RU2848179C2 - Injectable depot formulation containing particles of free cariprazine base - Google Patents

Abstract

FIELD: injectable depot formulation.

SUBSTANCE: the present invention discloses an injectable depot formulation and its use for treating mental disorders. The injectable depot formulation contains particles of free base cariprazine and a pharmaceutically acceptable carrier. The particles of free base cariprazine have a median particle size by volume (Dv50) in the range of 0.5 to 100 micrometres.

EFFECT: prolonged sustained release of cariprazine.

18 cl, 8 dwg, 23 tbl, 7 ex

Description

Field of technology to which the invention relates

The present invention relates to an injectable depot form containing cariprazine, and more particularly to an injectable depot form containing particles of cariprazine free base.

Information on the prior art

Cariprazine is an atypical antipsychotic classified as a potent partial agonist of dopamine D3 and D2 with preferential binding to the D3 receptor for the treatment of schizophrenia and bipolar disorder in adults. Cariprazine has superior therapeutic potential to other marketed antipsychotic medications and does not cause serious side effects associated with extrapyramidal symptoms due to its high selectivity for D3/D2. Oral cariprazine effectively prevents orthostatic hypotension, a side effect commonly observed in patients prescribed other types of antipsychotic medications. Compared with risperidone, patients taking orally cariprazine had lower scores on the Positive and Negative Syndrome Scale (PANSS), reflecting an improvement in the predominant negative symptoms of schizophrenia in a 26-week Phase 3B clinical trial.

Vraylar® (cariprazine capsules) is a prescription medication that received U.S. FDA approval in 2015 for marketing for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder, depressive episodes associated with bipolar I disorder (bipolar depression), and major depressive disorder (MDD), and is designed to be administered daily and immediate-release in dosages of 1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg, depending on the individual patient's efficacy and tolerability.

The active ingredient in Vraylar® capsule is cariprazine hydrochloride, which has the chemical structure shown

and which has the chemical name trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea hydrochloride. Cariprazine hydrochloride is a white to off-white, non-hygroscopic crystalline solid and forms two active metabolites in large amounts in the liver, namely, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which have similar activity to the parent compound cariprazine due to their similarities in in vitro receptor binding profile, plasma protein binding affinity, and brain penetration.

Injectable depot forms are widely used in the field of antipsychotic drugs, such as flupentixol decanoate (Fluanxol® Depot), fluphenazine decanoate (Modecate®), haloperidol decanoate (Haldol®), zuclopenthixol decanoate (Clopixol® Depot), aripiprazole monohydrate (Abilify Maintena®), aripiprazole lauroxyl (Aristada®), olanzapine pamoate (Zyprexa Relprevv®), paliperidone palmitate (Invega Sustenna®, Invega Trinza®, Invega Hafyera®), and risperidone (Risperdal Consta®, Perseris® Kit). These injectable depot forms exhibit delayed release over an extended period of two weeks to six months. The duration of action increases the sustained release time and reduces dosing frequency, thereby improving patient compliance and reducing relapse rates in patients with psychotic disorder requiring long-term treatment.

Extended-release injectable formulations of cariprazine have been developed as non-aqueous suspensions, aqueous suspensions, or microspheres.

U.S. Patent Application Publication No. 20170196855A1 discloses a technology platform useful for producing an extended-release formulation of cariprazine dispersed in a non-aqueous liquid carrier comprising a hydrophobic lipid, a hydrophilic organic solvent, or a combination thereof, and an amphiphilic agent. In this invention, the hydrophobic lipid carrier comprises a glycerol ester of a C6-C24 fatty acid, sesame oil, and a hydrophilic organic solvent. The hydrophilic organic solvent is polyethylene glycol, propylene glycol, and/or glycerol. The amphiphilic agent is sorbitan esters or polyethoxylated sorbitan esters. In this invention, a large amount of the hydrophilic organic solvent used in the non-aqueous carrier can cause irritation-related reactions at the injection site.

Chinese Patent No. 108261394B discloses an aqueous injection suspension containing cariprazine hydrochloride as the active pharmaceutical ingredient, which is capable of sustained action and high-dose dosing for at least one week. This sustained action may reduce dosing frequency. However, cariprazine hydrochloride can result in a formulation with an extremely acidic pH and high osmolality if excessive sodium hydroxide is used to neutralize the formulation.

Chinese Patent Application No. 112972388A discloses cariprazine formulations in the form of microspheres, microparticles, and nanoparticles dispersed in a polymer matrix material containing poly(d,l-lactide-glycotide) with a stable, sustained-release profile without the burst release typically associated with the initial stage of matrix degradation. The primary challenges in manufacturing cariprazine formulations in microsphere form are high cost and scalability.

Pharmaceutically acceptable salts of cariprazine, developed using a recrystallization method, were previously described in U.S. Patent Publication No. 7,943,621B2. In this patent, salt forms of cariprazine were prepared by reacting cariprazine free base with various acids, including hydrogen chloride, hydrogen bromide, maleic acid, and methanesulfonic acid, in aqueous or nonaqueous solvent systems. Among the various cariprazine salts, the monohydrochloride salt of cariprazine can be readily isolated in the highest yield and highest purity, making it suitable for industrial-scale production. The hydrochloride salts of cariprazine can remain stable in the solid state or in aqueous solution at ambient temperatures for at least two years. The suitable solubility of the hydrochloride salt allows cariprazine to be released immediately from the oral dosage form, and thus cariprazine hydrochloride is chosen as the active ingredient in Vraylar® (cariprazine capsules).

However, in an injectable depot formulation, the active ingredient must be slowly released from the injectable depot at the injection site to provide a prolonged effect. Therefore, the water-soluble hydrochloride salt of cariprazine in solid form may be unsuitable for development as an injectable depot formulation.

Therefore, specialists in this field are striving to develop an improved injectable depot form containing cariprazine with a sustained release of the drug, reduced dosing frequency, ease of administration, high patient compliance, and a reduced risk of adverse events.

Brief description of the invention

Thus, the object of the present invention is to provide an injectable depot form that can eliminate at least one of the disadvantages of the prior art.

According to the present invention, an injectable depot formulation comprises particles of cariprazine free base and a pharmaceutically acceptable carrier. The cariprazine free base particles have a median particle size by volume (Dv50) in the range of 0.5 μm to 100 μm.

Brief description of the drawings

Other features and advantages of the present invention will become apparent from the following detailed description of embodiment(s) with reference to the accompanying drawings. It should be noted that various features may not be drawn to scale.

Fig. 1 is a graph showing the cumulative amount of cariprazine released at various time points in a dissolution test for the injectable depot forms of Example 1, below.

Fig. 2 is a graph showing the cumulative amount of cariprazine released at various time points in the dissolution test for the injectable depot forms of Example 2, below.

