Pharmaceutical Compositions

Abstract

A pharmaceutical composition is provided. The pharmaceutical composition includes an active pharmaceutical ingredient (API), a polymer, and a solvent. The API includes cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof. The polymer includes polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof. A method of making the pharmaceutical composition is also provided.

Description

[Technical field]

[0001] The present disclosure relates to a pharmaceutical composition, and to a flowable pharmaceutical composition comprising cariprazine for use in an in-situ forming long-acting implant. [Background technology]

[0002] Cariprazine is a potent, orally active, third-generation antipsychotic. It acts as a dopamine D3-preferring D3 / D2 receptor partial agonist and a serotonin 5-HT1A receptor partial agonist, with the two major active metabolites being desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Cariprazine (Vraylar®) was approved for the treatment of schizophrenia and bipolar disorder by the U.S. Food and Drug Administration (FDA) in 2015 and the European Medicines Agency (EMA) in 2017.

[0003] There are currently several drawbacks to administering cariprazine for the treatment of schizophrenia in a once-daily oral immediate-release capsule. Patients with schizophrenia typically have low adherence to their treatment regimen. Treatment involving once-daily oral administration can result in irregular or inconsistent treatment, putting patients at risk for experiencing a psychotic relapse episode or crisis. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, antipsychotics are being developed to better control schizophrenia. Both a treatment that does not require caregivers to pay attention to daily dosing and a more stable plasma concentration level in patients after taking antipsychotics are desirable. [Means for solving the problem]

[0005] According to one embodiment of the present disclosure, a pharmaceutical composition is provided. The pharmaceutical composition comprises an active pharmaceutical ingredient (API), a polymer, and a solvent. The API comprises cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof. The polymer comprises polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof.

[0006] In some embodiments, the pharma- ceutically acceptable salt of cariprazine comprises cariprazine HCl. In some embodiments, in the mixture of cariprazine and a pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is 1:99 to 99:1. In some embodiments, in the mixture of cariprazine and a pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is 1:3 to 3:1 or 1:1 to 1:3. In some embodiments, in the mixture of cariprazine and a pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is 1:75 to 75:1, or 1:50 to 50:1, or 1:25 to 25:1, or 1:10 to 10:1, or 1:5 to 5:1. In some embodiments, the weight ratio of API in the pharmaceutical composition is 1% to 30%.

[0007] In some embodiments, the ratio of lactide to glycolide in the PLGA is between 48:52 and 100:0. In some embodiments, the polymer comprises more than one PLGA with various ratios of lactide to glycolide. In some embodiments, the concentration of the polymer in the pharmaceutical composition is between 150 mg / ml and 1000 mg / ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is between 340 mg / ml and 560 mg / ml. In some embodiments, the viscosity of the polymer is between 0.1 dl / g and 0.7 dl / g.

[0008] In some embodiments, the solvent comprises a water-miscible or partially water-miscible solvent. In some embodiments, the water-miscible solvent comprises dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water-miscible solvent comprises benzyl alcohol (BA).

[0009] In some embodiments, the weight ratio of API to polymer is 1:0.8 to 1:40. In some embodiments, the weight ratio of API to polymer is 1:0.9 to 1:39.6, or 1:0.9 to 1:30, or 1:0.9 to 1:20, or 1:0.9 to 1:10, or 1:0.9 to 1:5, or 1:0.9 to 1:3. In some embodiments, the weight ratio of polymer to solvent is 1:0.5 to 1:4. In some embodiments, the weight ratio of polymer to solvent is 1:0.5 to 1:3.5, or 1:0.5 to 1:3, or 1:0.5 to 1:2.5, or 1:0.5 to 1:2, or 1:0.5 to 1:1.5. In some embodiments, the weight ratio of API, polymer, and solvent is 1:0.8:0.4 to 1:40:160. In some embodiments, the weight ratio of API, polymer and solvent is from 1:0.8:0.6 to 1:30:110, or from 1:0.8:0.8 to 1:20:60, or from 1:0.8:1.0 to 1:10:10, or from 1:0.8:1.2 to 1:3:5, or from 1:0.9:1.35 to 1:3:4.5.

[0010] In some embodiments, the release rate of the pharmaceutical composition is less than 30% in the first 24 hours. In some embodiments, the release of the pharmaceutical composition lasts for more than 14 days. In some embodiments, the pharmaceutical composition is stored and used at a temperature between 4° C. and 25° C.

