Injectable storage release formulation comprising cariprazine free base particles

Abstract

The present disclosure discloses an injectable storage release formulation and use thereof for treating mental disorders. The injectable storage and release formula comprises cariprazine free alkali particles and a pharmaceutically acceptable carrier. The median particle diameter (Dv50) of the cariprazine free base particles by volume ranges from 0.5 [mu] m to 100 [mu] m.

Description

Technical Field

[0001] The present invention relates to an injectable depot formulation containing cariprazine, and more particularly to an injectable depot formulation containing cariprazine free base particles. Background Art

[0002] Cariprazine is an atypical antipsychotic used for the treatment of adult schizophrenia and bipolar disorders. It is classified as a potent dopamine D3 and D2 receptor partial agonist and preferentially binds to the dopamine D3 receptor. Cariprazine has the potential to be superior to other marketed antipsychotics due to its high D3 / D2 selectivity and does not cause serious side effects associated with extrapyramidal symptoms. Oral administration of cariprazine effectively protects patients from orthostatic hypotension, a side effect commonly seen in patients taking other types of antipsychotics. In a 26-week Phase 3B clinical trial, patients taking cariprazine orally achieved lower PANSS-factor scores compared to risperidone, reflecting a substantial improvement in predominant negative symptoms of schizophrenia.

[0003] (Cariprazine capsules) is a prescription drug that was approved by the US FDA in 2015 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar 1 disorder, depressive episodes associated with bipolar 1 disorder [bipolar depression], and major depressive disorder (MDD). This capsule is a daily rapid-release formula with a unit content of 1.5 mg, 3.0 mg, 4.5 mg or 6.0 mg (the dosage depends on the efficacy and tolerability of the individual patient).

[0004] The active ingredient of the capsule is cariprazine hydrochloride, which has a The chemical structure shown and the chemical name are trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride. Cariprazine hydrochloride is a non-hygroscopic white to off-white crystalline solid and is mostly further converted in the liver to produce its two active metabolites (i.e., desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR)) which are equivalent to the parent compound due to their similarity in in vitro receptor profile, plasma protein binding affinity and brain penetration.

[0005] Injectable depot formulations have been widely used in the field of antipsychotic drugs, for example, Flupentixol decanoate ( Depot), Flufenamic Acid Fluphhenazine decanoate Haloperidoldecanoate Zuclopenthixol decanoate ( Depot), Aripiprazole monohydrate (Abilify ), Aripiprazole Lauroxil Olanzapinepamoate (Zyprexa ), Paliperidone palmitate (Invega Invega Invega ), and risperidone Kit). These injectable storage release formulations exhibit a slow release period of more than two weeks to six months. The long-lasting effect increases the duration of sustained release and reduces the frequency of dosing, thereby improving patient compliance when long-term treatment is required and reducing the relapse rate of psychiatric patients.

[0006] Long-acting injectable formulations of cariprazine have been developed in the form of non-aqueous suspensions, aqueous suspensions, or microspheres.

[0007] U.S. Patent Application Publication No. 20170196855A1 discloses a technology platform that can be used to prepare an extended-release formulation of cariprazine, wherein cariprazine is dispersed in a non-aqueous liquid carrier comprising a hydrophobic lipid, a hydrophilic organic solvent, or a combination of the two, and an amphiphilic agent. In this invention, a hydrophobic lipid carrier comprises glyceryl esters of C6-C24 fatty acids, sesame oil, and a hydrophilic organic solvent. The hydrophilic organic solvent comprises polyethylene glycol, propylene glycol, and / or glycerin. The amphiphilic agent comprises sorbitan esters or polyethoxylated sorbitan esters. In this invention, a large amount of hydrophilic organic solvent used in the non-aqueous carrier may cause irritation-related reactions at the injection site.

[0008] Chinese invention patent case No. 108261394B discloses an injectable aqueous suspension containing cariprazine hydrochloride as an active pharmaceutical ingredient, which can achieve long-term and high-dose effects for at least one week. This long-term effect can reduce the frequency of administration. However, if a large amount of sodium hydroxide is used to neutralize the pH value, cariprazine hydrochloride may cause the formulation to have an extremely acidic pH value and high osmotic pressure.

[0009] China Invention Patent Application Publication No. 112972388A discloses microsphere, microparticle and nanoparticle formulations of cariprazine dispersed in a polymer substrate material containing poly(d, l-lactide-glycolide) with a stable sustained release profile without the drug burst effect commonly seen in the initial substrate disintegration stage. High cost and difficulty in scale-up production are the main issues faced by the preparation process of cariprazine microsphere formulations.

[0010] Various pharmaceutically acceptable salts of cariprazine prepared by crystallization technology have been reported in the past in U.S. Patent No. 7943621B2. In this patent document, the salt forms of cariprazine are obtained by reacting cariprazine free base with different acids [including hydrogen chloride, hydrogen bromide, maleic acid, and methanesulfonic acid] in an aqueous phase or a non-aqueous phase. Among the different salts of cariprazine, cariprazine monohydrochloride salt can be easily isolated with the highest yield and the highest purity, which is suitable for industrial-scale production. Cariprazine hydrochloride can maintain stability for at least two years at normal ambient temperature whether in the form of solid or aqueous solution. Cariprazine hydrochloride has appropriate solubility, allowing it to be immediately released from an oral dosage form, and is therefore selected as (Cariprazine capsules) is the active ingredient.

[0011] However, in an injectable depot-release formulation, the active ingredient needs to be slowly released at the injection site to exert a long-lasting effect. Therefore, the water-soluble hydrochloride of cariprazine in solid form may not be suitable for development as an injectable depot-release formulation.

