NZ723869B2 - Aripiprazole formulations having increased injection speeds - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a compound of Formula (I) that are useful for the intramuscular delivery of antipsychotic drugs using rapid injection rates.

Description

ARIPIPRAZOLE FORMULATIONS HAVING INCREASED INJECTION SPEEDS Related Applications This application claims priority to U.S. Provisional Application Serial No. 61/955,976 filed on March 20, 2014, the contents of which is hereby incorporated by reference in its entirety. ound U.S. Patent Nos. 4,734,416 and 528 disclose aripiprazole, 7-{4-[4-(2,3- dichlorophenyl)piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone or 7- { 4- [4-(2,3 - dichlorophenyl)piperazinyl]butoxy}—3,4-dihydro carbostyril, as an atypical antipsychotic agent useful in the treatment of schizophrenia, bipolar disease, depression, and other CNS disorders. Aripiprazole has the following chemical structure: Cl (\NWO GUM) Aripiprazole is sold under the trade name ABILIFY®. It acts as a dopamine D2 partial agonist, serotonin 5-HT1A or agonist, and is an antagonist of the serotonin 5- HTZA receptor. ABILIFY® is tly administered orally on a -day dosing schedule as Y® (aripiprazole) Tablets, ABILIFY LT® (aripiprazole) Orally Disintegrating Tablets, and ABILIFY® (aripiprazole) Oral Solution. Poor and variable patient compliance with a once—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.

U.S. Patent Nos. 7,807,680, 8,338,427, and 8,338,428 be cting aripiprazole sterile injectable formulations. Studies on aripiprazole free base injections showed a prolonged pharmacokinetic profile, but there have been reports of moderate to severe tissue irritation following intramuscular (IM) injection and subcutaneous (S C) injection. As such, there exists a need for improved methods of delivering antipsychotics, such as aripiprazole, thereby improving patient compliance and maximizing the cological profile of the active agent.

Summary ofthe Invention In part, the invention provided herein relates to the intramuscular administration of pharmaceutical compositions comprising compounds of Formula (I) to a t in need thereof using a rapid injection rate. It was discovered that the rapid injection rate resulted in fewer ion site failures, such as needle clogging. Surprisingly, the rapid injection rate did not cause a pain ity above a normal threshold or any injection site reactions in the subject in need thereof. Thus, ed herein is an improved method of administering pharmaceutical itions sing compounds of Formula (I), wherein the method comprises intramuscular administration using a rapid or instantaneous injection speed.

In one aspect, provided herein are methods of using pharmaceutical compositions comprising compounds of Formula (I) to treat ers of the central nervous system, such as schizophrenia. In another aspect, provided herein is a method of intramuscular administration of a pharmaceutical composition to a subject in need thereof, sing administering to said subject a therapeutically effective amount of the composition at an injection rate greater than or equal to 0.3 mL/s, wherein said pharmaceutical composition comprises: (a) 24 — 30 weight percent of a compound of Formula (I): Cl (\NWO Cl Nd n n is an integer between 4 and 14; (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment, the pharmaceutical ition comprises: (a) about 26.6 weight percent of a compound of Formula (I); (b) about 0.3? weight percent an laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an s vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment, component (a) of the pharmaceutical composition comprises a compound of Formula (I): C. (\NW0 C.aw N10) O wherein n is an integer between 9 and 11.

In yet another embodiment, the pharmaceutical composition comprises: (a) 24 — 30 weight percent Compound 1: CI (\NWO \(‘fi / (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the ition.

In still another embodiment, the said pharmaceutical composition comprises: (a) about 26.6 weight percent Compound 1; (b) about 0.37l weight t sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In some embodiments of the method, the injection is stered to the subject in the dorsal gluteal muscle. In other embodiments of the method, the injection is administered to the subject in the deltoid muscle.

In some embodiments of the , the needle does not experience injection failure due to needle clogging.

In other embodiments, the method does not elicit a pain intensity above a normal threshold in the subject. In other embodiments, the method does not elicit any ion site reactions in the subject.

In another aspect, provided herein is a method of treating a er of the l s system in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the composition at an intravenous injection rate r than or equal to 0.3 mL/s. In one embodiment of the method, the disorder is schizophrenia.

In certain ments of the methods described above, the intramuscular injection rate is greater than 0.3 mL/s.

In another aspect, provided herein is a kit useful for the ent of a disorder of the central s system, comprising a therapeutically effective amount of a pharmaceutical composition and further comprising instructions for intramuscular injection, wherein the intramuscular injection rate is greater than or equal to 0.3 mL/s. In one embodiment, the kit is adapted to be associated with a ent regimen. In another embodiment of the kit, the intramuscular injection rate is greater than 0.3 mL/s.

BriefDescription ofthe Figures Figure 1 shows the occurrence of needle clogs as a function of needle gauge and user experience upon injection of a pharmaceutical composition comprising Compound 1 into an open cell polyurethane foam substrate.

Figures 2A and 2B show a summary of needle clog incidence and injection failure as a function of needle gauge upon injection of a pharmaceutical composition comprising nd 1 into an open cell polyurethane foam substrate.

Figure 3 shows the percentage of incomplete and complete injections of a pharmaceutical compostion comprising Compound 1 performed using an INSTRON® at varied injection speeds into an open cell polyurethane foam substrate. s 4A and 4B show the occurrence of needle clogs as a function of injection speed upon injection of a pharmaceutical composition comprising nd 1 into an open cell polyurethane foam substrate.

Detailed Description In part, the invention provided herein s to the intramuscular administration of pharmaceutical itions comprising compounds of Formula (I) to a subject in need thereof using a rapid injection rate. It was discovered that the rapid ion rate resulted in fewer injection site failures, such as needle clogging. Surprisingly, the rapid injection rate did not cause a pain intensity above a normal threshold or any injection site reactions in the subject in need thereof. Thus, provided herein is an improved method of administering pharmaceutical compositions comprising compounds of Formula (I), wherein the method comprises intramuscular administration using a rapid or instantaneous injection speed.

Pharmaceutical Compositions and Methods ofAdministering Provided herein is an improved method of administering pharmaceutical compositions comprising a compound of a (1): Cl (\NM/O CI Nd Mic—fl O wherein n is an integer between 4 and 14; wherein the method comprises uscular administration using a rapid or instantaneous injection speed.

In another embodiment, the pharmaceutical composition comprises a compound of Formula (I): CI (\N/WO CI Nd Mic—fl o wherein n is an integer between 9 and 11.

In one aspect, provided herein is a method of intramuscular administration of a pharmaceutical composition to a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the composition at an injection rate greater than or equal to 0.3 mL/s, wherein said pharmaceutical composition comprises: (a) a nd of Formula (1): CI (\NWO ClON\J \HJLo—/ N n o wherein n is an r between 4 and 14; (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle.

In one embodiment, the pharmaceutical composition comprises: (a) a compound of Formula (1): CI (\N/WO \) O \HJLOJN n o wherein n is an integer between 9 and 11; (b) sorbitan e; (c) polysorbate 20; and (d) an aqueous vehicle.

Also provided herein are s of administering pharmaceutical compositions, wherein the pharmaceutical compositions comprise approximately 15 — 35 weight percent of a compound of Formula (I). In one embodiment of the method, the composition comprises approximately 20 — 30 weight percent of a compound of Formula (I). In another embodiment of the method, the composition comprises approximately 24 — 30 weight percent of a compound of Formula (I). In a particular embodiment of the method, the composition ses approximately 26.6 weight percent of a nd of Formula (I).

In an ment of the method, the pharmaceutical composition comprises: (a) 15 — 35 weight percent of a compound of a (I): C. 0W0 #0,on wherein n is an r between 4 and 14; (b) 0.25 — 0.45 weight percent sorbitan laurate; (c) 0.2 — 1 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are ve to the total weight of the composition.

In another embodiment of the method, the pharmaceutical composition comprises: (a) 15 — 35 weight percent of a nd of Formula (I): CI (\N/VVO wherein n is an integer between 9 and 11; (b) 0.25 — 0.45 weight percent sorbitan laurate; (c) 0.2 — 1 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In yet another embodiment of the method, the pharmaceutical ition comprises: (a) 24 — 30 weight percent of a compound of Formula (1): CI N/\/\/O CI “0 \(“InJ‘OJN O (I) wherein n is an integer between 4 and 14; (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous e wherein the percentages of (a), (b), and (c) are relative to the total weight of the ition.