[0011] According to one embodiment of the present disclosure, there is provided a method of making a pharmaceutical composition, the method comprising the steps of: dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution; the API comprising cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof; dissolving a polymer in the solution under continuous stirring; the polymer comprising polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof;

[0012] Detailed description will be given in the following embodiments with reference to the accompanying drawings. [Brief description of the drawings]

[0013] The present invention can be more fully understood from the following detailed description and examples, taken in conjunction with the accompanying drawings.

[0014] [Figure 1] 1 shows the release profiles of pharmaceutical compositions with different solvents according to one embodiment of the present disclosure. [Diagram 2] 1 shows the release profile of a pharmaceutical composition having polymers of different intrinsic viscosity according to one embodiment of the present disclosure. [Diagram 3] 1 shows the release profiles of pharmaceutical compositions with different lactide (L) / glycolide (G) ratios in the polymer according to one embodiment of the present disclosure. [Figure 4] 1 shows the release profiles of pharmaceutical compositions with different weight ratios of PLGA polymer according to one embodiment of the present disclosure. [Diagram 5] FIG. 1 shows the release profile of a pharmaceutical composition having different end groups of the PLGA polymer according to one embodiment of the present disclosure. [Figure 6] 1 shows the release profiles of pharmaceutical compositions with different polymer to solvent ratios according to one embodiment of the present disclosure. [Figure 7] 1 shows the release profiles of pharmaceutical compositions having different weight ratios of drug in the pharmaceutical composition according to one embodiment of the present disclosure. [Figure 8]1 shows the release profiles of pharmaceutical compositions with different weight ratios of cariprazine to polymer according to one embodiment of the present disclosure. [Figure 9] 1 shows the release profiles of pharmaceutical compositions with different cariprazine salt forms according to one embodiment of the present disclosure. [Figure 10] 1 shows the plasma concentration-time curve of cariprazine after subcutaneous administration of a pharmaceutical composition to rats according to one embodiment of the present disclosure. [Figure 11] 1 shows the plasma concentration-time curve of cariprazine following oral administration of Vraylar® to rats, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] According to one embodiment of the present disclosure, a pharmaceutical composition is provided. The pharmaceutical composition comprises an active pharmaceutical ingredient (API), a polymer, and a solvent. The API comprises cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof. The polymer comprises polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof.

[0016] In some embodiments, the pharmaceutical composition may be an injectable pharmaceutical composition. In some embodiments, the pharmaceutical composition may be an in-situ forming implant after injection. In some embodiments, the pharmaceutical composition may provide extended release of the API, e.g., cariprazine. Upon contact with water and physiological fluids, a depot is formed and turns into a solid implant in situ, providing extended release of cariprazine over time. Upon contact with aqueous body fluids, the pharmaceutical composition solidifies to form a solid / semi-solid implant due to outward diffusion of the solvent. The drug release rate may be controlled by the ratio of different polymers.

[0017] In some embodiments, the pharma- ceutically acceptable salt of cariprazine may comprise cariprazine HCl. In some embodiments, in the mixture of cariprazine and a pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is about 1:99 to about 99:1. In some embodiments, in the mixture of cariprazine and a pharma- ceutical acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is about 1:1 to about 1:3. In some embodiments, in the mixture of cariprazine and a pharma- ceutical acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is about 1:75 to about 75:1, or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1. In some embodiments, the weight ratio of the API in the pharmaceutical composition is about 1% to about 30%. The weight ratio is expressed as a percentage of the weight of the API in the total weight of the pharmaceutical composition.