[0012] Therefore, those skilled in the art have devoted themselves to developing an improved injectable storage-release formulation containing cariprazine, which has sustained drug release, reduced dosing frequency, convenient administration, high patient compliance, and reduced risk of adverse reactions. Summary of the invention

[0013] It is an object of the present disclosure to provide an injectable storage-release formulation that alleviates at least one of the disadvantages of the prior art.

[0014] According to the present disclosure, the injectable depot formulation comprises cariprazine free base particles and a pharmaceutically acceptable carrier, wherein the median particle size by volume (Dv50) of the cariprazine free base particles ranges from 0.5 μm to 100 μm. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Other features and advantages of the present disclosure will become apparent in the following detailed description of embodiments with reference to the accompanying drawings. It should be noted that various features may not be drawn to scale.

[0016] Figure 1 : is a graph showing the cumulative release amount of cariprazine at different time points in the dissolution test for the injectable storage-release formulation of Example 1 below.

[0017] Figure 2 : is a graph showing the cumulative release amount of cariprazine at different time points in the dissolution test for the injectable storage-release formulation of Example 2 below.

[0018] Figure 3 : is a graph showing the cumulative release of cariprazine at different time points in the dissolution test for the injectable storage-release formulation of Example 3 below.

[0019] Figure 4 4 is a graph showing the cumulative release of cariprazine at different time points in a dissolution test for the injectable storage-release formulation of Example 4 below.

[0020] Figure 5 : is a graph showing the cumulative release amount of cariprazine at different time points in the dissolution test for the injectable storage-release formulation of Example 5 below.

[0021] Figure 6 : is a graph showing the cumulative release amount of cariprazine at different time points in the dissolution test for the injectable storage-release formulation of Example 6 below.

[0022] Figure 7 is a graph showing mean plasma concentrations of cariprazine in rats relative to time following intramuscular administration of an injectable depot-release formulation of the present disclosure in the first pharmacokinetic study of Example 7 below.

[0023] Figure 8 The second pharmacokinetic study in Example 7 below shows that the oral administration Plot of mean plasma concentrations of cariprazine in rats versus time following capsule formulation. DETAILED DESCRIPTION

[0024] Before the present disclosure is described in more detail, it should be noted that if any prior art publication is referred to herein, this citation does not constitute an admission that the publication forms part of the common general knowledge in the art.

[0025] For the purpose of this specification, it will be clearly understood that the word "comprising" means "including but not limited to," and that the word "comprises" has a corresponding meaning.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs. Those skilled in the art will recognize many methods and materials similar or equivalent to the methods and materials described herein, which methods and materials can be used to implement the present disclosure. Of course, the present disclosure is in no way limited to the methods and materials described.

[0027] The applicant first used the shake-flask method to study the solubility of cariprazine hydrochloride and cariprazine free base, and found that the water solubility of cariprazine hydrochloride (>5 mg / mL) was significantly higher than that of cariprazine free base (0.006 mg / mL). In addition, cariprazine hydrochloride is a water-soluble salt, which means that a certain amount of cariprazine has been pre-dissolved in the injectable storage-release formulation, which may cause dose dumping in patients. Considering that cariprazine free base with lower water solubility will therefore show better sustained-release behavior, cariprazine free base was selected as the active ingredient in the injectable storage-release formulation.

[0028] The sparingly soluble salts of cariprazine are considered to have relatively lower water solubility compared to the water-soluble salts of cariprazine. The preparation of sparingly soluble salts of cariprazine has many advantages, such as ease of synthesis in a single crystalline form, reduced risk of solvate formation from the organic solvent used during synthesis, ease of isolation in higher yields and purity, and even lower water solubility than the free base form of cariprazine in some cases. However, some adverse clinical cases have been monitored in patients receiving the long-acting formulation of the salt of cariprazine.

[0029] In addition, water-insoluble salts such as olanzapine pamoate have also been used to develop injectable depot formulations, which are marketed as Zyprexa However, some people who receive Zyprexa as an intramuscular injection every 2 to 4 weeks The post-injection delirium / sedation syndrome (PDSS) in patients with sedation should be caused by the rapid increase in the plasma concentration of olanzapine. In vitro solubility tests also confirmed that human plasma samples had an 18-fold increase in the solubilization effect of olanzapine pamoate compared to the pH 7.6 solution used to simulate the muscle tissue environment. Therefore, it is possible that the injectable storage-release formulation accidentally infiltrated into the injection site by blood, resulting in the unexpected rapid dissolution of olanzapine pamoate, causing the subsequent irreversible dissociation of olanzapine pamoate to form the parent drug olanzapine and pamoic acid, ultimately leading to an overdose of olanzapine. In order to avoid the risk of abnormally high plasma drug concentrations in such salt form formulations after injection, the injectable storage-release formulation disclosed in the present invention uses cariprazine free base as the active ingredient.

[0030] Therefore, the present disclosure provides an injectable storage-release formulation, which comprises: cariprazine free base particles and a pharmaceutically acceptable carrier. The median particle size by volume (Dv50) of the cariprazine free base particles ranges from 0.5 μm to 100 μm.

[0031] In certain embodiments, the cariprazine free base particles have a volume median particle size (Dv50) ranging from 2 μm to 40 μm, from 5 μm to 40 μm, from 10 μm to 40 μm, or from 20 μm to 40 μm.

[0032] In certain embodiments, the cariprazine free base particles have a volume median particle size (Dv50) ranging from 2 μm to 25 μm, from 5 μm to 25 μm, or from 10 μm to 25 μm.

[0033] The term "injectable storage-release formulation" as used herein encompasses a formulation in solid form (e.g., powder, cake, granules, etc.) containing an active ingredient but no water for injection, as well as a formulation in the form of a suspension in which the active ingredient is dispersed in water for injection.