Fig. 3 is a graph showing the cumulative amount of cariprazine released at various time points in the dissolution test for the injectable depot forms of Example 3, below.

Fig. 4 is a graph showing the cumulative amount of cariprazine released at various time points in the dissolution test for the injectable depot forms of Example 4, below.

Fig. 5 is a graph showing the cumulative amount of cariprazine released at various time points in the dissolution test for the injectable depot forms of Example 5, below.

Fig. 6 is a graph showing the cumulative amount of cariprazine released at various time points in the dissolution test for the injectable depot forms of Example 6, below.

Fig. 7 is a graph showing the mean plasma concentration of cariprazine in rats as a function of time following intramuscular administration of the injectable depot forms of the present invention in the first pharmacokinetic study of Example 7, below.

Fig. 8 is a graph showing the mean plasma concentration of cariprazine in rats as a function of time after oral administration of a Vraylar® capsule in the second pharmacokinetic study of Example 7, below.

Detailed description of the invention

Before describing the present invention in more detail, it should be noted that if any prior art publication is referred to in this description, such reference does not constitute an admission that the publication is part of the general knowledge in the art in Taiwan or any other country.

For the purposes of this description, it will be understood that the word "comprising" means "including, but not limited to," and that the word "contains" has a corresponding meaning.

Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. One skilled in the art will be familiar with a variety of methods and materials similar or equivalent to those disclosed herein that can be used in practicing the present invention. Indeed, the present invention is in no way limited to the methods and materials described.

The applicants first conducted a solubility study of cariprazine hydrochloride and cariprazine free base using the shake-flask method and found that the aqueous solubility of cariprazine hydrochloride (>5 mg/mL) was significantly higher than that of cariprazine free base (0.006 mg/mL). Furthermore, cariprazine hydrochloride is a water-soluble salt, meaning that some cariprazine was already dissolved in the injectable depot formulation, which could lead to a potential dose dumping problem in patients. Considering that cariprazine free base, with its lower aqueous solubility, may exhibit a better sustained-release profile, cariprazine free base was selected as the active ingredient in the injectable depot formulation.

Sparingly soluble cariprazine salts are believed to have relatively low aqueous solubility compared to water-soluble cariprazine salts. The preparation of sparingly soluble cariprazine salts offers several advantages, including ease of synthesis as a single crystalline form, a reduced risk of solvate formation due to organic solvents used during synthesis, ease of isolation with high yield and purity, and even lower aqueous solubility than the free base form of cariprazine under certain circumstances. However, some adverse clinical events have been observed in patients receiving the extended-release salt formulation of cariprazine.

An example of a poorly soluble salt developed as an injectable depot formulation is olanzapine pamoate, the active ingredient in Zyprexa Relprevv®, used to treat schizophrenia. Some patients receiving intramuscular injections of Zyprexa Relprevv® once every 2-4 weeks experienced post-injection delirium/sedation syndrome (PDSS) due to a sudden increase in plasma olanzapine levels. An in vitro solubility study revealed that patients receiving olanzapine pamoate experienced an increase in plasma solubility that was 18-fold greater than the solubility in a pH 7.6 buffer used to simulate muscle tissue. It is possible that accidental blood contamination of the injectable depot formulation at the injection site leads to an unexpectedly rapid increase in the solubility of olanzapine pamoate, causing irreversible dissociation of olanzapine pamoate to form the parent drug olanzapine and pamoic acid, leading to olanzapine overdose. Since abnormal increases in plasma drug concentrations should be avoided during injection of a salt-forming compound, the injectable depot formulation of the present disclosure contains cariprazine free base as the active ingredient.

Thus, the present invention provides an injectable depot formulation comprising particles of cariprazine free base and a pharmaceutically acceptable carrier. The cariprazine free base particles have a median particle size by volume (Dv50) in the range of 0.5 μm to 100 μm.

In some embodiments, the cariprazine free base particles have a median particle size by volume (Dv50) in the range of 2 μm to 40 μm, 5 μm to 40 μm, 10 μm to 40 μm, or 20 μm to 40 μm.

In some embodiments, the cariprazine free base particles have a median particle size by volume (Dv50) in the range of 2 μm to 25 μm, 5 μm to 25 μm, or 10 μm to 25 μm.

As used herein, the term "injectable depot form" is intended to cover a formulation containing the active ingredient in solid form (e.g., powders, lozenges, granules, etc.) that does not contain water for injection, and a formulation containing the active ingredient in the form of an aqueous suspension that does contain water for injection.

As used herein, the term "median particle size by volume" of X µm means that 50% of the volume of cariprazine free base particles consists of particles having an equivalent diameter of less than X µm.

In some embodiments, the cariprazine free base particles are present in an amount in the range of 4 wt% to 65 wt% based on the total weight of the injectable depot form.

In some embodiments, the pharmaceutically acceptable carrier may comprise an agent that is at least one of a suspending agent, a buffering agent, and a tonicity adjusting agent.

In some embodiments, the suspending agent is present in an amount of from 0.2% to 10% by weight based on the total weight of the injectable depot form.

As used herein, the term "suspending agent" refers to an auxiliary substance added to dispersion systems to maintain particulate ingredients in suspension or to prevent other forms of physical instability. The most common suspending agents are aqueous polymers, including methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose.

In some embodiments, the suspending agent is a cellulose derivative, povidone, and polyethyleneglycol. In an illustrative embodiment, the suspending agent is a cellulose derivative.

In some embodiments, the cellulose derivative is carboxymethylcellulose, sodium carboxymethylcellulose, and methylcellulose. In an illustrative embodiment, the cellulose derivative is sodium carboxymethylcellulose.

In some embodiments, the buffering agent is present in an amount of from 0.01 wt.% to 2 wt.% based on the total weight of the injectable depot form.

As used herein, the term "buffering agent" refers to salts of a weak acid or weak base that are used in pharmaceutical solutions to control the pH of the formulated product.

In some embodiments, the buffering agent is monobasic sodium phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, or combinations thereof. In an exemplary embodiment, the monobasic sodium phosphate is sodium hydrogen phosphate monohydrate, and the disodium hydrogen phosphate is disodium hydrogen phosphate anhydrous.

In some embodiments, the tonicity adjusting agent is present in an amount in the range of 0.01 wt.% to 6.5 wt.% based on the total weight of the injectable depot form.

As used herein, the term "tonicity adjusting agent" refers to an agent used to control the osmotic pressure of a solution. A tonicity adjusting agent may be dextrose, glycerol, mannitol, potassium chloride, or sodium chloride.

In some embodiments, the tonicity adjusting agent is mannitol, glucose, sucrose, trehalose, and sodium chloride.

In some embodiments, the pharmaceutically acceptable carrier further comprises a wetting agent.