[0018] In some embodiments, the polymer may be a biodegradable and biocompatible controlled polymer. The polymer is degraded by in vivo enzymes. Therefore, the polymer is not toxic to the patient, does not accumulate in the human body, and does not induce an inflammatory response. The end groups of the polymer may be end-capped with an ester or a carboxylic acid. In some embodiments, the ratio of lactide to glycolide in the PLGA is about 48:52 to about 100:0. Different ratios of monomers in the PLGA result in different degradation times. For example, the higher the content of glycolide units, the shorter the time required for degradation. In some embodiments, the polymer may include more than one PLGA with various ratios of lactide and glycolide. In some embodiments, the lactide and glycolide in the PLGA are mixed in a ratio of about 48:52 to about 100:0. In some embodiments, the concentration of the polymer in the pharmaceutical composition is about 150 mg / ml to about 1000 mg / ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is about 340 mg / ml to about 560 mg / ml. In some embodiments, the viscosity of the polymer is about 0.1 dl / g to about 0.7 dl / g. In some embodiments, the viscosity of the polymer is about 0.14 dl / g to about 0.60 dl / g. In some embodiments, the viscosity of the polymer is about 0.14 dl / g to about 0.24 dl / g. Intrinsic viscosity is measured by a viscometer in chloroform at 25° C. and a concentration of 0.1% wt / v. Intrinsic viscosity is related to the molecular weight of the polymer. The higher the molecular weight of the polymer, the greater the viscosity of the liquid in which they are dissolved. In some embodiments, the average molecular weight of the polymer is about 4 kD to about 54 kD. In some embodiments, the average molecular weight of the polymer is about 4 kD to about 17 kD.

[0019] The solvent is used for injection into any living organism. The solvent is required to be unlikely to cause toxicity. The solvent is biocompatible and does not cause tissue necrosis or irritation at the injection site. The in-situ forming implant must rapidly diffuse from the polymer solution into the surrounding tissue when exposed to bodily fluids. The diffusion of the solvent causes precipitation of the polymer, and the formation of the implant effectively slows the release of the encapsulated active ingredient. In some embodiments, the solubility of the polymer in the solvent is greater than 1%. In some embodiments, the solvent may include a water-miscible solvent or a partially water-miscible solvent. In some embodiments, the water-miscible solvent may include dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water-miscible solvent may include benzyl alcohol (BA).

[0020] The weight ratio of the API to the polymer in the pharmaceutical composition can also contribute to controlling the initial release of the API from the implant. In some embodiments, the weight ratio of the API to the polymer is about 1:0.8 to about 1:40. In other embodiments, the weight ratio of the API to the polymer is about 1:0.9 to about 1:39.6, or about 1:0.9 to about 1:30, or about 1:0.9 to about 1:20, or about 1:0.9 to about 1:10, or about 1:0.9 to about 1:5, or about 1:0.9 to about 1:3. In some embodiments, the weight ratio of the polymer to the solvent is about 1:0.5 to about 1:4. In some embodiments, the weight ratio of the polymer to the solvent is about 1:0.5 to about 1:3.5, or about 1:0.5 to about 1:3, or about 1:0.5 to about 1:2.5, or about 1:0.5 to about 1:2, or about 1:0.5 to about 1:1.5. In some embodiments, the weight ratio of API to polymer to solvent is about 1:0.8:0.4 to about 1:40:160. In some embodiments, the weight ratio of API to polymer to solvent is about 1:0.8:0.6 to about 1:30:110, or about 1:0.8:0.8 to about 1:20:60, or about 1:0.8:1.0 to about 1:10:10, or about 1:0.8:1.2 to about 1:3:5, or about 1:0.9:1.35 to about 1:3:4.5.

[0021] In some embodiments, the pharmaceutical composition may further comprise an excipient, in some embodiments, the excipient may be, for example, an antioxidant.

[0022] In some embodiments, the release rate of the pharmaceutical composition in the first 24 hours may be less than about 30%. In some embodiments, the release rate of the pharmaceutical composition in the first 24 hours may be less than about 25%. In some embodiments, the release rate of the pharmaceutical composition in the first 24 hours may be less than about 20%. In some embodiments, the release rate of the pharmaceutical composition in the first 24 hours may be less than about 15%. In some embodiments, the release rate of the pharmaceutical composition in the first 24 hours may be less than about 10%. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 14 days. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 20 days. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 25 days. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 28 days. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 30 days. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 1.5 months. In some embodiments, the sustained release of the pharmaceutical composition may be for more than 3 months. In some embodiments, the sustained release of the pharmaceutical composition may be for greater than 6 months. In some embodiments, the pharmaceutical composition is stored and used at about 4° C. to about 25° C.