[0034] The term "median particle size by volume" as used herein is X μm, which means that 50% of the volume of cariprazine free base particles are composed of particles with an equivalent diameter less than X μm.

[0035] In certain embodiments, the concentration of the cariprazine free base particles ranges from 4 wt % to 65 wt % based on the total weight of the injectable storage-release formulation.

[0036] In certain embodiments, the pharmaceutically acceptable carrier may include at least one of the following: a suspending agent, a buffer agent, and a tonicity agent.

[0037] In certain embodiments, the concentration of the suspending agent is in the range of 0.2 wt % to 10 wt % based on the total weight of the injectable storage-release formulation.

[0038] The term "suspending agent" as used herein refers to an excipient added to a disperse system in order to maintain particulate components in suspension or to avoid other forms of physical instability. Water-soluble polymers are the most common suspending agents, including methylcellulose, sodium carboxymethyl cellulose, and hydroxypropylmethylcellulose.

[0039] In certain embodiments, the suspending agent comprises a cellulose derivative, povidone, and polyethylene glycol. In an exemplary embodiment, the suspending agent is a cellulose derivative.

[0040] In some embodiments, the cellulose derivative comprises carboxymethylcellulose, sodium carboxymethyl cellulose, and methyl cellulose. In an exemplary embodiment, the cellulose derivative is sodium carboxymethyl cellulose.

[0041] In certain embodiments, the buffer concentration ranges from 0.01 wt % to 2 wt % based on the total weight of the injectable storage-release formulation.

[0042] The term "buffer" as used herein refers to salts of weak bases or weak acids used in pharmaceutical solution preparations to adjust the pH value of the formulated product formulation.

[0043] In certain embodiments, the buffer comprises sodium phosphate monobasic, disodium hydrogen phosphate, citric acid, sodium citrate, or a combination thereof. In an exemplary embodiment, the sodium phosphate monobasic is sodium hydrogen phosphate monohydrate, and the disodium hydrogen phosphate is disodium hydrogen phosphate anhydrous.

[0044] In certain embodiments, the concentration of the tonicity agent ranges from 0.01 wt % to 6.5 wt % based on the total weight of the injectable storage-release formulation.

[0045] The term "tonicity agent" as used herein means an agent used to adjust the osmotic pressure of a solution. The tonicity agent can be classified into dextrose, glycerin, mannitol, potassium chloride, and sodium chloride.

[0046] In certain embodiments, the tonicity agent comprises mannitol, glucose, sucrose, trehalose, and sodium chloride.

[0047] In certain embodiments, the pharmaceutically acceptable carrier further comprises a wetting agent.

[0048] The term "wetting agent" as used herein means an agent that can reduce the surface tension of a liquid and can spread and penetrate a solid surface. The term "wetting agent" can be used interchangeably with the term "surfactant" (mainly referring to amphiphilic surfactants).

[0049] In certain embodiments, the wetting agent concentration ranges from 0.01 wt % to 3 wt % based on the total weight of the injectable storage-release formulation.

[0050] In certain embodiments, the wetting agent comprises polysorbate, poloxamer, lecithin, sorbitan monolaurate, and polyoxyethylene fatty acid esters. In one exemplary embodiment, the wetting agent is poloxamer. In another exemplary embodiment, the wetting agent is lecithin.

[0051] In certain embodiments, the pharmaceutically acceptable carrier further comprises a pH-adjusting agent.

[0052] In certain embodiments, the pH-adjusting agent has a concentration ranging from 0.01 wt % to 1 wt % based on the total weight of the injectable storage-release formulation.

[0053] In certain embodiments, the pharmaceutically acceptable pH-adjusting agent comprises sodium hydroxide and hydrogen chloride.

[0054] Another injectable storage-release formulation is also provided in the present disclosure, which comprises cariprazine free base particles and a pharmaceutically acceptable carrier. The Dv50 of the cariprazine free base particles ranges from 0.5 μm to 100 μm. The pharmaceutically acceptable carrier includes at least one of the following: a suspending agent, a buffer, a tonicity agent, or a combination thereof. The suspending agent may be selected from cellulose derivatives, polyvinyl pyrrolidone, and polyethylene glycol; the buffer may be selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, or a combination thereof; and the tonicity agent may be selected from mannitol, glucose, sucrose, trehalose, and sodium chloride.

[0055] In an exemplary embodiment, the suspending agent is sodium carboxymethylcellulose; the buffer is sodium dihydrogen phosphate monohydrate and sodium dihydrogen phosphate anhydrous; and the tonicity agent is mannitol.

[0056] The present disclosure also provides a method for treating psychosis, schizophrenia with cognitive impairment, bipolar disorder, acute mania, mild-to-moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, paranoid and delusional disorders, dyskinetic disorders, neuroleptics-induced parkinsonism, tardive dyskinesia, eating disorders, attention deficit disorder, hyperactivity disorders in children, depression, anxiety, sexual dysfunction, and the like. The invention relates to a method for treating depressive dysfunction, sleep disorders, emesis, aggression, autism, major depressive disorder or drug abuse, comprising the step of administering the injectable storage-release formulation to a subject in need thereof.

[0057] The present disclosure will be further described with reference to the following examples, but it should be understood that the examples are only for illustration and should not be construed as limitations on the implementation of the present disclosure.

[0058] Example

[0059] Example 1. Evaluation of the effect of cariprazine free base particles of different median particle size by volume (Dv50) on the in vitro dissolution of an injectable depot formulation (IDF)

[0060] The injectable storage-release formulation containing cariprazine free base particles (as an active ingredient) can be prepared according to the content of each ingredient in the formulation shown in Table 1 below.