In still another embodiment of the method, the pharmaceutical composition comprises: (a) 24 — 30 weight percent of a compound of Formula (I): CI (\N/WO c.f) MNd wherein n is an integer between 9 and 11; (b) 0.3 — 0.4 weight t sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous e wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In one embodiment of the method, the pharmaceutical composition comprises: (a) about 26.6 weight percent of a compound of Formula (I): CI (\NWO Cl0N\2 \HJLo—/ N “ O wherein n is an integer between 4 and 14; (b) about 0.3";' weight percent sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are ve to the total weight of the composition.

In another embodiment of the method, the pharmaceutical ition comprises: (a) about 26.6 weight percent of a compound of Formula (1): CI (\NWO Cl\©/N\) O \HJLo—l N ” O wherein n is an integer between 9 and 11; (b) about 0.37 weight percent sorbitan e; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous e wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In yet another embodiment of the method, the pharmaceutical composition comprises: (a) 15 — 35 weight t Compound 1: CI (\N/WO CI\©/N\) O %0—/N (b) 0.25 — 0.45 weight percent sorbitan e; (c) 0.2 — 1 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In still another ment of the method, the pharmaceutical composition comprises: (a) 24 — 30 weight percent Compound 1: CI (\NA/VO Cl\©/N\) O WOLOJN 1 (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In one embodiment of the method, the pharmaceutical composition comprises: (a) about 26.6 weight percent Compound 1: CI (\N/WO Cl\©/N\) O wilyN (b) about 0.3";' weight percent an laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an s vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment of the method, the pharmaceutical composition is injected at an injection rate r than or equal to 0.3 mL/s.

Component (C), Le, polysorbate 20, is sold under the trademark TWEEN ®. The polysorbate can be added in an amount that s e tension of a drug product or aids in sion stability of the drug product.

The ratio of components (b) to (c) can vary. In one embodiment, the ratio of components (b) to (c) is approximately 10 to 0.5, e.g., 10 to l, e.g., 8 to l, e.g., 5 to 2, by weight. In another embodiment, the ratio of components (b) to (c) is approximately 5 to 2, by weight. In still another embodiment, the composition comprises sorbitan monolaurate (SML) or sorbitan laurate, and polysorbate 20, n the ratio of sorbitan e and polysorbate is approximately 5 to 2, by weight. In still another embodiment, the composition comprises sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate and polysorbate 20 is approximately 3 to 1, by weight. In another embodiment, the composition comprises sorbitan laurate, and rbate 20, n the ratio of sorbitan laurate and polysorbate 20 is approximately 2 to 1, by weight. In yet another embodiment, the composition comprises 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 l, by weight. In a particular ment, the composition comprises sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate and polysorbate 20 is approximately a ratio of 3 to a range of 1 — 2, by weight. In one embodiment, the composition comprises sorbitan laurate and polysorbate 20, n the ratio of sorbitan laurate and polysorbate 20 is imately 3 to 1.2, by weight.

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

Table 1. Exemplary ratios of sorbitan monolaurate (SML) to polysorbate 20 in example itions of the invention.

SML % Polysorbate 20 % SML/Polysorbate 20 Ratio 1 0.8 1.25 0.5 0.5 1 0.5 0.2 2.5 1 0.5 2 0.5 0.8 0.625 1 0.2 5 0.5 0.1 5 The weight percent of components (b) and (c) can vary in the pharmaceutical itions provided herein. In one embodiment, the composition comprises about 0.2 — 1 weight t sorbitan laurate. In another embodiment, the composition comprises about 0.4 — 0.7 weight percent sorbitan laurate. In still r embodiment, the composition comprises about 0.5 weight percent sorbitan laurate.

In another embodiment, the composition comprises about 0.25 — 0.45 weight percent an laurate. In another embodiment, the composition comprises about 0.3 — 0.4 weight percent sorbitan laurate. In still another embodiment, the composition comprises about 0.37 weight percent sorbitan laurate.

In another embodiment, the composition comprises about 0.05 — 0.8 weight percent polysorbate 20. In yet another embodiment, the composition comprises about 0.1 — 0.3 weight percent polysorbate 20. In still another embodiment, the composition comprises about 0.2 weight t polysorbate 20. In yet another embodiment, the composition comprises about 0.15 weight t polysorbate 20.

The compositions provided herein can also have varying amounts of a compound of a (I). In one embodiment, the composition comprises approximately 15 — 35 weight percent of a compound of Formula (I). In another embodiment, the composition comprises approximately 24 — 30 weight t of a compound of Formula (I). In still another embodiment, the composition comprises approximately 20 — 26 weight percent of a compound of Formula (I). In a particular embodiment, the composition comprises approximately 26.6 weight percent of a compound of Formula (I).

The ratio of components (a) to (b) can vary. In one embodiment, the ratio of components (a) to (b) is within a range of 30 to 0.1 — 0.5, by weight. In another embodiment, the composition comprises a compound of Formula (I) and sorbitan laurate, wherein the ratio of the compound of Formula (I) to sorbitan laurate is within a range of 30 to 0.1 — 0.5, by weight. In yet another embodiment, the composition comprises Compound 1 and sorbitan laurate, n the ratio of Compound 1 to sorbitan laurate is within a range of 30 to 0.1 — 0.5, by .

In one embodiment, the ratio of components (a) to (b) is within a range of 30 to 0.3 — 0.5, by weight. In another embodiment, the composition comprises a nd of a (I) and sorbitan laurate, wherein the ratio of the nd of Formula (I) to an laurate is within a range of 30 to 0.3 — 0.5, by weight. In yet another embodiment, the ition comprises nd 1 and sorbitan laurate, wherein the ratio of Compound 1 to sorbitan laurate is within a range of 30 to 0.3 — 0.5, by weight.

In one embodiment, the ratio of components (a) to (b) is approximately 30 to 0.5, by weight. In another embodiment, the composition comprises a compound of Formula (I) and sorbitan laurate, wherein the ratio of the compound of Formula (I) to sorbitan laurate is approximately 30 to 0.5, by weight. In yet another embodiment, the composition ses Compound 1 and sorbitan laurate, wherein the ratio of nd 1 to sorbitan laurate is approximately 30 to 0.5, by .

In ratio of components (a) to (c) also can vary. In one embodiment, the ratio of components (a) to (c) is within a range of 30 to 0.1 — 2, by weight. In another embodiment, the composition comprises a compound of Formula (I) and polysorbate 20, wherein the ratio of the compound of Formula (I) to polysorbate 20 is within a range of 30 to 0.1 — 2, by weight. In yet another embodiment, the composition comprises nd 1 and polysorbate , wherein the ratio of Compound 1 to sorbitan laurate is within a range of 30 to 0.1 — 2, by weight.

In one embodiment, the ratio of components (a) to (c) is within a range of 30 to 0.1 — 0.4, by weight. In another embodiment, the composition ses a compound of Formula (I) and polysorbate 20, wherein the ratio of the compound of Formula (I) to polysorbate 20 is within a range of 30 to 0.1 — 0.4, by weight. In yet another embodiment, the composition comprises Compound 1 and polysorbate 20, wherein the ratio of Compound 1 to sorbitan laurate is within a range of 30 to 0.1 — 0.4, by weight.

In one ment, the ratio of components (a) and (c) is approximately 30 to 0.2, by weight. In another embodiment, the composition comprises a compound of Formula (I) and sorbitan laurate, wherein the ratio of the nd of Formula (I) to sorbitan laurate is approximately 30 to 0.2, by weight. In yet another embodiment, the composition comprises Compound 1 and an laurate, wherein the ratio of Compound 1 to sorbitan laurate is approximately 30 to 0.2, by weight.

The aqueous e 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 particular ment, the buffer is a phosphate .

The pharmaceutical compositions provided herein can r comprise additional components. For example, the pharmaceutical compositions can also contain an aqueous vehicle, which is a vehicle that dilutes and suspends the drug. The vehicle of interest herein is one that is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a reconstituted formulation. Exemplary vehicles e e water, sterile water for injection (WFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution. The buffer can be phosphate, citrate, tartrate, or acetate. In a particular embodiment, the vehicle is phosphate—buffered saline, which is a water-based salt solution containing either sodium chloride or potassium chloride and either sodium ate or potassium phosphate. In one embodiment, the phosphate buffer ses 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.

