorbitan laurate and polysorbate 20 were designed, executed and analyzed. These follow-on experiments are detailed below.

WO 29156 .2 METHODS Table 2: Amounts and Ratios of Surfactanct ents in Vehicles Examined Sorbitan Monolaurate Polysorbate 20 Nominal Mass Ratio --_01 7 7“ .n-- '-——- 0.5 0.1 0.625 1.25 .2.2 Compound A-7 Drug Product Compounding nd A-7 suspensions (265 mg/mLiIO %) were prepared by adding 3 mL of injection vehicles listed in Table l to 1032' mg of Compound A-7 bulk recrystallized drug substance in a 5m1_ siliconized glass vial. Each vial was sealed with a rubber stopper and an um seal. Suspensions vials were roughly mixed by vortexng and tapping to facilitate initial wetting of the solids. Each vial was then sonicated in a bath sonicator for 10 minutes, with ~5 second vortexing every minute. .2.4 Suspension particle size ement Particle size distribution of formulated suspension was measured on a Horiba LA910 laser diffraction particle size analyzer equipped with a flow through sample cell using 0.1% rbate 20 solution as measurement media. Suspension samples were prepared for measurement by re-suspending the vial containing drug product and then adding 0.1 mL of sion to 10 mL of 0.1% rbate 20 solution. A sample was then added dropwise to the Horiba flow-through sample cell until dispersion transmittance drops below 95%. The particle size metrics examined were volume diameter where 10%, 50%, and 90% of the particle size distribution was smaller than that diameter (Dv[10]. Dv[50], and Dv[90]).

WO 29156 .2.5 Sediment Height Measurements Sediment height was measured after allowing vials sit undisturbed for at least 24 hours. A close up picture of all vials together was taken using a digital camera, with ng such that the sediment layer could clearly be seen in the picture. The distance from the bottom of the vial to the surface of liquid layer and to the surface of sediment layer was measured from each picture. The ratio of line lengths from each vial were calculated and ed as sediment height in percentage, as shown in Figure 3. A sediment height of 100% would indicate that no nt layer is visible.

Injectability Injectability was conducted to assess the ability of the suspension to be passed through a 20 G or greater needle without ng, with minimal resistance applied through use of a mesh screen. .2. 7 Re-suspension time Re-suspension time was measured using a Burrel wrist action shaker. Vials were shaken at max amplitudeon the wrist action shaker in an inverted orientation (cap down) for 5 second intervals. Re-suspension time was recorded when no visual clumps or caked material was observed at the bottom of the vial. .2.8 Microscopy For microscopic analysis, 5 uL of sion was placed on a glass slide and then diluted with 20 uL of same vehicle used to make the suspension. The sample was covered with a coverslip and examined at 10x cation using an Olympus BX60 microscope. es were taken using an AxioCam MRc camera. .3 DESIGN OF EXPERIMENT Using JMP 9 software, a central composite design of experiment (DOE) was initiated with the factors of SML (O — 1% w/v) and rbate 20 (0.1 — 0.8% w/v) concentrations. Previous experiments showed that at least 0.1% polysorbate 20 is required to adequately wet a 25.6 wt % solids load of Compound A-7 bulk recrystallized drug substance therefore the lower limit of 0.1% is deemed to be the lowest possible level of the surfactant required to achieve wetting of the highly hydrophobic Compound A-7 crystals. The final DOE factors are summarized in Table 3.

Table 3: Design of Experiment Factors to look at varied concentrations of SML and polysorbate 20 Polysorbate 20 % SML/Polysorbate 20 .

Ratio The measured responses were: sediment height, pension time, particle size distribution (Dv[10], Dv[50], and Dv[90]), and injectability. Microscopy was also med on each sample. 6.0 RESULTS AND DISCUSSION 6.] Microscopy and Visual Observations Microscopy ofthree suspensions made with vehicle containing 0.2% polysorbate 20 and increasing amounts of SML are shown in Figure 4. It is ly clear that flocculation is occurring as SML content in the vehicle increases. Measured suspension PSD, listed below each image in units of microns, increases relative to the PSD method variability (approx. 2-3 microns) with increased degree of ation. This observation supports using suspension particle size ements to quantify flocculation in that the method preparation ins flocculation induced by the vehicle. The methodologies established by this type of pilot experiment facilitated the initiation ofDOE experimentation. 6.2 DOE ses The desired Compound A-7 drug product formulation attributes include maximum ease of resuspension and injectability, the ability of the suspension to be passed through a 20 or greater gauge needle without ng with minimal resistance applied h use of a mesh screen. pension time, sediment height, and suspension particle size distribution are all physical measurements of the formulated suspension used to assess ease of re-suspension. These responses are related since particle size of the suspension can be a measure of flocculation, which increases the sediment height and decreases re-suspension time. A summary of all responses measured is listed in Table 4.