[0061] Table 1

[0062]

[0063] Specifically, first, a mechanical stirrer was used to mix the excipients (i.e., sodium carboxymethylcellulose, mannitol, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate) at a speed range of 300 to 500 rpm, and a carrier solution was obtained after stirring for 3 hours. Then, cariprazine free base particles (in the form of solid powder) were added to the carrier solution, and mixed at a speed of 200 rpm for 18 hours at 25° C. to obtain a milky white suspension. The milky white suspension was homogenized at 11,000 rpm for 10 minutes to obtain an initial suspension. Then, the initial suspension was subjected to a wet ball milling process at 15° C. using an agitator bead mill to reduce the size of the cariprazine free base particles, thereby obtaining a suspension containing cariprazine free base particles having a target particle size, i.e., the suspensions of experimental groups D1 to D5. Then, the particle size distribution of the cariprazine free base particles was measured by laser scattering analysis using a particle size analyzer (Malvern Mastersizer 3000), and the results were expressed as volumetric diameters Dv10, Dv50, and Dv90. The results are shown in Table 2 below.

[0064] The concentration of cariprazine free base particles in each group of suspensions was analyzed and determined using the HPLC method. The measured actual concentration of cariprazine free base particles (see Table 2) was further divided by its theoretical drug concentration to obtain the content value (in %) (see Table 2). Each group of suspensions was filled into a glass bottle, stoppered and sealed, and then moist heat sterilized at 121°C for 40 minutes (over-sterilization program setting) to obtain a ready-to-use aqueous suspension of an injectable storage-release formulation for the experimental groups D1 to D5. In addition, a previous reference listed drug (Reference Listed Drug, RLD) (i.e., Oral capsules) were used as a control group and named as comparison group 1.

[0065] Table 2

[0066]

[0067]

[0068] Referring to Table 2, the Dv50 of cariprazine free base particles in the injectable storage-release formulations of experimental groups D1 to D5 were approximately 2 μm, 8 μm, 10 μm, 20 μm and 40 μm, respectively, and their content values ​​ranged from 95% to 105%.

[0069] The conditions shown in Table 3 below were used to test the injectable storage-release formulations of experimental groups D1 to D5 and the injectable storage-release formulations of comparative group 1. The oral capsules were subjected to dissolution test. As shown in Table 4, the HPLC method was used to analyze the The concentration of cariprazine free base particles in the oral capsules was used to calculate the cumulative release of cariprazine in each group (%).

[0070] Table 3

[0071]

[0072] Table 4

[0073]

[0074]

[0075] Results are shown in Figure 1 And in Tables 5 and 6.

[0076] Table 5

[0077]

[0078] Table 6

[0079]

[0080]

[0081] Figure 1 The injectable storage-release formulations of experimental groups D1 to D5 and the comparative group 1 are shown in FIG. The cumulative release of cariprazine from oral capsules at different time points in the dissolution test is shown in Figure 5; Tables 5 and 6 provide their values ​​and coefficients of variation. Figure 1 As shown in Tables 5 and 6, compared with the comparative group 1 containing cariprazine hydrochloride Compared with the oral capsules, the dissolution tests of the injectable storage-release formulation experimental groups D1 to D5, which contained cariprazine free base particles with Dv50 of 2μm, 8μm, 10μm, 20μm and 40μm, respectively, showed lower cumulative release amounts of cariprazine (%) at different time points, indicating that the cariprazine free base particles of the injectable storage-release formulation experimental groups D1 to D5, compared with The cariprazine hydrochloride in the oral capsule comparison group 1 can be released more slowly. Specifically, in experimental groups D1 to D5, the cumulative release of cariprazine free base particles was 15 th Minutes below 80%, and within 120 th The cumulative release of cariprazine hydrochloride in the comparative group 1 reached 100% within 10 minutes of the dissolution test. These results indicate that the injectable storage-release formulation experimental groups D1 to D5 containing cariprazine free base particles are significantly higher than those containing cariprazine hydrochloride. Compared with group 1, the oral capsules showed improved drug release and had a better sustained release effect.

[0082] Refer to Figure 1 As shown in Tables 5 and 6, compared with the injectable storage-release formulations D1 to D4, the injectable storage-release formulation D5 of cariprazine free base particles having the largest Dv50 value has the lowest percentage of the cumulative release of cariprazine free base particles (i.e., the slowest dissolution rate) at different time points in the dissolution test, which indicates that the injectable storage-release formulation of cariprazine free base particles having a relatively large particle size has a relatively slow in vitro dissolution rate, thereby showing an improved sustained release effect.

[0083] Example 2. Evaluation of the effect of adding different types of suspending agents on the in vitro dissolution of injectable storage-release formulations

[0084] In order to determine the effect of adding different types of suspending agents [e.g., sodium carboxymethylcellulose, povidone K30 and / or polyethylene glycol 4000] on the dissolution of the injectable storage-release formulation of the present invention, three different injectable storage-release formulations containing cariprazine free base particles were prepared using the formulations shown in Table 7 below, thereby obtaining experimental groups SA1, SA2 and SA3. The injectable storage-release formulations of the experimental groups SA1, SA2 and SA3 were subjected to content analysis, particle size distribution determination and dissolution test, respectively, to analyze the cumulative release of cariprazine. For comparison purposes, an injectable storage-release formulation was prepared, which had the same composition as the injectable storage-release formulation of Example 1, and was named experimental group D6 (cariprazine free base particle concentration: 63 mg / mL). The injectable storage-release formulation of the experimental group D6 was also used for the above-mentioned analysis and dissolution test.

[0085] The results of the particle size distribution analysis are shown in Table 8, and the results of the dissolution test are shown in Figure 2 and Table 9.