As used herein, the term "wetting agent" refers to an agent that can reduce the surface tension of a liquid, allowing the wetting agent to spread across and penetrate the surface of a solid. The term "wetting agent" can be used interchangeably with the term "surfactant," which is related to amphiphiles.

In some embodiments, the wetting agent is present in an amount of from 0.01 wt.% to 3 wt.% based on the total weight of the injectable depot form.

In some embodiments, the wetting agent is polysorbate, poloxamer, lecithin, sorbitan monolaurate, and polyoxyethylene fatty acid esters. In an exemplary embodiment, the wetting agent is poloxamer. In another exemplary embodiment, the wetting agent is lecithin.

In some embodiments, the pharmaceutically acceptable carrier further comprises a pH-regulating agent.

In some embodiments, the pH-regulating agent is present in an amount in the range of 0.01 wt.% to 1 wt.% based on the total weight of the injectable depot form.

In some embodiments, the pH adjusting agent comprises sodium hydroxide and hydrogen chloride.

The present invention also provides another injection depot form comprising particles of cariprazine free base and a pharmaceutically acceptable carrier. The cariprazine base particles have a Dv50 in the range of 0.5 μm to 100 μm. The pharmaceutically acceptable carrier contains at least one of a suspending agent, a buffering agent, a tonicity adjusting agent, and a combination thereof. The suspending agent can be selected from a cellulose derivative, povidone, and polyethylene glycol; the buffering agent can be selected from sodium monobasic phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, and combinations thereof; and the tonicity adjusting agent can be selected from mannitol, glucose, sucrose, trehalose, and sodium chloride.

In an illustrative embodiment, the suspending agent is sodium carboxymethylcellulose; the buffering agents are disodium hydrogen phosphate monohydrate and disodium hydrogen phosphate anhydrous; and the tonicity adjusting agent is mannitol.

The present invention also provides a method for treating psychosis, cognitive impairment associated with schizophrenia, bipolar disorder, acute mania, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders, neuroleptic-induced parkinsonism, tardive dyskinesia, eating disorders, attention deficit disorder, hyperactivity syndromes in children, depression, anxiety, sexual dysfunction, sleep disorders, vomiting, aggression, autism, major depressive disorder or drug abuse, which comprises the step of administering the above-mentioned injectable depot form to a subject in need thereof.

The present invention will be described by means of the following examples. However, it should be understood that the following examples are intended for illustrative purposes only and should not be construed as limiting the practice of the present invention.

EXAMPLES

Example 1. Evaluation of the effect of different median particle size by volume (Dv50) of cariprazine free base particles on the in vitro dissolution of an injectable depot formulation

An injectable depot formulation containing cariprazine free base particles (serving as the active ingredient) was prepared using the formulation shown below in Table 1.

Table 1

Components of cariprazine IDF Quantity Cariprazine free base particles 7.56 g Sodium carboxymethylcellulose 1.4976 g Mannitol 7.4880 g Sodium dihydrogen phosphate monohydrate 0.1043 g Disodium hydrogen phosphate anhydrous 0.1482 g Water (for injection) 120 ml

Specifically, the carrier solution was prepared by mixing the excipients, i.e., sodium carboxymethyl cellulose, mannitol, sodium dihydrogen phosphate monohydrate, and disodium hydrogen phosphate anhydrous, using a mechanical stirrer at a speed of 300 to 500 rpm for 3 hours, and then cariprazine free base particles (in the form of a solid powder) were added to the carrier solution, followed by stirring at 200 rpm for 18 hours at 25 ^° C to obtain a milky suspension. The milky suspension was then homogenized at 11,000 rpm for 10 minutes to obtain a primary suspension. The primary suspension was then subjected to a wet milling process using a ball mill and a bead mill at 15 ^° C to reduce the particle size of cariprazine free base, thereby obtaining suspensions containing cariprazine free base particles with the target particle sizes, namely, suspensions of experimental groups D1–D5. Laser light scattering analysis using a particle size analyzer (Malvern Mastersizer 3000) was then used to determine the particle size distribution of cariprazine free base, which are shown as volume diameters Dv10, Dv50, and Dv90. The results are presented below in Table 2.

The concentration of cariprazine free base particles in each group was determined by HPLC. The determined concentration of cariprazine free base particles (see Table 2) was divided by its theoretical concentration in the drug product to obtain the quantitative content (in %) (see Table 2). The suspensions of each group were filled into a glass vial, stoppered, sealed, and then sterilized by moist heat at 121 ^° C for 40 minutes (a cycle using the “mass kill” approach), thereby obtaining the injectable depot forms of the experimental groups D1-D5, each in the form of an aqueous ready-to-use suspension. In addition, a known reference product from the list (RLD), i.e., Vraylar® oral capsule containing cariprazine hydrochloride salt, was used as a control and designated as comparative group 1.

Table 2

Suspension Cariprazine concentration (mg/ml) Particle size distribution Quantity content (%) Dv10 (µm) Dv50 (µm) Dv90 (µm) Experimental group D1 52.5 0.76 2.17 4.42 104.0 Experimental group D2 50.0 2.70 8.40 28.30 101.0 Experimental group D3 52.5 4.17 9.59 33.00 102.5 Experimental group D4 50.0 8.36 22.20 75.50 95.1 Experimental group D5 50.0 7.40 40.30 125.00 99.2

Referring to Table 2, the Dv50 of cariprazine free base particles in the injectable depot forms of the experimental groups D1-D5 are approximately 2 μm, 8 μm, 10 μm, 20 μm and 40 μm, respectively, and their quantitative content is in the range of 95% to 105%.

The injectable depot forms from the experimental groups D1-D5 and the Vraylar® oral capsule from the comparative group 1 were subjected to the dissolution test using the conditions shown below in Table 3. The concentration of cariprazine free base particles in the experimental groups D1-D5 and the Vraylar® oral capsule from the comparative group 1 were analyzed by HPLC as shown in Table 4 to determine the cumulative amount of released cariprazine (in %) in each group.

Table 3

Parameter Conditions device USP Apparatus 2 (Paddle) Rotation speed 50 rpm Dissolution medium 0.25% SDS Temperature 37.0 ± 0.5 ^o C Sample Introduction IDF cariprazine Taking a sample 5 ml Capture mode Automatically Time of taking 3, 6, 10, 15, 30, 60, 120 min Sample processing before HPLC analysis Immediate filtration through a 0.22 µm filter

Table 4

Parameter Conditions Column YMC triat C18, 250×4.6 mm, 5 µm Detector UV at 215 nm Flow rate 1.2 ml/min Mobile phase (MP) MPA: ACN
MPB: 1.74 g K ₂ HPO ₄ /5% diethylamine in 1 liter of water, pH 6.5 Elution ratio MPA:MPB = 60:40 Volume of administration 20 µl Column temperature 25 ^o C Sampler temperature 25 ^o C Opening hours 12 min

The results are shown in Fig. 1 and Tables 5 and 6.