Optionally, the pharmaceutical compositions can further comprise a dispersant, such as, for example, carboxymethyl cellulose (CMC), carboxymethyl ose , cross- linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and low substituted hydroxypropyl cellulose magnesium aluminum silicate, or a mixture thereof. In a particular embodiment, the pharmaceutical composition ses carboxymethyl cellulose (CMC).

In one ment, the pharmaceutical composition comprises: (a) a compound of Formula (1): CI (\NM/O (”é/Nd O \H’lLo—/ N n o wherein n is an integer between 4 and 14; (b) an laurate; (c) rbate 20; (d) CMC; (e) sodium phosphate dibasic anhydrous; (t) sodium dihydrogen phosphate monobasic dihydrate; and (g) water for injection.

In another embodiment, the pharmaceutical composition comprises: (a) a compound of Formula (I): C. (\N/WO c.aw may O wherein n is an integer between 9 and 11; (b) sorbitan laurate; (c) polysorbate 20; (d) CMC; (e) sodium phosphate dibasic anhydrous; (0 sodium dihydrogen phosphate monobasic ate; and (g) water for injection.

In yet r embodiment, the pharmaceutical composition comprises: (a) Compound 1: (b) sorbitan laurate; (c) polysorbate 20; (d) CMC; (e) sodium phosphate dibasic anhydrous; (f) sodium dihydrogen phosphate monobasic dihydrate; and (g) water for injection.

The pharmaceutical compositions of these methods also offer minimized excipient levels While co-optimizing both re-suspendability and acceptable injectability, and maintain good physiochemical attributes of the antipsychotic agent. The compositions require reduced resuspension times using, for example, hand shaking. In one ment, the pharmaceutical compositions can be re—suspended for injection within 1 — 60 seconds of handshaking. Accordingly, the pharmaceutical compositions described herein can also be referred to as “ready to use.” When the pharmaceutical composition is to be used as an injectable composition, including but not limited to injection h a needle or needle—less injection, it can be formulated into a conventional injectable vehicle. Suitable vehicles include biocompatible and ceutically acceptable solution and/or emulsions.

When the pharmaceutical ition is to be used as an injectable composition, ing but not limited to injection through a needle or needle—less injection, it can be formulated into a conventional able vehicle. Suitable vehicles include biocompatible and ceutically acceptable solution and/or emulsions.

The compositions provided herein do not elicit any injection site reactions normally associated with antipsychotic agents, such as aripiprazole, derivatives thereof, prodrugs thereof, and salts f.

As used herein, the term “injection site reaction” refers to inflammation or abnormal redness of the tissue and/or the skin at a site of injection in an individual.

The modulation of the tissue se following intramusclar (IM) administration is described by the spreadability of the drug and ing depot morphology; spreading of the drug along the fascial planes of muscle is desirable rather than the formation of a concentrated mass of drug in a small area.

Depot logy resulting from IM injection of aripiprazole and compounds of Formula (I) have been described. Injections of slow-releasing 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 (FBR). The spherical nature of these reactions can result in localized discomfort and pain, as the FBR increases in size ssing on nerve fibers ating muscle tissue and with the release of pro-inflammatory cytokines from the site.

Surprisingly, the ceutical compositions provided herein do not elicit an injection site reaction following IM administration. Therefore, in one embodiment, IM adminstration of the phramaceutical compositions provided herein are associated with a reduced tissue and skin on at the site of injection. In one embodiment, the injection site reaction is d by a particular amount, e. g., about 90%, 80%, 70%, 60%, 50%, 40%, %, 20%, 10%, 5%, etc. In another embodiment, there is no injection site reaction ing IM administration. In particular embodiments, there is no tissue or skin reaction at the site of injection following IM administration. In particular ments, IM administration is not associated with the symptoms of the injection site reaction, including, but not limited to: redness, tenderness, warmth, itching, pain at ion site, blistering, nodule formation, and severe skin damage. In one embodiment, components (a), (b), and (c) of the pharmaceutical composition are in a container, and the aqueous vehicle is in a separate ner, wherein said ner is any receptacle and closure therefor le for storing, shipping, dispensing, and/or ng a pharmaceutical product. Examples of such containers include, at least, for e, plastic and glass Vials, ampules, pre-filled syringes and cartridges, and the like.

In certain embodiments, the pharmaceutical composition is stored in a sealed (e. g., septum stoppered), colorless, glass vial.

In other embodiments, pre-filled dual-chamber syringes and/or cartridges are utilized with the pharmaceutical compositions provided herein. Pre-filled dual-chamber syringes enable the sequential stration of two separate compositions with a single syringe push, thereby replacing two syringes with one. The benefits of a single delivery capability include increasing the speed and ease of drug administration; reducing risk of infection by reducing the number of connections; lowering the risk of drug administration or sequence , and r delivery of compositions requiring combination prior to administration. The dual- chamber syringe can odate lized, powder, or liquid formulations in the front chamber ed with the aqueous vehicle.

Prefilled syringes can contain the exact deliverable dose of desired the pharmaceutical compositions provided herein. The prefilled syringes can contain volumes from about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, 4.5 mL, 5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9 mL, 9.5 mL, 10 mL or more or any other volume increment thereof.

The dual syringe and/or cartridge can be side-by—side chambers with separate syringe plungers that mix into a single chamber or linear chambers with one r. The dual chamber syringe and/or cartridges can also have a stopper or connector in the middle to serve as a barrier between the two chambers. The stopper or connector can be removed to allow mixing or combining of the individual ents in the two rs. For example, the front chamber can accommodate components (a), (b), and (c) of the pharmaceutical compositions provided herein, and the rear chamber can accommodate the aqueous vehicle.

Thus, in one embodiment, the pre-filled dual-chamber syringe contains components (a), (b), and (c) of the pharmaceutical compositions provided herein in the front chamber and the aqueous vehicle in the rear chamber.

The ceutical compositions can be formulated. The terms “pharmaceutical composition3, “formulation3’ 4“ , , injectable composition”, etc. are used synonymously throughout the ation.

The pharmaceutical compositions described herein may also be in the form of an emulsion. The term “emulsion” as used in this ication denotes a two—phase system in which one phase is finely sed 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 ses both hydrophilic and lipophilic groups in the emulsifier agent.

The pharmaceutical compositions bed 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 les of one substance (6. g., a drug) are scattered throughout another substance (e. g., a liquid). Dispersions include suspensions and colloids.

The methods of the invention include administering the compositions described herein, thereby obtaining an extended release or sustained release profile in the patient.

“Extended—release” or ined-release” includes dosage forms whose elease characteristics of time course and/or location are chosen to accomplish therapeutic 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 compound of Formula (I) 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 compositions can be administered as a single or sole (undivided) dose. However, the composition is also useful for those individuals that require constant or chronic therapy, such as those that receive repeated doses over several hours, days, weeks, , or more. In such dosing regimens, the method can comprise a first stration of a first ed release composition and a second administration of a second extended release ition. The second composition can be the same, ntially the same or different as the first and can include the same active agent or a ent 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 s in the release of agent for a period of l, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, l3, 14 days, or more.

The injectable, pharmaceutical compositions described herein can be injected into a patient in any number of ways. The term “injectable” as used herein refers to a composition that is le to be delivered to an individual in an injection, such as with an injection device, including one that employs a syringe or a cartridge, which may be housed in a manual ion device or an auto-injection device, for example. Specifically, the injectable composition is suitable 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 stration, intradermal administration, subcutaneous administration or intramuscular administration. The term “intravenous administration” means administration into a vein. “Intradermal administration” 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. In red embodiments, the injection is in the gluteal muscle or the deltoid muscle.

Antigsychotic Agents In one embodiment, the compound is a compound of a (I): /\/\x0 U VOL N nO_/o wherein n is an integer between 4 and 14.

In an ment, the compound is a compound of Formula (I): CI (\NWO CIONd O \HJLo—/ N “ O (I) wherein n is an integer between 9 and 11.

In a particular embodiment of Formula (I), n is 4 (Compound A). In another particular embodiment of Formula (I), n is 10 (Compound 1). Compounds A and l are depicted below: ”(j/W0 {if \ATJOWQP CGD 0N/\/\/o #304" o Rapid Inz'ection Speeds The standard ce for IM adminstration of ychotics is to inject medications at a rate that does not exceed 1 mL per 10 seconds or 0.1 mL/s [Cocoman & Murray, Journal of Psychiatric and Mental Health Nursing, 2008, Vol. 15, pp. 424—434]. Healthcare sionals suggest that this slow, steady injection rate promotes patient comfort and helps to avoid damage to the muscle tissue [Workman, Nuring Standard, 1999, Vol. 13, pp. 47-53].