[0086] Table 7

[0087]

[0088] Table 8

[0089]

[0090]

[0091] Referring to Table 8, the injectable storage-release formulation experimental groups SA1 to SA3 and experimental group D6 containing cariprazine free base particles all have similar particle size distribution characteristics. Specifically, the Dv50 values ​​of the cariprazine free base particles in each group range from 18 μm to 20 μm, and their content values ​​range from 90% to 105%.

[0092] Table 9

[0093]

[0094] Figure 2 is a graph showing the cumulative release of cariprazine from the injectable storage-release formulations of experimental groups SA1 to SA3 and experimental group D6 at different time points in the dissolution test; and Table 9 provides their values. Figure 2As shown in Table 9, the percentage of the cumulative release of cariprazine at different time points in the dissolution test of the injectable storage-release formula experimental group SA1 containing sodium carboxymethylcellulose as a suspending agent, the injectable storage-release formula experimental group SA2 containing sodium carboxymethylcellulose as a first suspending agent and povidone K30 as a second suspending agent, and the injectable storage-release formula experimental group SA3 containing polyethylene glycol 4000 as a suspending agent, had no significant difference from the experimental group D6, indicating that the injectable storage-release formulas of the experimental groups SA1 to SA3 and the experimental group D6 had similar sustained release characteristics. Therefore, the addition of povidone K30 or polyethylene glycol 4000 has no negative impact on the sustained release of the injectable storage-release formula containing cariprazine free base particles disclosed in the present invention.

[0095] Example 3. Evaluation of the effect of adding different types of wetting agents on the in vitro dissolution of injectable storage-release formulations

[0096] In order to determine the effect of adding different types of wetting agents [e.g., polysorbate 80, polysorbate 20 or poloxamer 188] on the dissolution of the injectable storage-release formulation of the present disclosure, three different injectable storage-release formulations containing cariprazine free base particles were prepared using the formulations shown in Table 10 below, thereby obtaining injectable storage-release formulations of experimental groups SA1+WA1, SA1+WA2 and SA1+WA3. In this example, the injectable storage-release formulation experimental group SA1 in Example 2 was used as a control. The injectable storage-release formulation experimental groups SA1+WA1 to SA1+WA3 and the experimental group SA1 were subjected to content analysis, particle size distribution determination and dissolution test, respectively, to calculate their cumulative release of cariprazine.

[0097] The results of the particle size distribution analysis are shown in Table 11, and the results of the dissolution test are shown in Figure 3 And Table 12.

[0098] Table 10

[0099]

[0100] Table 11

[0101]

[0102]

[0103] Referring to Table 11, the injectable storage-release formulations of each experimental group SA1+WA1, SA1+WA2, SA1+WA3 and experimental group SA1 showed that the Dv50 values ​​of cariprazine free base particles ranged from 10 μm to 20 μm; and the content values ​​ranged from 95% to 105%. However, according to the Dv10, Dv50 and Dv90 values ​​shown in Table 11, compared with the injectable storage-release formulation experimental group SA1 without a wetting agent, the injectable storage-release formulation experimental groups SA1+WA1, SA1+WA2 and SA1+WA3 containing polysorbate 80, polysorbate 20 and poloxamer 188 as wetting agents, respectively, all had cariprazine free base particles with smaller particle sizes.

[0104] Table 12

[0105]

[0106] Figure 3 is a graph showing the cumulative release of cariprazine at different time points in the dissolution test for the injectable storage-release formulation experimental groups SA1+WA1 to SA1+WA3 and the experimental group SA1; and Table 12 provides their values. Figure 3 As shown in Table 12, the percentage of the cumulative release of cariprazine at different time points in the dissolution test of the injectable storage-release formula experimental groups SA1+WA1, SA1+WA2 and SA1+WA3 was not significantly different from that of the injectable storage-release formula experimental group SA1 without a wetting agent. These results indicate that the injectable storage-release formulas of the experimental groups SA1, SA1+WA1, SA1+WA2 and SA1+WA3 all have similar sustained release characteristics. Therefore, the addition of polysorbate 80, polysorbate 20 or poloxamer 188 as a wetting agent has no negative impact on the sustained release of the injectable storage-release formula containing cariprazine free base particles disclosed in the present invention.

[0107] Example 4. Evaluation of the effect of adding two different suspending agents and a wetting agent on the in vitro dissolution of an injectable storage-release formulation

[0108] In order to determine the effect of adding two different suspending agents (e.g., sodium carboxymethylcellulose and povidone K30) and a single wetting agent [e.g., polysorbate 80, polysorbate 20 or lecithin] on the dissolution of the injectable storage-release formulation in the present disclosure, three different injectable storage-release formulations containing cariprazine free base particles were prepared using the formulations shown in Table 13 below, thereby obtaining injectable storage-release formulations of experimental groups SA2+WA1, SA2+WA2 and SA2+WA4. In this example, the injectable storage-release formulation experimental group SA2 in Example 2 was used as a control. The injectable storage-release formulation experimental groups SA2+WA1 to SA2+WA4 and the experimental group SA2 were subjected to content analysis, particle size distribution determination and dissolution test, respectively, to analyze their cumulative release of cariprazine.

[0109] The results of the particle size distribution analysis are shown in Table 14, and the results of the dissolution test are shown in Figure 4 And Table 15.

[0110] Table 13

[0111]

[0112]

[0113] Table 14

[0114]

[0115] Referring to Table 14, the injectable storage-release formulations of each experimental group SA2+WA1, SA2+WA2, SA2+WA4 and the experimental group SA2 showed that the Dv50 values ​​of cariprazine free base particles ranged from 10 μm to 20 μm, and the content values ​​ranged from 90% to 110%. However, according to the Dv10, Dv50 and Dv90 values ​​shown in Table 14, the injectable storage-release formulation experimental group SA2+WA4 containing lecithin as a wetting agent had cariprazine free base particles with smaller particle sizes compared to the injectable storage-release formulation of the experimental group SA2 (without a wetting agent) and the experimental groups SA2+WA1 and SA2+WA2 containing polysorbate 80 and polysorbate 20 as wetting agents, respectively.