Table 5

Time (min) Comparison group 1 Experimental group D1
(Dv50=2 µm) Experimental group D2
(Dv50=8 µm) Cumulative amount of released cariprazine (%) Coefficient of variation
(%) Cumulative amount of released cariprazine (%) Coefficient of variation (%) Cumulative amount of released cariprazine (%) Coefficient of variation
(%) 3 104.1 4.8 61.2 3.1 37.6 3.1 6 106.0 1.6 66.2 1.4 41.2 3.2 10 104.1 5.3 69.0 1.3 44.1 2.7 15 101.2 1.8 70.7 1.0 47.0 2.7 30 102.6 4.7 77.1 1.7 53.4 2.0 60 100.5 2.4 86.3 3.1 63.5 2.0 120 102.8 0.8 96.5 4.3 78.8 1.5

Table 6

Time (min) Experimental group D3
(Dv50=10 µm) Experimental group D4
(Dv50=20 µm) Experimental group D5
(Dv50=40 µm) Cumulative amount of released cariprazine (%) Coefficient of variation
(%) Cumulative amount of released cariprazine (%) Coefficient of variation
(%) Cumulative amount of released cariprazine (%) Coefficient of variation
(%) 3 26.4 0.5 20.7 0.7 16.5 1.9 6 30.7 0.3 23.7 0.5 19.5 2.0 10 33.4 0.2 26.2 1.8 22.2 1.6 15 36.0 0.5 28.5 0.9 24.8 2.4 30 41.3 0.5 33.5 1.7 30.0 3.3 60 48.2 0.9 39.6 1.4 37.0 4.4 120 58.5 3.0 49.4 3.0 47.4 5.4

Fig. 1 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the injectable depot forms from experimental groups D1-D5 and the Vraylar® oral capsule from comparative group 1, with the numerical values and their coefficient of variation presented in Tables 5 and 6. As shown in Fig. 1 and in Tables 5 and 6, compared with the Vraylar® oral capsule of Comparative Example 1, which contains cariprazine hydrochloride salt, the injectable depot forms of the experimental groups D1-D5, containing cariprazine free base particles, which have a Dv50 of 2 μm, 8 μm, 10 μm, 20 μm and 40 μm, respectively, showed lower percentage values of the cumulative amount of cariprazine released at various time points in the dissolution test, suggesting that the cariprazine free base particles of the injectable depot form of the experimental groups D1-D5 were released much more slowly compared with the cariprazine hydrochloride salt of the Vraylar® oral capsule of Comparative Example 1. Specifically, the cumulative amount of cariprazine free base particles released in each of the experimental groups D1-D5 was less 80% at 15 minutes and was still less than 100% at 120 minutes in the dissolution test (i.e., not completely released after 120 minutes), whereas the cumulative amount of cariprazine hydrochloride salt released in Comparative Group 1 was greater than 100% after 10 minutes in the dissolution test. These results indicate that the injectable depot forms from experimental groups D1-D5, each containing cariprazine free base particles, exhibit improved sustained-release characteristics compared to the Vraylar® oral capsule from Comparative Group 1, which contains cariprazine hydrochloride salt.

Referring again to Fig. 1 and Tables 5 and 6, compared to injectable depot forms D1-D4, injectable depot form D5, which contains cariprazine free base particles having the highest Dv50 value, had the lowest percentage values of the cumulative amount of cariprazine free base particles released at various time points in the dissolution test (i.e., the slowest dissolution rate), indicating that the injectable depot form containing cariprazine free base particles with a relatively large particle size had a relatively slower dissolution rate in vitro and thus exhibits improved sustained release characteristics.

Example 2. Evaluation of the effect of adding different types of suspending agents on the in vitro dissolution of an injection depot form

In order to determine the effect of adding different types of suspending agents, i.e., sodium carboxymethylcellulose, povidone K30 and/or polyethyleneglycol 4000, on the dissolution of the injection depot of the present invention, three different injection depots containing cariprazine free base particles were prepared using the formulation shown in Table 7 below to obtain injection depots of experimental groups SA1, SA2 and SA3. Each of the injection depots of experimental groups SA1, SA2 and SA3 was analyzed and then subjected to particle size distribution determination and dissolution test to determine the cumulative amount of released cariprazine. For comparison, an injection depot containing the same components as the injection depots of Example 1 was prepared and named as experimental group D6 (cariprazine free base particle concentration: 63 mg/mL). The injectable depot form of the experimental group D6 was also subjected to the above analysis and dissolution test.

The result of the particle size distribution analysis is shown in Table 8, and the result of the solubility test is shown in Fig. 2 and Table 9.

Table 7

Component (quantity) Experimental group D6 Experimental group SA1 Experimental group SA2 Experimental
SA3 group Cariprazine free base particles (g) 1.26 1.26 1.26 2.52 Sodium carboxymethylcellulose (g) 0.249 0.375 0.375 -- Povidone K30 (g) -- -- 0.180 -- Polyethylene glycol 4000 (g) -- -- -- 1.80 Mannitol (g) 1,248 1,248 1,248 2.50 Sodium dihydrogen phosphate monohydrate (g) 0.0174 0.0174 0.0174 0.04 Disodium hydrogen phosphate anhydrous (g) 0.0246 0.0246 0.0246 0.05 Water (for injection) q.s. up to 20 ml q.s. up to 20 ml q.s. up to 20 ml q.s. up to 40 ml

Table 8

Groups Particle size distribution Quantitative content (%) Dv10 (µm) Dv50 (µm) Dv90 (µm) Experimental group D6 4.2 19.8 76.9 96.0 Experimental group SA1 4.1 18.3 77.6 104.1 Experimental group SA2 4.4 20.0 77.3 94.2 Experimental group SA3 4.5 20.0 81.2 94.6

Referring to Table 8, the injectable depot formulations containing cariprazine free base particles from experimental groups SA1 through SA3 and experimental group D6 showed similar particle size distribution profiles. Specifically, in each group, the cariprazine free base particles had a Dv50 value ranging from 18 µm to 20 µm; their assay content ranged from 90% to 105%.