In an effort to prevent needle ng, manual administration of the pharmaceutical compositions provided herein was performed using faster injection rates. This study surprisingly ed that the faster the user injected the pharmaceutical compositions provided herein, the less likely the user was to experience a needle clog. These observations are quantitatively supported by the results from injections of the pharmaceutical compositions provided herein performed using an N® at controlled injection speeds. Indeed, as shown in Figure 3, faster injection speeds are associated with a se in the number of injection clogs whereas slower injection speeds are associated with an increased incidence of needle clogging. Furthermore, Table 6 (Example 3) reveals that sed injection speeds are associated with an increase in measured gravimetric dose delivery and, thus, better flow properties. In fact, manual administration of the pharmaceutical compositions provided herein revealed that slower injection rates were associated with an increased incidence of injection site failure due to needle ng (see, e.g., Figures 3, 4A, and 4B).

As shown in Figures 1, 2A, and 2B, an se in the incidence of needle clogs was observed with increased needle gauge (i.e., sed needle inner diameter). Additionally, needle clogs were more pronounced among first time or inexperienced users. Injection failures were also noted primarily with first time users with needle gauges of 21 to 23. No injection failures were noted with experienced users, regardless of needle gauge. Given the results of the in vitro injectability assessment of the pharmaceutical composition administered using various needle gauges, a 20 gauge needle is preferred in order to mitigate the risk of needle clogs.

Rapid injection rates are not typically associated with the injection of drugs due the increased potential for injection site reactions to occur. In fact, the ibing information for many al antipsychotics specifies “slow ion” (see Table 2). Surprisingly, however, it has been discovered that the rapid injection rate of the pharmaceutical compositions provided herein does not elicit injection site reactions or elevated pain intensities (above a normal threshold).

Table 2 summarizes the injection site reactions associated various atypical antipsychotics, including Compound 1. The symptoms of the injection site reaction include, but are not limited to: redness, tenderness, warmth, g, pain at injection site, blistering, nodule formation, and severe skin damage. Injection site reactions and/or elevated pain levels were reported in patients upon slow ion of ABILIFY MAINTENA® (Aripiprazole Monohydrate), RISPERDAL® CONSTA® (Risperidone), and ® SUSTENNA® eridone Palmitate) in ison with a placebo. In contrast, injection site reactions and/or elevated pain levels were reported in <1% of patients upon fast injection of Compound 1.

Table 2. Summary Of Injection Site Reactions (ISRs) ated With Atypical Antipsychotics* Atypical Antipsychotics ABILIFY INVEGA ® Key product RISPERDAL® features MAINTENA® NA® nd l . . CONSTA® (Ar1p1prazole . .

. , (Paliperidone (Risperidone) Monohydrate) Palmitate) 0 Multiple step DFU, (it is supplied in a vial) requires 0 Multiple step 0 Simple DFU, . Simple reconstitution, in PFS, DFU DFU, Vial, diluent supplied ’ PFS ’ requlres 1n dose pack (1n homogeneous How Supplied/ re- Administration suspension reconstitution, PFS) re-suspension 0 Inject entire 0 Inject , . Inject InjeCt 1mmed1ately. contents of the deep into the rapidly 0 Inject Slowly syringe muscle. intramuscularly into selected gluteal or deltoid muscle 0 39mg: 0 441mg: 0382:1314 0.50mL 0 $66me? 0 12 5mg‘ 2mL Injection 0 400mg: 2mL 0 117mg: 2 4mg. . 25'm . 2'mL volume ‘ . 300mg: 1.5mL 0.75mL . g; 0 882mg. 0 50mg. 2mL . 156mg 3‘2mL 1.00mL 0 234mg: 1.50mL . epgclzprsfurlated 0 0 Lyophilized 0 rystal Formulation Flocculated s1on powder . suspens1on micropspheres 0 Patient reported: 0 Patient reported: ISR: 6.3% ISR: no moderate 0 Patient (no placebo) or severe reported: 0 Investigator reactions were ISR: reported: ed in any Redness, 0 ISR: < 1% Redness, subject Induration, in rate 0 Example 5 Induration, 0 Investigator ng, > Swelling, reported: mild 5% pain t redness, swelling (occurring in 4-26% of or induration in twice as often patients (first to last as placebo) (first to last injection) injection) 0 22G, 1.5 inch 0 20GT1W, 2 inch . 20G 1 Sin Need1e .’ ‘ g utea o . . glzuéeall 5. inch ' 21G’ 1'5“" & 2m gauge/length . 21G UTW, 1 > 90kg or 1 . (Sign1m ’ inch deltoid inch 23G < 90kg deltoid *Information ed from the prescribing information of ABILIFY MAINTENA®, RISPERDAL® CONSTA®, and INVEGA® SUSTENNA® Accordingly, provided herein are methods for intramuscular administration of a pharmaceutical composition to a subject in need f, comprising administering to said subject a eutically effective amount of the composition at an injection rate greater than or equal to 0.3 mL/s, wherein the pharmaceutical composition is as defined above. In some embodiments, the ion rate is greater than 0.3 mL/s. In particular embodiments, the injection rate is greater than about 0.35 mL/s, or greater than about 0.4 mL/s, greater than about 0.5 mL/s, or greater than about 0.6 mL/s, or greater than about 0.7 mL/s, or greater than about 0.8 mL/s, or greater than 0.9 mL/s. In some embodiments, the ion rate is in the range of from about 0.3 mL/s to about 1 mL/s.

In some embodiments of the method, the pharmaceutical composition is injected using a 20 to 23 gauge needle. In other ments of the method, the needle is a 20 gauge needle. In other embodiments of the method, the needle is a 21 gauge needle. In particular embodiments, the needle does not experience injection failure due to needle clogging.

In particular embodiments of the method, a 20 to 23 gauge needle is used to intramuscularly administer a therapeutically effective amount of the composition at an injection rate greater than or equal to 0.3 mL/s, wherein the pharmaceutical composition is as defined above.

In some embodiments, the method does not elicit any injection site reactions in the In some ments of the , the injection is administered to the subject in the dorsal gluteal muscle. In other embodiments of the method, the ion is administered to the subject in the deltoid muscle.

The administration by injection of a preparation comprising a pharmaceutical nd is often required to be med in a relatively short time and with a relatively high local concentration of the pharmaceutical agent. This practice is generally referred to in the field as “bolus” injection. The term “bolus injection” thus identifies the administration at once (in general within less than few seconds) of a pharmaceutical agent at a high concentration, differently from a gradual administration of the agent (e. g. by means of intramuscular (IM) infusion).

Accordingly, in one embodiment, the method comprises intramuscularly administering a bolus injection of the pharmaceutical composition. In particular embodiments, the bolus injection is administered at a very rapid injection rate. In some embodiments, the bolus injection is injected with an injection rate that is greater than 0.3 mL/s. In other embodiments, the bolus injection is injected instantaneously. In particular embodiments, the needle does not experience ion failure due to needle clogging.

Lyoghilization The pharmaceutical compositions described herein can be formulated in such a way that the active ingredient and the active ingredient-retaining substance may be dissolved in a suitable t and subjected to lyophilization (or freeze-drying) to obtain a sterile cake of the active ingredient and the active ient-retaining substance.

In one aspect, the pharmaceutical compositions described herein are lyophilized prior to administration. Lyophilization is carried out using techniques common in the art [Tang et al., Pharm Res. 2004, 21, 191—200, and Chang et al., Pharm Res. 1996, 13, 243-249], and has been optimized for the pharmaceutical composition bed herein.

A lyophilization cycle is, in one aspect, composed of three steps: freezing, primary drying, and secondary drying [A.P. Mackenzie, Phil Trans R Soc London, Ser B, Biol 1977 , 278, 167]. In the ng step, the solution is cooled to initiate ice formation. Furthermore, this step induces the crystallization of the bulking agent. The ice sublimes in the primary drying stage, which is conducted by reducing chamber pressure below the vapor re of the ice, using a vacuum and ucing heat to promote sublimation. Finally, adsorbed or bound water is removed at the secondary drying stage under reduced chamber pressure and at an elevated shelf temperature. The process produces a material known as a lized cake.