[0116] Table 15

[0117]

[0118]

[0119] Figure 41 is a graph showing the cumulative release of cariprazine from the injectable storage-release formulations of the experimental groups SA2+W1 to SA2+W4 and the experimental group SA2 at different time points in the dissolution test; and Table 15 provides their values. Figure 4 As shown in Table 15, the percentage of the cumulative release of cariprazine at different time points in the dissolution test for the injectable storage-release formula experimental group SA2+WA1 containing polysorbate 80 as a wetting agent, the injectable storage-release formula experimental group SA2+WA2 containing polysorbate 20 as a wetting agent, and the injectable storage-release formula experimental group SA2+WA4 containing lecithin as a wetting agent, had no significant difference from the injectable storage-release formula experimental group SA2 containing the same suspending agent but without a wetting agent. These results indicate that the injectable storage-release formulas of the experimental groups SA2, SA2+WA1, SA2+WA2, and SA2+WA4 all have similar sustained release characteristics. Therefore, the addition of polysorbate or lecithin has no negative impact on the sustained release of the injectable storage-release formula containing cariprazine free base particles disclosed in the present invention.

[0120] Example 5. Evaluation of the effect of lyophilization process on in vitro dissolution of injectable storage-release formulations

[0121] In order to determine whether the freeze-dried form of the injectable storage-release formulation affects its stability, in this example, the injectable storage-release formulation of the experimental group SA1 in Example 2 (cariprazine free base particle concentration: 63 mg / mL) was subjected to a freeze-drying process according to the steps and conditions listed in Table 16 below, thereby obtaining the injectable storage-release formulation of the experimental group SA1_freeze-dried. The injectable storage-release formulation of the experimental group SA1 in Example 2 that was not subjected to the freeze-drying process was used as a control. The injectable storage-release formulation of the experimental group SA1_freeze-dried and the experimental group SA1 were subjected to content analysis, particle size distribution determination, and dissolution test as described in Example 1 to analyze their cumulative release of cariprazine.

[0122] The results of the particle size distribution analysis are shown in Table 17, and the results of the dissolution test are shown in Figure 5 And in Table 18.

[0123] Table 16

[0124]

[0125]

[0126] Table 17

[0127]

[0128] Referring to Table 17, the experimental group SA1_freeze-dried and the injectable storage-release formulation of the experimental group SA1 containing cariprazine free base particles showed almost similar particle size distribution characteristics. Specifically, the Dv50 values ​​of the cariprazine free base particles ranged from 10 μm to 11 μm, and the content values ​​ranged from 95% to 101%.

[0129] Table 18

[0130]

[0131] Figure 5 is a graph showing the cumulative release of cariprazine in experimental group SA1_freeze-dried and experimental group SA1 at different time points in the dissolution test; and Table 18 provides the values. Figure 5 As shown in Table 18, there was no significant difference in the percentage of cumulative release of cariprazine at different time points in the dissolution test between the injectable storage-release formulations of the experimental group SA1_freeze-dried and the experimental group SA1, indicating that the freeze-drying process would not have a negative impact on the release of cariprazine free base particles in the injectable storage-release formulation, and that the freeze-dried injectable storage-release formulation could maintain its stability.

[0132] Example 6. Evaluation of the effect of different concentrations of cariprazine free base particles on the in vitro dissolution of an injectable storage release formulation

[0133] In order to determine the effect of increasing the number and / or concentration of cariprazine free base particles on the dissolution of the injectable storage-release formulation of the present disclosure, four different injectable storage-release formulations containing cariprazine free base particles were prepared using the formulations shown in Table 19 below and according to the steps described in Example 1, thereby obtaining injectable storage-release formulations of experimental groups C1, C2, C3 and C4 with concentrations of 84 mg / mL, 187 mg / mL, 336 mg / mL and 481 mg / mL, respectively. In addition, the injectable storage-release formulation of experimental group C4 was further subjected to the freeze-drying treatment described in Example 5, and then the injectable storage-release formulation obtained by freeze-drying was re-dissolved with an appropriate amount of water, thereby obtaining injectable storage-release formulations of experimental groups C5 and C6 with concentrations of 548 mg / mL and 618 mg / mL, respectively. Thereafter, the injectable storage-release formulations of experimental groups C1 to C6 were subjected to dissolution tests as described in Example 1 to analyze their cumulative release of cariprazine.

[0134] The results of the dissolution test are shown in Figure 6 And Table 20.

[0135] Table 19

[0136]

[0137] Table 20

[0138]

[0139] Figure 6 FIG20 is a graph showing the cumulative release of cariprazine from the injectable storage-release formulations of experimental groups C1 to C6 at different time points in the dissolution test, and Table 20 provides their values. Figure 6 As shown in Table 20, there is no significant difference in the cumulative percentage of cariprazine released from the injectable storage-release formulations of the experimental groups C1 to C6 at different time points in the dissolution test, indicating that increasing the concentration of cariprazine free base particles will not have a negative impact on the release of the injectable storage-release formulation, and that the injectable storage-release formulation of the present invention has a high drug load characteristic.

[0140] Example 7. Evaluation of the effect of different Dv50 cariprazine free base particles on the detection of cariprazine in plasma in vivo

[0141] As the results in Example 1 show, the injectable storage-release formulation of the present invention containing cariprazine free base particles is more effective than that containing cariprazine hydrochloride. Oral capsules have a lower dissolution rate. Applicants performed pharmacokinetic studies using animal models to determine the effect of different Dv50 of cariprazine free base particles on their in vivo dissolution in rat plasma, and also compared rats that were intramuscularly administered with an injectable storage formulation containing cariprazine free base particles, and with oral administration with Variability of pharmacokinetic profiles among rats of capsule formulations.