Table 4 Injectable '- (20-25 Dv[10] Dv[50] Dv[90] ension gauge (um) (um) Tim (S) -51.3 I— - II-II __ I-———- -m n--I- Ii..:jj-66.2-55.8-70.851.866.7 6.3 ension Time, Sediment Height and le Size Responses- A photograph of vials containing suspension afier sedimentation with sediment height calculations is shown in Figure 5. In the two panels of Figure 6 are plotted the Vobserved re-suspension time vs.—_Dv[10] and Dv[SO] values for each suspension. The measured re-suspension time and particle size metrics exhibit an inverse relationship for the sions with smaller ed particle size (below 11 and 32 microns for Dv[l 0] and Dv[50], respectively). Larger measured suspension particle sizes, likely caused by flocculation, facilitate faster re-suspension than smaller ones.

Trends of particle size (Dv[ 1 0] and Dv[50]) with vehicle composition were modeled resulting in‘surface plots (not shown). As SML concentration increased and polysorbate 20 concentration sed, suspension particle size reflected by Dv[10] and Dv[50] increased. The smallest Dv[10] and Dv[50] were measured from suspensions containing rbate 20 with no addition of SML. For suspensions containing 0.1% polysorbate 20, Dv[lO] and Dv[50] increased y with increasing SML. These data are consistent with the understanding that SML is required for the flocculation of the drug product, which results in an increase in apparent suspension particle size and therefore a decrease in re—suspcnsion time. 6.5 Formulation Space The desired Compound A-7 drug product is comprised of an injection e which facilitates re-suspension with optimal ease without sing injectability of the suspension to an unacceptable level. Increases in measured suspension le size parameters directly correlate to ease of re-suspension but inversely correlate with injectability. Hence, a formulation with high SML wt % and low polysorbate 20 wt % would have the shortest re-suspension time but would also have the worst injectability.

The optimal vehicle composition is one where a balance between ease ofresuspension and injectability is ed through a balance in the amounts and ratios of SML and polysorbate 20. The profiles in Figure 6 show that when the measured suspension Dv[lO] is greater than 11 um or the measured suspension Dv[SO] is greater than 32 microns, optimal re-suspension time is achieved. The values of 11 and 32 microns for Dv[lO] and Dv[50], respectively, were used to set limits within the modeled data in order to define the acceptable formulation space. us experiments showed that at least 0.1% polysorbate 20 is required to tely wet a 25.6 wt % 256 mg/mL i 10% concentration of Compound A-7 bulk recrystallized drug substance. In"oi‘der to t for small s in nd A-7 bulk recrystallized drug substance surface area as well as potential loss of polysorbate 20 on stability, at least 0.2 % polysorbate 20 is recommended for the vehicle composition.

At this polysorbate 20 concentration, 0.5% SML concentration minimizes excipient levels while still maximizing re-suspendability with acceptable injectability. This surfactant combination is ted in Figure 7 by the intersection of the horizontal and vertical lines. 7.0 Example 11 Conclusion Formulation performance 'of Compound A-7 suspensions containing g amounts and ratios of SML and polysorbate 20 were evaluated and a robust region for the drug product which meets all target product attributes was established. Compound A—7 suspension drug t formulated in an injection vehicle containing 0.5% SML and 0.2% polysorbate 20 is within the robust region of the formulation space, as derived fiom analysis of the DOE executed. This vehicle composition minimizes excipient levels while co-optimizing endabilty and acceptable injectability.

EXAMPLE III — INJECTION SITE REACTION MODULATION Subcutaneous Infection SiteReaclion Model Protocol and Data The following experimental ol and data relate to the effect of vehicle on the ISRs caused by aneous (SC) administration of aripiprazole (ARP) free base to rats.