Thereafter the cake can be reconstituted with either sterile water or suitable diluent for injection.

In one aspect, provided herein is a lyophilized cake comprising a ceutical composition, n said pharmaceutical composition comprises: (a) 15 — 35 weight percent of a compound of Formula (I); (b) 0.25 — 0.45 weight t sorbitan laurate; and (c) 0.2 — 1 weight percent polysorbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment of the lyophilized cake, the pharmaceutical ition comprises: (a) 24 — 30 weight percent of a compound of Formula (I); (b) 0.3 — 0.4 weight percent sorbitan laurate; and (c) 0.1 — 0.3 weight percent polysorbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the ition.

In still another embodiment of the lyophilized cake, the pharmaceutical composition comprises: (a) about 26.6 weight percent of a compound of Formula (I); (b) about 0.371 weight percent sorbitan laurate; and (c) about 0.15 weight percent rbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In an embodiment of the lyophilized cake, the pharmaceutical composition comprises: (a) 15 — 35 weight percent Compound 1: CI (\N/WO \) O W504N (b) 0.25 — 0.45 weight percent sorbitan laurate; and (c) 0.2 — 1 weight percent polysorbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another ment of the lyophilized cake, the pharmaceutical composition comprises: (a) 24 — 30 weight percent Compound 1: CI (\N/WO \) O wfiioJN (b) 0.3 — 0.4 weight percent sorbitan laurate; and (c) 0.1 — 0.3 weight percent polysorbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In still another embodiment of the lyophilized cake, the pharmaceutical composition comprises: (a) about 26.6 weight percent Compound 1: CI (\N/WO CI\©/N\) O 1 (b) about 0.37I weight t an laurate; and (c) about 0.15 weight t polysorbate 20 wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In some embodiments, the lyophilized cake comprises approximately 1400 mg of the pharmaceutical composition. In preferred embodiments, the compound of Formula (I) is Compound 1.

In some embodiments, the lyophilized cake is reconstituted in an aqueous vehicle (e.g., e water for injection, an aqueous buffer, or saline solution). In particular embodiments, the lyophilized cake is reconstituted in 3.0 mL of an aqueous vehicle (e. g., sterile water for injection, an aqueous buffer, or saline on). In particular embodiments, the lyophilized cake is reconstituted in 2.5 mL of an aqueous vehicle (e. g., sterile water for injection, an aqueous buffer, or saline solution). In ular embodiments, the lyophilized cake is reconstituted in 2.0 mL of an aqueous vehicle (e.g., sterile water for injection, an aqueous buffer, or saline solution). In some embodiments, the lyophilized cake can be reconstituted for injection within 1 — 60 seconds of handshaking. In preferred embodiments, the lyophilized cake can be reconstituted for injection within 10 — 20 s of handshaking.

In one embodiment, the lyophilized cake of the pharmaceutical composition is administered as part of a bolus injection.

In one aspect, provided herein is a method for preparing a lyophilized cake of the pharmaceutical compositions ed herein.

In one embodiment, during the lyophilization process, the solvent system used, such as by way of example only, e water for injection is substantially removed by ation. In another embodiment, less than about 5 % residual solvent remains after lyophilization; in other embodiments, less than about 3 % remains; in yet other embodiments, less than about 2 % remains; in further embodiments, less than about 1 % or about 0.1 % remains.

In one ment, the lyophilization process comprises the steps of: (l) placing the sample to be lyophilized (i.e., the pharamceutical composition comprising a compound of Formula (I), sorbitan laurate, and polysorbate 20) in a suitable vial and placing the vial into a lization chamber frozen in a bath until sion was solidified; (2) cooling the lyophilization chamber and ng the pressure of the system; and holding until ation of the solvent system is substantially complete; and (3) slowly increasing the temperature of the lyophilization chamber to allow the samples to reach an ed shelf temperature.

In another embodiment, the lyophilization process comprises the steps of: (l) placing the sample to be lyophilized (i.e., the pharamceutical composition sing a nd of Formula (I), sorbitan laurate, and polysorbate 20) in a suitable vial and placing the vial into a lyophilization chamber frozen in a methanol-dry ice bath until suspension was solidified; (2) cooling the lyophilization chamber to —75 OC and reducing the pressure of the system to below 100 mTorr; and holding until sublimation of the solvent system is substantially complete (about 72 hours); and (3) slowly increasing the temperature of the lyophilization chamber to allow the samples to reach a temperature of about 20 0C to about 30 0C.

In one embodiment, the lyophilized cake is in a container, and the aqueous vehicle is in a separate container, wherein said container is any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product. Examples of such ners include, at least, for example, plastic and glass vials, ampules, pre—filled syringes and cartridges, and the like.

In some embodiments, pre-filled hamber syringes and/or cartridges are utilized with the lyophilized cakes provided herein. The dual-chamber syringe can accommodate lyophilized, powder in the front chamber combined with the aqueous vehicle in the rear chamber.

Prefilled syringes can contain the exact deliverable dose of desired the pharmaceutical compositions ed herein. The prefilled syringes can contain volumes from about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, 4.5 mL, 5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9 mL, 9.5 mL, 10 mL or more or any other volume increment thereof.

The dual syringe and/or dge can be side-by—side chambers with separate syringe plungers that mix into a single chamber or linear chambers with one r. The dual r syringe and/or cartridges can also have a stopper or connector in the middle to serve as a barrier between the two chambers. The stopper or tor can be removed to allow mixing or combining of the compounds in the two chambers. For example, the front chamber can accommodate the lyophilized cake provided herein, and the rear chamber can accommodate the aqueous vehicle. Thus, in one embodiment, pre-filled dual-chamber syringe contains the lized cake provided herein in the front chamber and the aqueous e in the rear chamber.

Methods of Treatment The ceutical compositions of the methods provided herein can be used for the treatment of a variety of disorders in a t in need thereof. For example, the pharmaceutical compositions described herein can be used to treat anxiety, depression, bipolar disorder, autism-related irritability, and psychotic conditions including acute mania, phrenia, and schizophreniform disorder in a subject. In another embodiment, the pharmaceutical compositions of the methods provided herein can be used to treat bipolar disorder-related agitation and schizophrenic-related agitation.

In one , provided herein is a method of treating a disorder of the central s system in a subject in need thereof, comprising administering to said subject a therapeutically amount of the composition at an intramuscular injection rate greater than or equal to 0.3 mL/s, wherein said pharmaceutical composition comprises: (a) 15 — 35 weight percent of a compound of Formula (I): (b) 0.25 — 0.45 weight percent sorbitan laurate; (c) 0.2 — 1 weight t polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In one ment of the method of treatment, the pharmaceutical composition comprises: (a) 24 — 30 weight percent of a compound of Formula (I); (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the ition.

In another embodiment of the method of treatment, the pharmaceutical composition comprises: (a) about 26.6 weight percent of a compound of Formula (I); (b) about 0.37 weight percent sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous e wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In still embodiment of the method of treatment, the pharmaceutical composition comprises: (a) 15 — 35 weight t of Compound 1: (b) 0.25 — 0.45 weight percent an laurate; (c) 0.2 — 1 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In yet another embodiment of the method of treatment, the pharmaceutical composition ses: (a) 24 — 30 weight percent of Compound 1: Cl (\NWO Cl\©/N\) O \nfloLoJN 1 (b) 0.3 — 0.4 weight percent an laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In one embodiment of the method of treatment, the pharmaceutical composition comprises: (a) about 26.6 weight percent of Compound 1: CI n0N/VVO VOL N o 1 . (b) about 0.3? weight t sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In an embodiment of all these methods, the method ses administering to a subject in need thereof a therapeutically effective amount of the composition at an injection rate greater than or equal to 0.3 mL/s. In ular embodiments, the injection rate is greater than about 0.35 mL/s, or greater than about 0.4 mL/s, greater than about 0.5 mL/s, or greater than about 0.6 mL/s, or greater than about 0.7 mL/s, or greater than about 0.8 mL/s, or greater than 0.9 mL/s. In some embodiments, the method of administration is intramuscular.