[0142] A. First Pharmacokinetic Study Using the Injectable Storage-Release Formulation of the Disclosure:

[0143] As shown in Table 21 below, the four injectable storage-release formulations in this example are similar to the injectable storage-release formulation experimental groups D1, D3, D4 and D5 described in Example 1, and the preparation method refers to the steps described in Example 1.

[0144] Table 21

[0145] Injectable storage release formulation Dv50(μm) Experimental group D1 2 Experimental group D3 10 Experimental group D4 20 Experimental group D5 40

[0146] Wistar rats (6 to 8 weeks old) were housed in an animal room with an independent air-conditioning system and the following laboratory conditions: 12-hour light and 12-hour dark cycle, temperature controlled at 23°C ± 2°C, and relative humidity maintained at 40% to 70%. Rats were allowed ad libitum access to water and food. All experimental procedures involving experimental rats were in accordance with the relevant regulations on animal protection in Taiwan, China, and were performed in accordance with the guidelines of Animal Care Committee, Taiwan, China.

[0147] The rats were randomly divided into four groups, namely, experimental group D1, experimental group D3, experimental group D4, and experimental group D5, wherein the number of rats in the experimental groups D1 and D3 was 6, respectively, and the number of rats in the experimental groups D4 and D5 was 4, respectively.

[0148] The rats in experimental groups D1 to D5 were administered intramuscularly with the injectable depot-release formulations of experimental groups D1 to D5. The intramuscular administration was performed by injecting an aqueous suspension containing cariprazine free base particles into the thigh muscle of each rat at a concentration of 28 mg / kg in a single dose. st Days (i.e., 10 days after administration) th and 30 th minutes, and 1 st , 2 nd , 3 rd , 5 th , 7 th , 10 th and 24 th hours), and in 3 rd , 5 th , 7 th , 10 th , 14 th ,twenty one th With 28 th Blood samples were collected from the tail vein of each rat on each day and then analyzed using ( 5500 LC-MS / MS system) (AB Sciex) was used to analyze the mean plasma concentration. th and 42 nd Blood samples were collected on the 2nd day after administration, and for the rats in the experimental groups D4 and D5, blood samples were collected on the 35th day after administration. th , 42 nd , 49 th With 56 th Blood samples were collected on the day.

[0149] Table 22

[0150]

[0151]

[0152] Figure 7 is a graph showing the mean plasma concentration of cariprazine in rats of experimental groups D1, D3, D4 and D5 relative to time after intramuscular administration of the injectable storage-release formulation of the present disclosure in the first pharmacokinetic study; and Table 22 provides the pharmacokinetic parameters measured by the first pharmacokinetic study. Figure 7 As shown in the results, after intramuscular administration of the injectable storage-release formulation containing cariprazine free base particles to rats in experimental groups D1, D3, D4 and D5, the average plasma concentration of cariprazine gradually reached a peak after 100 hours and then slowly decreased, and cariprazine was still continuously detected in the plasma of rats after the 28-day test of the first pharmacokinetic study. In particular, cariprazine was still detected in the plasma of rats until 42 days after administration. nd Cariprazine was still detectable in the plasma of rats in the experimental group D3, and it was not until 56 days after administration that cariprazine was detected. th Cariprazine was still detected in the plasma of rats in the experimental groups D4 and D5. In addition, as shown in Table 22, the T 1 / 2 The values ​​corresponded to the increase in the size of cariprazine free base particles in these groups; and the high AUC values ​​were measured in experimental groups D1, D3, D4, and D5, respectively. all The values ​​suggest that the cariprazine free base particles released from the injectable storage-release formulation have good bioavailability. These results indicate that the injectable storage-release formulations containing cariprazine free base particles with a Dv50 range of 2 μm to 40 μm have been confirmed to maintain a sustained release effect in vivo for at least 28 days.

[0153] B. Use Second Pharmacokinetic Study of Capsules:

[0154] Six Wistar rats (6 to 8 weeks old) were grouped into Comparative Group 1. The capsules were dissolved in 0.1% acetic acid to prepare an aqueous suspension containing cariprazine hydrochloride, which was then orally administered to the rats in the comparison group 1 by oral gavage at a concentration of 1 mg / kg per rat. th with 30 th minutes, and 1 st , 2 nd , 3 rd , 5 th , 7th , 10 th and 24 th Hours later, blood samples were collected from the tail vein of each rat, and the mean plasma concentration was analyzed according to the procedure described in item A above.

[0155] Table 23

[0156]

[0157] Figure 8 In the second pharmacokinetic study, oral administration of Table 23 provides a graph comparing the mean plasma concentrations of cariprazine in rats of Group 1 versus time following capsule formulation; and Table 24 provides the pharmacokinetic parameters measured by the second pharmacokinetic study. Figure 8 As shown, in the administration of a drug containing cariprazine hydrochloride After administration of the capsule, the average plasma concentration of cariprazine reached a peak within 2 hours, then rapidly decreased within 10 hours; and 24 hours after administration, cariprazine was no longer detected in the plasma of the rats in the comparison group 1. 1 / 2 The values ​​(see Table 23) were relatively smaller than those of experimental groups D1, D3, D4 and D5 (see Table 22). This result indicates that compared with the injectable storage-release formulation containing cariprazine free base particles administered intramuscularly to rats as described in item A of this embodiment, the oral administration of the cariprazine hydrochloride containing cariprazine hydrochloride The capsules failed to show a sustained release effect.