Table 9

Time (min) Cumulative amount of released cariprazine (%) Experimental group D6 Experimental group SA1 Experimental group SA2 Experimental group SA3 3 20.7 22.6 23.1 25.9 6 23.7 25.6 25.9 29.8 10 26.2 27.7 28.7 32.5 15 28.5 30.4 31.4 35.2 30 33.5 34.9 37.3 41.6 60 39.6 40.9 45.1 49.3 120 49.4 50.1 56.7 61.1

Fig. 2 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the injectable depot forms from experimental groups SA1 to SA3 and experimental group D6, and Table 9 presents their numerical values. As shown in Fig. 2 and in Table 9, the percentage values of the cumulative amount of cariprazine released at different time points in the dissolution test for the injectable depot form of the experimental group SA1, which contained sodium carboxymethylcellulose as a suspending agent, the injectable depot form of the experimental group SA2, which contained sodium carboxymethylcellulose as a first suspending agent and povidone K30 as a second suspending agent, and the injectable depot form of the experimental group SA3, which contained polyethylene glycol 4000 as a suspending agent, were not significantly different from those of the experimental group D6, indicating that each of the injectable depot forms of the experimental groups SA1-SA3 and the experimental group D6 has a similar sustained release profile. Therefore, the addition of povidone K30 or polyethyleneglycol 4000 does not adversely affect the sustained release of the injectable depot form containing cariprazine free base particles of the present invention.

Example 3. Evaluation of the effect of adding different types of wetting agents on the in vitro dissolution of an injectable depot form

To determine the effect of adding different types of wetting agents, i.e., polysorbate 80, polysorbate 20, or poloxamer 188, on the dissolution of the injectable depot form of the present invention, three different injectable depot forms containing particles of cariprazine free base were prepared using the formulation shown in Table 10 below, yielding injectable depot forms from experimental groups SA1+WA1, SA1+WA2, and SA1+WA3. In this example, the injectable depot form from experimental group SA1 of Example 2 served as a control. Each of the injectable depot forms from experimental groups SA1+WA1 to SA1+WA3 and experimental group SA1 was analyzed and then subjected to particle size distribution determination and dissolution testing in order to determine the cumulative amount of released cariprazine.

The result of particle size distribution analysis is shown in Table 11, and Fig. 3 and Table 12 show the result of solubility test.

Table 10

Component (quantity) Experimental group SA1 Experimental group SA1+WA1 Experimental group SA1+WA2 Experimental group SA1+WA3 Cariprazine free base (g) 1.26 1.26 1.26 1.26 Sodium carboxymethylcellulose (g) 0.375 0.375 0.375 0.375 Polysorbate 80 (g) -- 0.072 -- -- Polysorbate 20 (g) -- -- 0.6 -- Poloxamer 188 (g) -- -- -- 0.06 Mannitol (g) 1,248 1,248 1,248 1,248 Sodium dihydrogen phosphate monohydrate (g) 0.0174 0.0174 0.0174 0.0174 Disodium hydrogen phosphate anhydrous (g) 0.0246 0.0246 0.0246 0.0246 Water (for injection) q.s. up to 20 ml q.s. up to 20 ml q.s. up to 20 ml q.s. up to 20 ml

Table 11

Groups Particle size distribution Quantity content (%) Dv10 (µm) Dv50 (µm) Dv90 (µm) Experimental group SA1 4.1 18.3 77.6 104.1 Experimental group SA1+WA1 3.1 11.8 53.6 104.2 Experimental group SA1+WA2 3.7 15.1 62.5 100.9 Experimental group SA1+WA3 3.8 16.5 68.5 96.0

Referring to Table 11, each of the injectable depot forms of the experimental groups SA1+WA1, SA1+WA2, SA1+WA3 and the experimental group SA1 showed a particle distribution of cariprazine free base with a Dv50 value in the range of 10 μm to 20 μm; and a quantitative content in the range of 95% to 105%. However, based on the Dv10, Dv50 and Dv90 values shown in Table 11, the injectable depot forms of the experimental groups SA1+WA1, SA1+WA2, SA1+WA3, which contained polysorbate 80, polysorbate 20 and poloxamer 188, respectively, serving as a wetting agent, contain cariprazine free base particles with particle sizes smaller than those of the injectable depot form of the experimental group SA1, which was prepared without a wetting agent.

Table 12

Cumulative amount of released cariprazine (%) Time (min) Experimental group SA1 Experimental group SA1+WA1 Experimental group SA1+WA2 Experimental group SA1+WA3 3 22.6 25.3 24.6 23.2 6 25.6 29.0 28.1 26.2 10 27.7 31.8 31.0 28.8 15 30.4 34.1 33.6 30.9 30 34.9 38.9 39.3 35.9 60 40.9 45.7 48.2 42.7 120 50.1 55.3 58.6 52.4

Fig. 3 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the experimental groups SA1+WA1 through SA1+WA3 and the experimental group SA1, and their numerical values are presented in Table 12. As shown in Fig. 3 and Table 12, the percentage values of the cumulative amount of cariprazine released at different time points in the dissolution test for the injectable depot forms of the experimental groups SA1+WA1, SA1+WA2, and SA1+WA3 were not significantly different from those of the injectable depot form of the experimental group SA1, which was prepared without a wetting agent. These results indicate that each of the injectable depot forms of the experimental groups SA1, SA1+WA1, SA1+WA2, and SA1+WA3 has a similar sustained release profile. Thus, the addition of polysorbate 80, polysorbate 20 or poloxamer 188 as a wetting agent does not adversely affect the sustained release of the injectable depot form containing cariprazine free base particles of the present invention.

Example 4. Evaluation of the effect of adding two different suspending agents and one wetting agent on the in vitro dissolution of an injectable depot form

To determine the effect of adding two different types of suspending agents (i.e., sodium carboxymethylcellulose and povidone K30) and one wetting agent, i.e., polysorbate 80, polysorbate 20, or lecithin, on the dissolution of the injectable depot forms of the present invention, three different injectable depot forms containing cariprazine free base particles were prepared using the formulation shown in Table 13 below to obtain injectable depot forms containing cariprazine free base particles from experimental groups SA2+WA1, SA2+WA2, and SA2+WA4. In this example, the injectable depot form from experimental group SA2 of Example 2 served as a control. Each of the injectable depot forms from the SA2+WA1 to SA2+WA4 experimental groups and the SA2 experimental group was analyzed and then subjected to particle size distribution and dissolution testing to determine the cumulative amount of cariprazine released.

The result of the particle size distribution analysis is shown in Table 14, and the result of the solubility test is shown in Fig. 4 and Table 15.