In another embodiment, the pharmaceutical composition comprises: (e) 24 — 30 weight percent of a compound of Formula (I): CI N/WO CI “0 \HJLo—/ N “ O wherein n is an integer between 4 and 14; (f) 0.3 — 0.4 weight percent sorbitan laurate; (g) 0.1 — 0.3 weight percent polysorbate 20; and (h) an aqueous vehicle wherein the percentages of (a), (b), and (c) are ve to the total weight of the composition, for use in therapy by uscular administration at an injection rate greater than or equal to 0.3 mL/s.

In yet another embodiment, the pharmaceutical composition comprises: (a) 24 — 30 weight percent of Compound 1: CI (\NWO Cl\©/N\) O MiloJN (b) 0.3 — 0.4 weight percent an laurate; (c) 0.1 — 0.3 weight percent rbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition, for use in therapy by intramuscular administration at an injection rate greater than or equal to 0.3 mL/s.

In still another ment, the pharmaceutical composition comprises: (i) 24 — 30 weight percent of a compound of Formula (1): CI NM/O Cl n0 \NJLOJN n o wherein n is an integer between 4 and 14; (j) 03 — 0.4 weight percent sorbitan laurate; (k) 0.1 — 0.3 weight percent polysorbate 20; and (1) an aqueous vehicle wherein the tages of (a), (b), and (c) are relative to the total weight of the composition, for use in a method of treating a disorder of the central nervous system, wherein the composition is intramuscularly stered at an intramuscular injection rate greater than or equal to 0.3 mL/s.

In another embodiment, the pharmaceutical ition comprises: (a) 24 — 30 weight percent of Compound 1: CI (\NWO CI Nd \HJL N o (b) 0.3 — 0.4 weight t sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the ition, for use in a method of treating a disorder of the central nervous system, wherein the composition is intramuscularly administered at an intramuscular injection rate greater than or equal to 0.3 mL/s.

In certain embodiments of the method of treating a disorder of the central nervous system, the method is for maintenance treatment. In other ments of the , the method is for acute treatment.

In some ments of the method, the disorder of the central nervous system is schizophrenia, r I disorder, or autistic er. In one embodiment of the method, the disorder is schizophrenia. In another embodiment of the method, the disorder is schizophreniform disorder.

In particular embodiments of the method, the uscular injection rate is greater or equal to than 0.3 mL/s. In other embodiments of the method, the intramuscular ion rate is greater than 0.3 mL/s.

In one embodiment, a therapeutically effective amount of the agent is given to a subject using the pharmaceutical compositions ed herein. The term “therapeutically effective amount” is further meant to define an amount resulting in the improvement of any parameters or 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 ion 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 stician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically ive 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 ement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose n selected; the use of concomitant medication; and other nt 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, 85, 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 example, administration can be one to three times daily for a time course of one day to several days, weeks, months, and even years, and may even be for the life of the patient. Practically speaking, a unit dose of any given ition 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 schedule will be known by those of ordinary skill in the art or can be determined experimentally using routine methods. ary dosing schedules include, without limitation, stration five times a day, four times a day, three times a day, twice daily, once daily, every other day, three times , twice weekly, once weekly, twice monthly, once monthly, and so forth. Unit dose preparations provided herein can contain a compound of Formula (I) in the range of about 20 to about 900, e.g., about 60 to about 800, mgs prazole 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. ageously, the present invention relates to a kit comprising a unit dosage of the pharmaceutical composition of the methods disclosed herein.

In one aspect, provided herein is a kit useful for the treatment of a disorder of the central nervous system, comprising a therapeutically effective amount of a pharmaceutical ition and further comprising instructions for intramuscular injection, wherein the intramuscular injection rate is greater than or equal to 0.3 mL/s, n said pharmaceutical composition comprises: (a) a compound of Formula (1): CI I/\N/\/\,O (”g/Nd O \fiJLo—l N “ O wherein n is an integer between 4 and 14; (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In one embodiment, the ceutical composition comprises: (b) a compound of Formula (1): QUNQCI N/VVO —’ N n o n n is an r between 9 and 11; (b) sorbitan laurate; (c) polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another ment of the kit, the pharmaceutical composition comprises: (a) 24 — 30 weight percent of a compound of Formula (I): C. (\N/WO c.aw #1.) O wherein n is an integer between 4 and 14; (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment of the kit, the pharmaceutical composition comprises: (a) 24 — 30 weight percent of a compound of Formula (I): wherein n is an integer between 9 and 11; (b) 0.3 — 0.4 weight percent an e; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the tages of (a), (b), and (c) are relative to the total weight of the composition.

In still another embodiment of the kit, the pharmaceutical composition comprises: (a) about 26.6 weight percent a compound of Formula (1): CI (\NWO Cl0N\J \fiJLo—l N “ O n n is an integer between 4 and 14; (b) about 0.371 weight percent sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In still another embodiment of the kit, the pharmaceutical composition comprises: (a) about 26.6 weight percent a compound of a (1): C. 0W0 were) 0 wherein n is an integer between 9 and 11; (b) about 0.37 weight percent sorbitan laurate; (0) about 0.15 weight t polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are ve to the total weight of the composition.

In another aspect, provided herein is a kit useful for the treatment of a disorder of the central nervous system, comprising a therapeutically effective amount of a pharmaceutical composition and further comprising instructions for uscular injection, wherein the intramuscular injection rate is greater than or equal to 0.3 mL/s, wherein said pharmaceutical composition ses: (m) 15 — 35 weight percent of Compound 1: CI (\N/WO CIUNd O M1454N (n) 0.25 — 0.45 weight percent an laurate; (o) 0.2 — 1 weight percent polysorbate 20; and (p) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In another embodiment of the method, the pharmaceutical composition comprises: (a) 24 — 30 weight percent nd 1: CI (\N/VVO Cl\©/N\) O M1454N (b) 0.3 — 0.4 weight percent sorbitan laurate; (c) 0.1 — 0.3 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In still another embodiment of the , the pharmaceutical composition comprises: (a) about 26.6 weight percent of Compound 1: Cl (\NWO (b) about 0.37 weight percent sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an s vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

In some embodiments, the kit is adapted to be associated with a treatment regimen. In red embodiments of the kit, the intravenous injection rate is greater than 0.3 mL/s.

In some embodiments of the kit, the instructions are for uscular injection, wherein the intramuscular injection rate is rapid or taneous. In other preferred embodiments of the kit, the instructions are for intramuscular injection, wherein the intrmuscular injection rate is greater than 0.3 mL/s. In certain embodiments, the ion rate is greater than about 0.35 mL/s, or greater than about 0.4 mL/s, greater than about 0.5 mL/s, or greater than about 0.6 mL/s, or greater than about 0.7 mL/s, or greater than about 0.8 mL/s, or r than 0.7 mL/s, or greater than 0.8 mL/s, or greater than 0.9 mL/s. In an embodiment, the instructions are for administering approximately 3.4 mL of the pharmaceutical composition within 10 seconds. In another embodiment, the instructions are for administering approximately 1.6 mL of the pharmaceutical composition within 5 seconds.

In yet another embodiment of the kit, the instructions are for administering the injection to the subject in the dorsal gluteal muscle. In an embodiment of the kit, the instructions are for administering the injection to the subject in the deltoid muscle.

A “kit” as used in the instant application includes a ner for containing the separate unit dosage forms such as a glass Vial or prefilled e (PFS). The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically able material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container). The ner employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.

In some embodiments, the kit includes a 20 to 23 gauge needle. In other embodiments of the kit, the needle is a 20 gauge needle. In other embodiments of the kit, the needle is a 21 gauge needle.

Definitions The terms ”, “treated”, “treating”, or “treatment” includes the diminishment or alleviation of at least one m associated or caused by the state, disorder or disease being treated. For example, ent can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

The term “weight percent” is meant to refer to the quantity by weight of a compound and/or component in a composition as the quantity by weight of a constituent component of the composition as a percentage of the weight of the total composition. The weight percent can also be calculated by multiplying the mass fraction by 100. The “mass fraction” is the ratio of one substance of a mass ml to the mass of the total composition mt. weight percent = (ml/mt) * 100 As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, ally a biological activity associated with an injection site reaction.

The term “use” includes any one or more of the following embodiments of the invention, respectively: the use in the ent of pain the use for the cture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the cture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the ion for the treatment of these diseases; and nds of the invention for use in the treatment of these diseases; as appropriate and expedient, if not stated otherwise.