[0158] In summary, these results show that the size of cariprazine free base particles is a key factor in regulating the sustained release effect of the injectable storage-release formulation containing cariprazine free base particles of the present disclosure. The increase in the size of cariprazine free base particles leads to a slower release from the injectable storage-release formulation, resulting in a slower in vitro dissolution rate. Because the injectable storage-release formulation containing cariprazine free base particles of the present disclosure also shows a controllable in vivo sustained release effect, it is expected to be used as an anti-psychotic drug with reduced dosing frequency.

[0159] In the above description, for the purpose of illustration, many specific details have been described for a thorough understanding of the specific embodiments. However, it will be apparent to those skilled in the art that one or more other specific embodiments may be implemented without some of these specific details. It should also be understood that "one embodiment", "an embodiment", an embodiment with a sequence number, etc., referred to throughout this specification, means that a particular feature, structure or characteristic may be included in the implementation of the present disclosure. It should be further understood in the description that, in order to streamline the present disclosure and facilitate the understanding of various different inventive aspects, various different features are sometimes grouped together in a single specific embodiment, figure or description thereof, and when implementing the present disclosure, if appropriate, one or more features or specific details from one specific embodiment may be implemented together with one or more features or specific details from another specific embodiment.

[0160] While the present disclosure has been described with reference to specific embodiments which are considered to be exemplary, it is to be understood that the disclosure is not limited to the specific embodiments disclosed, but is intended to cover a variety of different configurations that are to be included in the spirit and scope of the broadest interpretation, including all such modifications and equivalent configurations.

Claims

1. An injectable storage-release formulation comprising: cariprazine free base particles and a pharmaceutically acceptable carrier, wherein the volume median particle size (Dv50) of the cariprazine free base particles ranges from 0.5 μm to 100 μm.

2. The injectable storage-release formulation according to claim 1, wherein the volume median particle size (Dv50) of the cariprazine free base particles ranges from 2 μm to 40 μm.

3. The injectable storage-release formulation according to claim 1, wherein Based on the total weight of the injectable storage-release formulation, the concentration of the cariprazine free base particles ranges from 4 wt % to 65 wt %.

4. The injectable storage-release formulation according to claim 1, wherein the pharmaceutically acceptable carrier comprises at least one of the following: a suspending agent, a buffer and a tonicity agent.

5. The injectable storage-release formulation according to claim 4, wherein Based on the total weight of the injectable storage-release formulation, the concentration of the suspending agent ranges from 0.2 wt % to 10 wt %.

6. The injectable storage-release formulation according to claim 4, wherein the suspending agent comprises a cellulose derivative, povidone, polyethylene glycol, or a combination thereof.

7. The injectable depot formulation according to claim 6, wherein the cellulose derivative comprises carboxymethyl cellulose, sodium carboxymethyl cellulose, and methyl cellulose.

8. The injectable storage-release formulation according to claim 4, wherein The concentration of the buffer is in the range of 0.01 wt % to 2 wt % based on the total weight of the injectable storage-release formulation.

9. The injectable stored-release formulation according to claim 4, wherein the buffer comprises sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, or a combination thereof.

10. The injectable storage-release formulation according to claim 4, wherein The concentration of the tonicity agent ranges from 0.01 wt % to 6.5 wt % based on the total weight of the injectable storage-release formulation.

11. The injectable depot formulation according to claim 4, wherein the tonicity agent comprises mannitol, glucose, sucrose, trehalose, and sodium chloride.

12. The injectable depot formulation according to claim 4, wherein the pharmaceutically acceptable carrier further comprises a wetting agent.

13. The injectable storage-release formulation according to claim 12, wherein The concentration of the wetting agent ranges from 0.01 wt % to 3 wt % based on the total weight of the injectable storage-release formulation.

14. The injectable storage-release formulation according to claim 12, wherein the wetting agent comprises poly BCPI-240373 Sorbitan esters, poloxamer, lecithin, sorbitan monolaurate, and polyoxyethylene fatty acid esters.

15. The injectable depot formulation according to claim 4, wherein the pharmaceutically acceptable carrier further comprises a pH adjuster.

16. The injectable storage-release formulation according to claim 15, wherein The pH-adjusting agent has a concentration ranging from 0.01 wt % to 1 wt % based on the total weight of the injectable storage-release formulation.

17. The injectable depot formulation according to claim 15, wherein the pH-adjusting agent comprises sodium hydroxide and hydrogen chloride.

18. A method for treating psychosis, schizophrenia with cognitive impairment, bipolar disorder, acute mania, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, psychotic depression, mania, delusions and delusional disorders, movement disorders, psychotic stabilizer-induced Parkinson's syndrome, tardive dyskinesia, eating disorders, attention deficit disorder, childhood hyperactivity disorder, depression, anxiety, sexual dysfunction, sleep disorders, vomiting, aggression, autism, major depressive disorder or drug abuse, comprising the step of administering an injectable depot formulation according to claim 1 to a subject in need thereof.

19. An injectable storage-release formulation comprising cariprazine free base particles and a pharmaceutically acceptable carrier, wherein the volume median particle size (Dv50) of the cariprazine free base particles ranges from 0.5 μm to 100 μm, wherein the pharmaceutically acceptable carrier comprises at least one of the following: a suspending agent, a buffer, a tonicity agent, and a combination thereof, wherein the suspending agent comprises a cellulose derivative, povidone and polyethylene glycol, the buffer comprises sodium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid and sodium citrate, and the tonicity agent comprises mannitol, glucose, sucrose, trehalose and sodium chloride.

20. The injectable storage-release formulation according to claim 19, wherein the volume median particle size (Dv50) of the cariprazine free base particles ranges from 8 μm to 40 μm.

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