Description of Experimental Dcsigg: Overview of experimental design: There were 7 groups (n=6) in this study evaluating ISRs caused by ARP ated in 7 different es; a standard vehicle was used as the control to which other compositions of vehicle were compared. All groups received a single SC injection of ARP at a dose of 30 mg in a 1 mL dose volume.

A 21- gauge, 1 inch needle attached to a 1 cc syringe was used to administer the drug.

Ten days following injection with ARP, animals were euthanized by C02 asphyxiation, and the ISR was excised and weighed. Weights of the ISRs were plotted t dose administered.

Materials and methods: Aripiprazole (ARP) dose 30 mgs; Control Vehicle: 0.1% Polysorbate 20 (Tween® 20)/, 3% CMC, 0.9% NaCl in water Vehicle A: 0.2% Polysorbate 20 (Tween® 20)/ 0.5% sorbitan laurate (Span® 20) in PBS buffer (10 mM, pH ~7) Vehicle F: 0.2% rbate 4O (Tween® 40)/ 0.5% sorbitan monopalmitate (Span® 40) in PBS buffer (10 mM, pH ~7) RELPREVV® Vehicle: CMC, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and water for injection Number of study animals: 42; Age: at least 6 — 8 weeks; Body weight range: 300-350 grams upon t from supplier.

Description of experiment, animal allocation and procedures: Test Period ures: Animals were dosed with ARP on Day 0. On Study Day , all animals were euthanized, and the injection site reaction tissue/material was retrieved surgically and weighed immediately.

Figures 8A and 8B demonstrate that formulations comprising sorbitan laurate trated a cant reduction in injection site reaction ed to formulations with no sorbitan laurate. Figure 8A shows results from experiments with aripiprazole (free base), and Figure 8B shows results from experiments with olanzapine pamoate.

EXAMPLE IV — SOLUBILITY OF COMPOUND A-7 IN VEHICLES CONTAINING VARYING S OF SORBITAN MONOLAURATE.

Sample preparation: a. Injection es comprised of ca. 10 mM phosphate buffer, 0.2% polysorbate , saline and various amount of sorbitan laurate (0%—0.75%) were prepared. The ion vehicles were stirred for 4 hours before preparing suspension preparation. b. Approximately 1.252t0.05 g of Compound A-7 were added to 15 mL injection vehicles in a 20—mL glass scintillation vial with a 7/8” X 5/16” stirring bar. The suspension was vigorously stirred on Chemglass CG—1990-T-50 hotplate at 25 °C which was controlled using a thermal sensor. c. At each time point, a total of 3 mL of -mixed suspension were erred into two 1.5-mL centrifuge tubes using a plastic pipette. The tubes were centrifuged at 14,000 rpm for 4 minutes. The supernatant of both tubes were combined and centrifuged again at 14,000 rpm for 4 s. The HPLC sample was then prepared with final (2nd) centrifuged supernatant by diluting 0.4 mL supernatant with 0.6 mL THF. d. tration of dissolved Compound A-7 was determined using HPLC. 2012/029625 The data illustrated in Figure 9 highlight the trends in Compound A-7 concentration in solution as a function of SML content in the injection vehicle.

Surprisingly, the addition of a second surfactant, SML, decreases solubility up to 0.5 wt % SML with solubility increasing again above 0.5 wt.% (e.g. 0.75 wt%) (middle line).

EXAMPLE V — PRODRUG SYNTHESIS URES S nthesis o Ari i razole Prodru s EVEN};t -— Cl\‘/N\/l(>ng {\N/\/\/o-i 3 (“UN 7' ‘ Example 1 Aripiprazole Compound A-l: Preparation of 7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)- 1-(hydroxymethyl)-3,4-dihydroquinolin-Z(1H)-one A mixture of Aripiprazole (20g, 45 mmol), triethylamine (lmL, 7.1 mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide (200 mL) was heated to 80°C for 20 h'. The reaction mixture was , diluted with ethyl acetate (400 mL) and washed with water/brine (1:1, 3 x 500 mL). The organic phase was dried over MgSO4, d and evaporated to dryness under vacuum to give hemi-aminal A-l as a white solid (18.6 g, ning 25% Aripiprazole, 65% yield based on A-l).