The term “subject” is intended to include sms, e. g., prokaryotes and eukaryotes, which are capable of ing from or afflicted with a disease, disorder or condition associated with the activity of a protein kinase. Examples of subjects include mammals, e.g., humans, 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 cancer, inflammation, cardiac hypertrophy, and HIV infection, and other diseases or conditions described herein (e.g., a protein kinase—associated disorder). In another embodiment, the subject is a cell.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without ive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable t/risk ratio.

As used herein, “therapeutically effective amount” indicates an amount that results in a desired pharmacological and/or physiological effect for the ion. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom f and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition.

As used herein, the term “pharmaceutically acceptable r”, and cognates thereof, refers to adjuvants, binders, diluents, etc. known to the skilled artisan that are suitable for administration to an individual (e. g., a mammal or non—mammal). Combinations of two or more carriers are also contemplated in the t invention. The pharmaceutically able carrier(s) and any additional components, as described herein, should be compatible for use in the intended route of administration (e. g., oral, parenteral) for a particular dosage form. Such suitability will be easily recognized by the skilled artisan, particularly in view of the teaching provided . Pharmaceutical itions described herein include at least one pharmaceutically acceptable carrier or excipient; preferably, such compositions include at least one carrier or excipient other than or in addition to water.

When used with respect to methods of treatment/prevention and the use of the compounds and ceutical compositions f described herein, an individual “in need f ’ may be an individual who has been diagnosed with or previously d for the condition to be d. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family y of the condition, life- style factors indicative of risk for the condition, etc.). Typically, when a step of administering a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the ular condition to be treated.

In some embodiments, the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate. In some embodiments, the mammal is a e. In some embodiments, the primate is a human. In some embodiments, the individual is human, including adults, children and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non—human primate such as chimpanzees and other apes and monkey species. In some ments, the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “individual” does not denote a particular age or sex.

As used herein and in the appended claims, the singular forms “a” “an”, and “the” include plural forms, unless the context y dictates otherwise.

Unless defined otherwise or clearly ted by context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention s.

All relevant preferred features and ments apply to each of the claims and ents of invention mentioned above.

Exemplification Example I —Synthesis Procedures Synthesis of Compound] ©N/\/\/O CHZO /\/\/O DMF, NEt3 Aripiprazole rN Compound A-l: Preparation of 7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy) (hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one A e of Aripiprazole (20g, 45 mmol), triethylamine (lmL, 7.1 mmol), formaldehyde (37% aqueous solution, 70 mL) and ylformamide (200 mL) was heated to 80°C for 20 h. The reaction mixture was cooled, diluted with ethyl acetate (400 mL) and washed with water/brine (1:1, 3 x 500 mL). The organic phase was dried over MgSO4, filtered and evaporated to dryness under vacuum to give hemi-aminal A-l as a white solid (18.6 g, containing 25% Aripiprazole, 65% yield based on A-l).

Compound la: (7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl acetate A solution of Compound 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 resulting crude mixture, ethyl acetate (150 mL) and heptane (50 mL) was added. The solution was washed with NaHC03 (5% s solution, 250 mL,). After 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% NaHC03 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 l: ethyl acetate (5 :95) as the eluent. ons containing the desired product were combined and d-tartaric acid (12.5 g dissolved in 60:5 ethanol: water) was added, resulting in the precipitation of the desired product (48.78 g, 89% yield). 1H NMR (CDC13, 300MHz) 8 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). nd 1: (7-(4-(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl dodecanoate CIfjNd Compound 1 was ed in an analogous fashion to Compound 1a. The desired product was ed as a crystalline solid (0.3 g, 21 % yield). The molecular weight was confirmed by mass spectrometer analysis. 1H NMR (CDC13, 300MHz) 8 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-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl benzylcarbamate CI (\N/Vvo CI N NTOVN O 0 To a on of hemi—aminal A-l (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15 g, 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 e 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 MgS O4, filtered and evaporated under vacuum. The residue was further purified by chromatography on silica eluting with ethyl acetate/ dichloromethane/methanol (1:1:0.1) to give the desired t as an off white foam (530 mg, 14% yield). 1H NMR (CDC13, 300MHz) 5 1.58—1.88 (m, 4H), 2.48 (t, 2H), 2.60- 2.72 (m, 6H), 2.85 (m, 2H), 3.00-3.12 (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.

Compound A: (7-(4—(4-(2,3-dichlorophenyl)piperazinyl)butoxy)oxo-3,4- dihydroquinolin-l(2H)-yl)methyl ate of)”MM 0 0 Compound A was prepared in an analogous fashion to Compound A-28. The desired t was ed as a yellow solid (3.69g, 87% yield). 1H NMR (CDCl3, 300MHz) 5 0.78 (t, 3H), 1.11-1.28 (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. e 11 — Exemplary ations Table 3. Example formulation of the invention.

Dose (%w/w) Polysorbate 20 Sodium Chloride Sodium Phosphate Dibasic Anhydrous m Sodium Dihydrogen Phosphate Monobasic Dihydrate Water for Injection QS to 100 pH range: 5.0 — 7.4 e 111: In vitro assessments of Compound 1 PFS product performance when administered using various needle gauges and at varied injection speeds An in vitro assessment was carried out with an pre—filled syringe (PFS) containing the formulation of Example 11. Product performance was assessed by measuring the amount of drug product that was ed after resuspension into a foam resistance model (gravimetric dose delivery with applied resistance). The drug product was injected into open cell (250 to 300 um pore size) polyurethane foam and the gravimetric delivered dose is measured. The injection was performed manually by either users who were rized as experienced or inexperienced or by an INSTRON® universal g machine at constant injection speed (INSTRON®, Norwood, MA). An experienced user is defined as those that have ted injections of the Compound 1 drug product previously, such as, physicians or lab analysts.

An rienced user is defined as personnel that are not lab analysts or those that have never conducted injections of the Compound 1 drug product. Mean inner diameters for needle gauges used in this experiment are listed in Table 4.

Table 4. Terumo Needle Gauge and Mean Internal Needle Diameter Needle Internal Needle Needle Gauge Diameter 0””) 23 405 22 485 21 575 660 Manual in vitro assessment of PFS iniectabilty: A total of 1460 injections by 44 users were completed according to the following y steps: 1. Resuspend the syringe contents by shaking vigorously for ~30 seconds 2. Attach needle to the syringe 3. Prime the syringe by bringing it into an upright position, tap the syringe to bring air to the top and then carefully depress the plunger rod until ~1-2 drops of suspension are ed 4. Inject the full contents into foam in a rapid and continuous manner ( < 10 seconds) . If a clog occurs, replace the needle and attempt to complete the injection. If a second clog occurs, continue to the next step 6. Record the weight of the suspension following completion of the injection to determine gravimetric dose ry.

Each user was given a spare needle in the event of a needle clog. Each needle clog was recorded as were injection failures (defined by inability to deliver entire contents of a syringe following use of the spare (2nd) needle).

In vitro assessment of PFS iniectabilty using an INSTRON® universal materials tester in compression mode at varied injection speeds: Ten injections were performed at each injection speed according to the following primary steps: 1. Resuspend the e contents on a Burrel wrist action shaker for 30 Seconds. 2. Prime the syringe by bringing it into an upright position, tap the syringe to bring air to the top and then carefully depress the r rod until ~1—2 drops of sion are ed. 3. Place the e in the INSTRON® syringe test fixture. 4. Inject the contents of the syringe into the foam at constant injection speed to max force of 40 N.

. Record the weight ing completion of the injection to determine gravimetric dose delivery.

One needle replacement was allowed per syringe tested. Each needle clog was recorded as were injection failures ed by inability to deliver entire contents of a syringe following use of the spare (2nd) needle).

Manual in vitro assessment of Compound 1 PFS Injectability A summary of needle clogs as a function of needle gauge and user experience is shown in Figure l. A summary of needle clog incidence and injection failures as a function of needle gauge and user experience is shown in Figures 2A and 2B. Measured gravimetric dose delivery was compared to the expected dose ry of the high dose. etric dose delivery results and number of injections that delivered less than 75% of expected as a function of needle gauge for all users are summarized in Table 5.