Table 13

Component (quantity) Experimental group SA2 Experimental group SA2+WA1 Experimental group SA2+WA2 Experimental group SA2+WA4 Cariprazine free base (g) 1.26 1.26 1.26 1.26 Sodium carboxymethylcellulose (g) 0.375 0.375 0.375 0.375 Povidone K30 (g) 0.18 0.18 0.18 0.18 Polysorbate 80 (g) -- 0.072 -- -- Polysorbate 20 (g) -- -- 0.6 -- Lecithin (g) -- -- -- 0.18 Mannitol (g) 1,248 1,248 1,248 1,248 Sodium dihydrogen phosphate monohydrate (g) 0.0174 0.0174 0.0174 0.0174 Disodium hydrogen phosphate anhydrous (g) 0.0246 0.0246 0.0246 0.0246 Water (for injection) q.s. up to 20 ml q.s. up to 20 ml q.s. up to 20 ml q.s. up to 20 ml

Table 14

Groups Particle size distribution Quantity content (%) Dv10 (µm) Dv50 (µm) Dv90 (µm) Experimental group SA2 4.4 20.0 77.3 94.2 Experimental group SA2+WA1 3.9 16.3 66.2 92.9 Experimental group SA2+WA2 4.4 19.9 80.9 94.5 Experimental group SA2+WA4 3.3 13.0 57.1 109.5

Referring to Table 14, each of the injectable depot forms from the experimental groups SA2+W1, SA2+W2, SA2+W4 and the experimental group SA2 showed a particle size distribution of cariprazine free base with a Dv50 value ranging from 10 μm to 20 μm; and a quantitative content ranging from 90% to 110%. However, based on the Dv10, Dv50, and Dv90 values shown in Table 14, the injectable depot form of the experimental group SA2+WA4, which contained lecithin as a wetting agent, contains particles of cariprazine free base with a particle size smaller than the particle size of the injectable depot forms of the experimental group SA2 (without a wetting agent), as well as the particle size of the experimental groups SA2+WA1 and SA2+WA2, which contained polysorbate 80 and polysorbate 20, respectively, serving as a wetting agent.

Table 15

Cumulative amount of released cariprazine (%) Time (min) Experimental group SA2 Experimental group SA2+WA1 Experimental group SA2+WA2 Experimental group SA2+WA4 3 23.1 24.1 23.0 30.0 6 25.9 26.9 25.3 33.7 10 28.7 29.2 27.9 36.4 15 31.4 31.9 30.3 38.6 30 37.3 38.0 35.7 43.8 60 45.1 46.4 42.9 50.9 120 56.7 59.3 53.6 60.9

Fig. 4 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the experimental groups SA2+WA1 to SA2+WA4 and the experimental group SA2, and Table 15 provides their numerical values. As shown in Fig. 4 and in Table 15, the percentage values of the cumulative amount of cariprazine released at different time points in the dissolution test for the injectable depot form of the experimental group SA2+WA1, which contained polysorbate 80 as a wetting agent, the injectable depot form of the experimental group SA2+WA2, which contained polysorbate 20 as a wetting agent, and the injectable depot form of the experimental group SA2+WA4, which contained lecithin as a wetting agent, were not significantly different from those for the injectable depot forms of the experimental group SA2, which contained the same suspending agents but without a wetting agent. These results indicate that each of the injectable depot forms of the experimental groups SA2, SA2+WA1, SA2+WA2, and SA2+WA4 has a similar sustained release profile. Thus, the addition of polysorbate or lecithin does not adversely affect the sustained release nature of the injectable depot form containing cariprazine free base particles of the present invention.

Example 5. Evaluation of the effect of the lyophilization process on the dissolution of the injectable depot form in vitro

In order to determine the effect of the lyophilized form of the injectable depot form on its stability, in this example, the injectable depot form of the experimental group SA1 of Example 2 (cariprazine free base particle concentration: 63 mg/mL) was subjected to a lyophilization process performed in accordance with the steps and conditions listed below in Table 16, so as to obtain the injectable depot form of the experimental group SA1_Lyophilized. The injectable depot form of the experimental group SA1 of Example 2, which was not subjected to the lyophilization process, served as a control. Each of the injectable depot forms of the experimental group SA1_Lyophilized and the experimental group SA1 was analyzed and then subjected to particle size distribution determination and dissolution test as described in Example 1 to determine the cumulative amount of cariprazine released therefrom.

The result of the particle size distribution analysis is shown in Table 17, and the result of the solubility test is shown in Fig. 5 and Table 18.

Table 16

Stage Temperature ( ^o C) Pressure Time period (hour) 1 Freezing -40 Environment 1 2 Extra freezing -40 Environment - 100 mTorr As needed 3 Primary drying 5 100 mTorr 2880 4 Secondary drying 30 400 mTorr 0.25

Table 17

Group Particle size distribution Quantity content (%) Dv10 (µm) Dv50 (µm) Dv90 (µm) Experimental group SA1 2.8 11.0 46.5 98.6 Experimental group SA1_Lyophilized 2.7 10.0 41.6 101.0

Referring to Table 17, the injectable depot forms containing cariprazine free base particles from the SA1 experimental group and the SA1_Lyophilized experimental group showed a nearly similar particle size distribution profile. Specifically, the dispersed cariprazine free base particles had a Dv50 value in the range of 10 μm to 11 μm; and the assay content ranged from 95% to 101%.

Table 18

Cumulative amount of released cariprazine (%) Time (min) Experimental group SA1 Experimental group SA1_lyophilized 3 35.7 36.1 6 39.5 40.2 10 42.0 42.6 15 44.7 45.4 30 50.3 51.2 60 58.0 58.9 120 70.4 71.4

Fig. 5 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the SA1_Lyophilized experimental group and the SA1 experimental group, and their numerical values are provided in Table 18. As shown in Fig. 5 and Table 18, the percentage values of the cumulative amount of cariprazine released from the injectable depot forms of the SA1_Lyophilized experimental group and the SA1 experimental group at different time points in the dissolution test were not significantly different from each other, indicating that the lyophilization process does not negatively affect the release of cariprazine free base particles from the injectable depot form, and the lyophilized injectable depot form remains stable.

Example 6. Evaluation of the effect of different concentrations of cariprazine free base particles on the in vitro dissolution of the injectable depot form

To determine the effect of increasing the amount and/or concentration of cariprazine free base particles on the dissolution of the injectable depot form of the present invention, four different injectable depot forms containing cariprazine free base particles were prepared using the formulation shown below in Table 19 and in accordance with the procedures described in Example 1 to obtain injectable depot forms of experimental groups C1, C2, C3 and C4 having concentrations of 84 mg/mL, 187 mg/mL, 336 mg/mL and 481 mg/mL, respectively. In addition, the injectable depot form of experimental group C4 was further subjected to the lyophilization process described in Example 5, followed by reconstitution of the lyophilized injectable depot form with an appropriate amount of water, resulting in injectable depot forms of experimental group C5 and experimental group C6 having concentrations of 548 mg/mL and 618 mg/mL, respectively. Each of the injectable depot forms from experimental groups C1-C6 was then subjected to a dissolution test as described in Example 1 to determine the cumulative amount of cariprazine released by them.

The result of the solubility test is shown in Fig. 6 and Table 20.