Compound 1: (7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl acetate Cl (WM/O CIUNJ _ 0"“ A solution of nd A-l (50.63 g, 0.105 mol) in ous tetrahydrofuran (THF, 80 mL) was treated with acetic anhydride (15.3 mL, 0.16 mol) and heated for 2.0 hours at 60°C (oil-bath). To the above solution, triethylamine (2.0 mL, 0.014 mol) was added and stirred for 16 hours at 60°C. The solvent was removed using a rotator evaporator. To the ing crude mixture, ethyl acetate (150 mL) and e (50 mL) was added. The solution was washed with NaHCO; (5% aqueous solution, 250 mL,).

Afier separation of the two layers, pH of the aqueous layer was adjusted to above 7. The aqueous layer was further extracted using the organic mixture. The organic layer was separated and washed with 5% NaHCO; solution, followed by deionized water, and brine. The solution was dried using anhydrOus MgSO4, filtered and evaporated under vacuum. The resulting product was purified using silica gel column chromatography using ethanol: ethyl acetate (5:95) as the eluent. Fractions containing the d product were combined and d-tartaric acid (12.5 g dissolved in 60:5 l: water) was added, resulting in the precipitation of the desired product (48.78 g, 89% yield). 1H NMR , 300MHz) 6 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t, 2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H).

Compound A-7: (7—(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl dodecanoate CI meA/O_ ORCFNJ o 'O—-’ 0 Compound A-7 was prepared in an analogous fashion to Compound 1. The desired t was isolated as a crystalline solid (0.3 g, 21 % yield). The molecular weight was confirmed by mass spectrometer analysis. Figure 2-6 shows the PXRD, IR, Raman, TGA spectrum of the desired product. ‘H NMR , 300MHz) 6 0.87 (t, 3H), 1.24 (m, 16H), 1.62 (m, 2H), 1.83 (m, 2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86 (dd, 2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.07 (dd, 1H), 7.14 (m, 2H).

Compound A-28: (7-(4-(4-(2,3-dichlor0phenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)—yl)methylbenzylcarbamate C, (\N/WO eo 0 To a solution of hemi-aminal A1 (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15g, 1.3 mmol) and triethylamine ( 1.1 mL, 7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. The reaction mixture was then heated at 35°C for 20 hours, cooled and washed with water/brine (1:1, 50 mL). The organic phase was dried over MgSO4, filtered and ated under vacuum. The residue was further purified by tography on silica eluting with ethyl acetate/dichloromethane/methanol (1:1:0.1) to give the desired product as an off white foam (530 mg, 14% yield). 1H NMR (CDCl3, 300MHz) δ 1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m/z (M+H) 611.12 and 613.10. nd A-4: (7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-1(2H)-yl)methyl hexanoate Cl N Cl N O N O O Compound A-4 was prepared in an analogous fashion to Compound A-28. The desired product was isolated as a yellow solid (3.69g, 87% yield). 1H NMR (CDCl3, 300MHz) δ 0.78 (t, 3H), .28 (m, 4H), 1.40-1.78 (m, 6H), 2.20-2.40 (m, 4H), 2.40- 2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00 (m, 4H), 3.88-4.00 (m, 2H), 5.75-5.83 (m, 2H), 6.55-6.62 (m, 2H), 7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H). m/z (M+H) 576.4 and 578.4.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless the context requires ise, the word "comprise", and ions such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of rs or steps but not the ion of any other integer or step or group of integers or steps.

Claims (8)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A pharmaceutical composition sing: (a) compound A-7: (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle.

2. The composition of claim 1, wherein the ratio of components (b) to (c) is imately 5 to 2, by weight.

3. The composition of claim 1 or 2, comprising about 0.2 – 1 weight percent sorbitan laurate.

4. The composition of any one of claims 1 to 3, comprising about 0.4 – 0.7 weight percent sorbitan laurate.

5. The ition of any one of claims 1 to 4, comprising about 0.5 weight percent sorbitan e.

6. The composition of any one of claims 1 to 5, comprising about 0.05 – 0.8 weight percent polysorbate 20.

7. The composition of any one of claims 1 to 6, comprising about 0.1 – 0.3 weight percent polysorbate 20.

8. The composition of any one of claims 1 to 7, comprising about 0.2 weight percent polysorbate 20.