Table 5. In Vitro Assessment of ability by Gravimetric Dose Delivery Needle Total Number (%) of Injections Grav1metr1c Dose Delivery Gauge Number of less than 75 % of expected (g), Average 1 SD Injections dose delivery 23 390 4 (1.0%) 3.41 i 0.15 22 350 3 (0.9%) 3.41J_r 0.19 21 370 1 (0.3%) 3.42 i 0.11 350 0 (0%) 3.41 i 0.05 In vitro assessment of PFS iniectabilty using an INSTRON® A summary of lete and complete injections performed using the INSTRON® at varied injection speeds is shown in Figure 3. A summary of the resultant gravimetric dose delivery results is shown in Table 6.

Table 6. Gravimetric Dose Delivery Results From Injections Performed Using an INSTRON® at Varied Injection Speeds ion Speed Gravimetric Dose Delivery(g), Average 1 SD 180 0.99 i 0.37 225 2.26 i 0.86 260 2.81 10.51 300 3.23 i 0.12 360 3.27 i 0.05 450 3.30 i 0.03 Example IV— Exemplary Suspension Lyophilization for Increased Dose Suspension Lyophilization: 1. Re-suspended Compound 1 injectable suspension (i.e., the formulation of Example 11) was pooled into BD 50 mL polypropylene conical tube. Total twenty PFS were pooled into four conical tubes.

Conical tubes were frozen in a ol-dry ice bath until suspension was solidified.

Tubes were allowed to freeze further 15 min to ensure complete freezing of a sion.

Lyophilizer condenser was cooled to -75 OC and vacuum was maintained below 100 mTorr.

Frozen tubes were transferred into lyophilizer vacuum flask. Vacuum flask was attached to bulk lyophilizer port and immediately vacuum was d.

Lyophilization was continued for about 72 hours.

After 72 hours vacuum was released and vacuum flask was removed from the lyophilizer.

Conical tubes containing lized product were capped at an ambient condition and tapped on a hard surface to break the cake.

Iniectability Evaluation: 1. Lyophilized product was filled into cyclic olefin copolymer (COC) PFS barrel or glass vial.

Required volume of water for injection was added.

Lyophilized product was reconstituted and ed into a foam (model: injectability with resistance) following ions for use (DFU) for Compound 1 injectable suspension.

Test parameters and observations were recorded in Table 7.

Table 7. Injectability Evaluation Container/ Mass Reconstitution Observations Closure (mg) Volume (mL) 0 Product was acceptably reconstituted mL COC within 10-29 sec shaking 900 3.0 0 PFS Rapid and uous injection resulted in complete injection into a foam 0 Product was acceptably reconstituted mL COC within 10-29 sec g 900 3.0 0 PFS Rapid and continuous injection resulted in complete injection into a foam 0 Product was ably reconstituted within 10-20 sec shaking 0 Slow ion resulted in needle clog mL CDC 900 2.0 into a foam 0 Clog was removed and complete injection was performed rapidly into a foam 0 Product was acceptably reconstituted mL COC within 10-29 sec g 900 2.0 0 PFS Rapid and uous ion resulted in complete injection into a foam 0 Product was acceptably reconstituted mL Glass within 10-29 sec shaking 1400 2.5 0 Vials Rapid and continuous injection ed in complete injection into a foam 0 Product was acceptably reconstituted mL Glass within 10—29 sec shaking 1400 2.5 0 Vials Rapid and continuous injection resulted in complete injection into a foam 0 Product was acceptably reconstituted mL Glass within 10-2Q sec shaking 1400 2.5 0 Vials Rapid and continuous injection resulted in complete injection into a foam e V: Rapid Intramuscular (1M) Injection of Compound I on pain and injection site reactions (IRS) Injection site reactions and pain upon IM injection of Compound 1 are a potential safety concern. A Phase 3, multicenter, extension study was conducted in 81 sites to assess the effect of rapid IM injections of Compound 1 on human patients diagnosed with stable phrenia. Briefly, 332 subjects enrolled in the study were assigned PFS. Compound 1 is formulated as a pre-filled syringe (PFS) of an extended release aqueous suspension of a therapeutically effective amount of Compound 1. An injection volume of 3.4 mL or 1.6 mL of the aqueous suspension was administered according to protocol I at a rate of less than 10 s by inserting the 20 gauge needle in the gluteal muscle. ISRs upon IM ion of Compound 1 were assessed at each visit. Over 5000 injections of nd 1 have been administered uscularly with an ISR rate of less than 1%.

Protocol I 1. TAP the pre-filled syringe at least 10 times to dislodge any al that may have settled. 2. SHAKE the pre-filled syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension. 0 If the syringe is not used within 15 minutes, re-suspend by shaking vigorously for 30 seconds. 3. SELECT the injection needle. For ts with a larger amount of subcutaneous tissue overlying the gluteal muscle, use the longer of the needles provided to ensure the injectate reaches the intramuscular mass. Both the 11/2 and 2 inch administration needles are provided to accommodate varying patient body habitus. 4. ATTACH the injection . Remove the syringe tip cap with an easy counter— clockwise twisting motion. Attach the appropriate needle with an easy clockwise ng motion. Remove the needle sheath with straight, firm pull.

. PRIME the syringe to remove air. Bring the syringe into upright position and tap the syringe to bring air to the top. Remove air by depressing the plunger rod. A few drops of suspension will be released. 6. ADMINISTER the entire contents intramuscularly. Inject in a rapid and continuous manner (less than 10 seconds). DO NOT inject intravenously or subcutaneously.

° Prior to ion aspirate for blood. [Ifblood aspirates, do not inject. Replace with new needle (Steps 3 & 4) and administer into an adjacent site in the same gluteal muscle (Steps 5 & 6).] ° Ifyou are unable to complete the injection, replace with new needle (Steps 3 & 4) and readminister into an adjacent site in the same gluteal muscle (Steps 5 & 6). 7. DISPOSE of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container.

Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by nce to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims (18)

Claims 1.

1. Use of a pharmaceutical composition in the manufacture of a medicament for treating a disorder of the central nervous system in a subject n said pharmaceutical composition comprises: 5 (a) 24 – 30 weight percent of a compound of Formula (I): n n is an integer between 4 and 14; (b) 0.3 – 0.4 weight percent sorbitan e; (c) 0.1 – 0.3 weight percent polysorbate 20; and 10 (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are ve to the total weight of the composition; the medicament is formulated for intramuscular administration at an intramuscular injection rate of less than 10 seconds; and 15 the total injection volume of the ceutical composition is 1.6 mL, 2.4 mL, 3.2 mL, or 3.4 mL.

2. The use of claim 1, wherein the said pharmaceutical composition comprises: (a) about 26.6 weight percent Compound 1: 20 (b) about 0.37 weight percent sorbitan laurate; (c) about 0.15 weight percent polysorbate 20; and (d) an aqueous vehicle wherein the percentages of (a), (b), and (c) are relative to the total weight of the composition.

3. The use of claim 1 or claim 2, wherein the administration is instantaneous.

4. The use of any one of claims 1 to 3, wherein the pharmaceutical composition is injected using a 20 to 23 gauge needle.

5. The use of claim 4, wherein the needle is a 20 gauge . 5

6. The use of claim 4, wherein the needle is a 21 gauge needle.

7. The use of any one of claims 1 to 6, wherein the injection is formulated for administration in the dorsal gluteal muscle.

8. The use of any one of claims 1 to 6, wherein the injection is formulated for administration in the deltoid muscle. 10

9. The use of any one of claims 1 to 8, wherein the needle does not ence injection failure due to needle clogging.

10. The use of any one of claims 1 to 9, wherein the method does not elicit a pain intensity above a normal threshold in the subject.

11. The use of any one of claims 1 to 10, wherein the method does not elicit any injection 15 site reactions in the subject above a normal threshold in the subject.

12. The use of claim 11, wherein the symptoms of the injection site reaction e but is not limited to redness, tenderness, warmth, itching, pain at injection site, ring, nodule formation, and severe skin damage.

13. The use of any one of claims 1 to 12, wherein imately 3.4 mL of the 20 pharmaceutical composition is formulated for injection within 10 s.

14. The use of any one of claims 1 to 12, wherein approximately 1.6 mL of the pharmaceutical composition is formulated for injection within 5 seconds.

15. The use of any one of claims 1 to 14, wherein the disorder is schizophrenia.

16. The use of any one of claims 1 to 14, wherein the disorder is bipolar disorder. 25

17. The use of any one of claims 1 to 14, wherein the disorder is depression.

18. The use of any one of claims 1 to 14, n the disorder is anxiety.