Table 19

Component (quantity) Experimental
group C1
(84 mg/ml) Experimental group C2
(187 mg/ml) Experimental group C3
(336 mg/ml) Experimental group C4
(481 mg/ml) Cariprazine free base (g) 1.68 4.2 8.4 9.0 Sodium carboxymethylcellulose (g) 0.1664 0.1664 0.1664 0.1664 Mannitol (g) 0.832 0.832 0.832 0.832 Sodium dihydrogen phosphate monohydrate (g) 0.0116 0.0116 0.0116 0.0116 Disodium hydrogen phosphate anhydrous (g) 0.0165 0.0165 0.0165 0.0165 Water (for injection) q.s. up to 20 ml q.s. up to 22.5 ml q.s. up to 25 ml q.s. up to 20 ml

Table 20

Cumulative amount of released cariprazine (%) Time (min) Experimental group C1
(84 mg/ml) Experimental group C2
(187 mg/ml) Experimental group C3
(336 mg/ml) Experimental group C4
(481 mg/ml) Experimental group C5
(548 mg/ml) Experimental group C6
(618 mg/ml) 3 22.5 21.5 21.1 21.9 16.6 15.4 6 25.6 23.8 23.7 26.2 22.0 21.2 10 28.6 26.5 26.9 29.0 25.5 25.3 15 30.9 28.8 29.4 31.1 28.4 28.2 30 36.2 35.0 35.3 37.1 34.1 34.0 60 44.2 43.5 44.9 45.0 41.8 41.9 120 53.8 55.1 57.3 56.0 53.1 52.8

Fig. 6 is a graph showing the cumulative amount of cariprazine released at different time points in the dissolution test for the experimental groups C1-C6, and the numerical values thereof are provided in Table 20. As shown in Fig. 6 and Table 20, the percentage values of the cumulative amount of cariprazine released from the injectable depot forms of the experimental groups C1-C6 at different time points in the dissolution test did not differ significantly from each other, indicating that the increased concentration of cariprazine free base particles does not negatively affect its release from the injectable depot forms, and that the injectable depot form of the present invention has a high drug load.

Example 7. Evaluation of the effect of different Dv50 particles of cariprazine free base on the in vivo detection of cariprazine in blood plasma

Since the results in Example 1 demonstrate that the injectable depot form containing the cariprazine free base particles of the present invention had a slower dissolution rate than the Vraylar® oral capsule containing the cariprazine hydrochloride salt, applicants conducted pharmacokinetic studies using an animal model to determine the effect of different Dv50s of cariprazine free base particles on their in vivo dissolution in blood plasma in rats, and to determine the difference in pharmacokinetic profiles between rats administered intramuscularly with the injectable depot form containing the cariprazine free base particles of the present invention and rats administered orally with the Vraylar® capsule.

A. First pharmacokinetic study using the injectable depot form of the present invention

The four injectable depot forms of this example, as shown below in Table 21, were similar to the injectable depot forms of experimental groups D1, D3, D4 and D5, as described in Example 1, and were prepared using the methods described in Example 1.

Table 21

Injectable depot form Dv50 (µm) Experimental group D1 2 Experimental group D3 10 Experimental group D4 20 Experimental group D5 40

Wistar rats (6 to 8 weeks old) were housed in an animal facility with an independent air-conditioning system under the following laboratory conditions: a 12-hour light/12-hour dark cycle, a temperature of 23 ^° C ±2 ^° C, and a relative humidity of 40%-70%. Rats had ad libitum access to food and water. All experimental procedures involving experimental rats complied with the legal provisions of the Taiwan Animal Welfare Act and were conducted in accordance with the recommendations of the Animal Care Committee of the Council of Agriculture of Taiwan.

The rats were randomly divided into four groups, namely, experimental group D1, experimental group D3, experimental group D4 and experimental group D5, and the number of rats in each of the experimental groups D1 and D3 was 6, and the number of rats in each of the experimental groups D4 and D5 was 4.

Rats in the experimental groups D1-D5 were administered intramuscularly with the injectable depot forms from the experimental groups D1-D5, respectively. Intramuscular administration was performed by injecting a single dose of an aqueous suspension containing cariprazine free base particles into the thigh muscle of rats at a concentration of 28 mg/kg per rat. From rats in each of the experimental groups D1, D3, D4, and D5, blood samples were collected from the tail vein of each rat on day 1 (i.e., at 10 and 30 minutes and at 1, 2, 3, 5, 7, 10, and 24 hours after administration) and on days 3, 5, 7, 10, 14, 21, and 28, and then subjected to mean plasma concentration measurement using a QTRAP® 5500 LC-MS/MS system (AB Sciex). For rats in the D3 experimental group, blood samples were also collected on days 35 and 42 after administration, whereas for rats in the D4 and D5 experimental groups, blood samples were also collected on days 35, 42, 49, and 56 after administration.

Table 22

Pharmacokinetic parameters Experimental group D1
(Day _0-28 ) Experimental group D3
(Day _0-42 ) Experimental group D4
(Day _0-56 ) Experimental group D5
(Day _0-56 ) T _1/2 (h) 77.8±14.8 113.7±25.2 141.6±28.8 196.8±48.0 C _max (ng/ml) 83.2±8.5 40.0±11.4 39.9±6.6 28.8±9.8 T _max (h) 112.0±19.6 104.0±39.2 120±0.0 72±55.2 AUC _all (h*ng/ml) 13256.8±950.8 12369.1±2077.3 15482.4±2520 11793.6±2808

Fig. 7 is a graph showing the mean plasma concentration of cariprazine in rats of experimental groups D1, D3, D4 and D5 after intramuscular administration of the injectable depot forms containing cariprazine free base particles of the present invention throughout the time period in the first pharmacokinetic study; and Table 22 presents the parameters determined in the first pharmacokinetic study. As shown in Fig. 7, in each of the experimental groups D1, D3, D4 and D5, after intramuscular administration of the injectable depot forms containing cariprazine free base particles, the mean plasma concentration of cariprazine gradually reached a peak value only after 100 hours and then slowly decreased, and cariprazine was continuously detected in the plasma of rats throughout the 28-day time period of the first pharmacokinetic study. In particular, cariprazine was still detectable in the plasma of rats from the D3 experimental group until day 42 after administration and was still detectable in the plasma of rats from the D4 and D5 experimental groups until day 56 after administration. In addition, as shown in Table 22, the T _1/2 value increased in the D1, D3, D4 and D5 experimental groups, which is consistent with the increase in the particle size of cariprazine free base in these groups; while the high AUC _all value determined in each of the D1, D3, D4 and D5 experimental groups suggests that the cariprazine free base particles released from the injectable depot formulations have good bioavailability. These results indicate that the injectable depot formulations containing cariprazine free base particles with Dv50 in the range of 2 μm to 40 μm exhibit a sustained release behavior in vivo for at least 28 days.

B. Second pharmacokinetic study using Vraylar® capsules

Six Wistar rats (6 to 8 weeks old) were assigned to form comparative group 1. Vraylar® capsules were dissolved in 0.1% acetic acid to prepare an aqueous suspension containing cariprazine hydrochloride salt, which was then orally administered to the rats of comparative group 1 via oral gavage at a concentration of 1 mg/kg per rat. Blood samples were collected from the tail vein of each rat at 10 and 30 minutes and at 1, 2, 3, 5, 7, 10, and 24 hours post-administration and then subjected to mean plasma concentration measurement using the procedures described above in section A.

Table 23

Pharmacokinetic parameters Comparison group 1
(hour _0-24 ) T _1/2 (hour) 3.28±0.33 C _max (ng/ml) 19.6±3.69 T _max (hour) 2.67±0.52 AUC _all (h*ng/ml) 138.29±33.45

Fig. 8 is a graph showing the mean plasma concentration of cariprazine in the rats of comparative group 1 after oral administration of Vraylar® capsules over a 24-hour period in the second pharmacokinetic study; while Table 23 presents the parameters determined in the second pharmacokinetic study. As shown in Fig. 8, after administration of Vraylar® capsule containing cariprazine hydrochloride salt, the mean plasma concentration of cariprazine reached a peak value within 2 hours and then rapidly decreased within 10 hours; and cariprazine was no longer detected in the plasma of the rats of comparative group 1 24 hours after the administration. In addition, the sustained-release nature was not easily observed after oral administration of Vraylar® capsule because the T _1/2 value of comparative group 1 (see Table 23) was relatively shorter than that of experimental groups D1, D3, D4 and D5 (see Table 22). These results indicate that, compared to the injectable depot formulation containing cariprazine free base particles administered intramuscularly to rats as described in Section A of this Example, the orally administered Vraylar® capsule containing cariprazine hydrochloride salt failed to demonstrate a sustained release pattern.

Taken together, these results demonstrate that the particle size of cariprazine free base is a critical factor modulating the sustained-release nature of injectable depot formulations containing cariprazine free base particles of the present invention. Increasing the particle size of cariprazine free base results in a slower release from the injectable depot formulation, resulting in a slower dissolution rate in vitro. Because the injectable depot formulation containing cariprazine free base particles of the present invention also exhibits a controlled, sustained-release effect in vivo, it is expected to be useful as an antipsychotic drug with reduced dosing frequency.

In the above description, numerous specific details have been set forth for purposes of explanation in order to provide a thorough understanding of the embodiment(s). However, it will be apparent to one skilled in the art that one or more other embodiments may be practiced without some of these specific details. It should also be understood that reference to "one embodiment," "an embodiment," "an embodiment with an ordinal number," etc. in the present description means that a particular feature, structure, or characteristic may be used in practicing the present invention. It should also be understood that in the description, various features are sometimes grouped together in a single embodiment, drawing, or description thereof for the purpose of simplifying the disclosure and promoting an understanding of various aspects of the invention; this does not mean that each of these features must be practiced in the presence of all the other features. In other words, in any embodiment described, when the implementation of one or more features or specific details does not affect the implementation of another one or more features or specific details, said one or more features can be isolated and practiced separately without said other one or more features or specific details. It should also be understood that one or more features or specific details from one embodiment may be practiced together with one or more features or specific details from another embodiment, if desired, in practicing the present invention.

Although the invention has been disclosed in accordance with what is considered to be exemplary embodiment(s), it is understood that the invention is not limited to the disclosed embodiment(s), but is intended to cover various combinations of features included within the spirit and scope of the invention in the broadest interpretation so as to cover all such modifications and equivalent combinations.

Claims (18)

1. An injectable depot form as an antipsychotic drug, containing particles of cariprazine free base and a pharmaceutically acceptable carrier, wherein the particles of cariprazine free base have a median particle size by volume (Dv50) in the range from 2 μm to 40 μm and said pharmaceutically acceptable carrier contains a buffering agent, which is present in an amount of from 0.01 wt.% to 2 wt.% based on the total weight of the injectable depot form. 2. The injectable depot form according to claim 1, wherein the particles of free base of cariprazine are present in an amount of from 4% by weight to 65% by weight based on the total weight of the injectable depot form. 3. The injection depot form according to claim 1, wherein the pharmaceutically acceptable carrier also contains at least one of a suspending agent and a tonicity adjusting agent. 4. The injection depot form according to claim 3, wherein the suspending agent is present in an amount of from 0.2% by weight to 10% by weight based on the total weight of the injection depot form. 5. The injection depot form according to claim 3, wherein the suspending agent is a cellulose derivative, povidone, polyethylene glycol or combinations thereof. 6. The injectable depot form according to claim 5, wherein the cellulose derivative is carboxymethylcellulose, sodium carboxymethylcellulose and methylcellulose. 7. The injectable depot form of claim 1, wherein the buffering agent is monobasic sodium phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, or combinations thereof. 8. The injectable depot form according to claim 3, wherein the tonicity adjusting agent is present in an amount of from 0.01% by weight to 6.5% by weight based on the total weight of the injectable depot form. 9. The injectable depot form according to claim 3, wherein the tonicity adjusting agent is mannitol, glucose, sucrose, trehalose and sodium chloride. 10. An injection depot form according to claim 3, wherein the pharmaceutically acceptable carrier additionally contains a wetting agent. 11. The injection depot form according to claim 10, wherein the wetting agent is present in an amount of from 0.01% by weight to 3% by weight based on the total weight of the injection depot form. 12. An injection depot form according to claim 10, wherein the wetting agent is polysorbate, poloxamer, lecithin, sorbitan monolaurate and polyoxyethylene fatty acid esters. 13. An injection depot form according to claim 3, wherein the pharmaceutically acceptable carrier additionally contains a pH-regulating agent. 14. The injection depot form according to claim 13, wherein the pH-regulating agent is present in an amount of from 0.01 wt.% to 1 wt.% based on the total weight of the injection depot form. 15. An injection depot form according to claim 13, wherein the pH-regulating agent comprises sodium hydroxide and hydrogen chloride. 16. A method for treating psychosis, schizophrenia, bipolar disorder, mania, depression or major depressive disorder, comprising the step of administering an injectable depot form according to claim 1 to a subject in need thereof. 17. An injectable depot form as an antipsychotic drug, comprising particles of cariprazine free base and a pharmaceutically acceptable carrier, wherein the particles of cariprazine free base have a median particle size by volume (Dv50) in the range of 2 μm to 40 μm, wherein the pharmaceutically acceptable carrier contains a suspending agent, a buffering agent and an agent for adjusting tonicity, wherein the suspending agent is sodium carboxymethylcellulose, povidone K30 and polyethyleneglycol 4000 or combinations thereof, the buffering agent is sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate anhydrous, and the agent for adjusting tonicity is mannitol, wherein the buffering agent is present in an amount of from 0.01 wt.% to 2 wt.% based on the total weight of the injectable depot form. 18. The injectable depot form of claim 17, wherein the particles of cariprazine free base have a median particle size by volume (Dv50) in the range of 8 μm to 40 μm.