[0023] According to one embodiment of the present disclosure, there is provided a method of making a pharmaceutical composition, the method comprising the steps of: dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution; the API comprising cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof; dissolving a polymer in the solution under continuous stirring; the polymer comprising polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof;

[0024] In some embodiments, a method of making another pharmaceutical composition is provided, comprising the steps of: dissolving a polymer in a solvent under continuous stirring to form a solution; dispersing an active pharmaceutical ingredient (API) in the solution; EXAMPLES

[0025] Example 1 Methods for making pharmaceutical compositions and releasing drugs

[0026] The pharmaceutical composition was prepared as follows: first, cariprazine or a pharma- ceutical acceptable salt thereof was dispersed in a solvent selected from dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) or benzyl alcohol (BA) to form a suspension solution; then, under continuous stirring for 10 minutes, a PLGA polymer selected from 502H, 503H, 653H, 752H and 752S was dissolved in the suspension solution; the solution mixture was left overnight until the PLGA polymer was completely dissolved.

[0027] To measure the drug release profile of cariprazine, 50 mg of the pharmaceutical composition was injected into 10 mL of acetate buffer in a glass vial, capped, and placed in an incubator shaker at 37° C. and 100 rpm to form a medium. At predetermined time points (t=1, 2, 4, 7, 10, 14, 21, and 28 days), the medium was collected to measure the release of cariprazine. At each time point, 2 mL of medium was collected and replaced with 2 mL of fresh acetate buffer to form a dissolution sample. The dissolution sample was analyzed by high performance liquid chromatography (HPLC) under the conditions shown in Table 1.

[0028] [Table 1]

[0029] Example 2 A study on suitable solvents for use in pharmaceutical compositions

[0030] In the present invention, the solvent suitable for use in the pharmaceutical composition was first evaluated. It was known that the solubility of the polymer in the solvent can affect the formation of the pharmaceutical composition and the release of cariprazine from the pharmaceutical composition. Therefore, the solubility of the polymer in the solvent was evaluated to find the range suitable for use in the pharmaceutical composition.

[0031] In this example, the pharmaceutical compositions were as follows:

[0032] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in a water-miscible solvent, a partially water-miscible solvent, or a water-immiscible solvent to form a solution, and then dissolving PLGA (model number: 502H) polymer in the solution. Water-miscible solvents such as NMP and DMSO belong to the fast phase inversion system and highly polar solvents. Partially water-miscible solvents such as benzyl alcohol (BA) belong to the slow inverting system. Non-water-miscible solvents such as benzyl benzoate (BB) belong to the non-polar solvents. The pharmaceutical compositions with different solvents were named TF8-BB, TF8-BA, TF8-N, and TF8-D and are shown in Table 2.

[0033] [Table 2]

[0034] The results showed that the BB solvent was not suitable for use in the pharmaceutical composition because the PLGA polymer could not be well dissolved in the BB solvent. Meanwhile, the pharmaceutical composition with the BA solvent (TF8-BA) formed a very flexible and deformable implant. Figure 1 shows the release profiles of the pharmaceutical compositions with different solvents according to this example. As shown in Figure 1, the release profile of cariprazine released from the pharmaceutical composition with the DMSO solvent (TF8-D) was similar to that of the pharmaceutical composition with the NMP solvent (TF8-N). In addition, the accumulated release percentage of cariprazine released from TF8-D and TF8-N in one day was both less than 10%. The pharmaceutical compositions TF8-N and TF8-D showed a slower release rate over 14 days, so NMP and DMSO solvents were superior to BA solvent for use in the pharmaceutical composition. It was shown that the release of cariprazine was closely related to the properties of the solvent.

[0035] Example 3 Study of polymers with different intrinsic viscosities

[0036] In this example, the pharmaceutical compositions were as follows:

[0037] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in NMP solvent and then dissolving PLGA polymers with different intrinsic viscosities (IV). The model numbers of the PLGA polymers were 502H, 503H, 504H, and 505. Among them, the IV of the 502H polymer was the lowest, and the IV of the 505 polymer was the highest. The pharmaceutical compositions with different PLGA polymers were named 502H-TF8, 503H-TF8, 504H-TF8, and 505-TF8, and are shown in Table 3.

[0038] [Table 3]

[0039] Figure 2 shows the release profile of the pharmaceutical compositions with different inherent viscosity polymers according to this example. The results show that the release rate of cariprazine in the pharmaceutical composition with lower IV PLGA polymer (named 502H-TF8) was faster and sustained for 14 days compared to the pharmaceutical compositions with higher IV PLGA polymer (named 503H-TF8 and 504H-TF8). Meanwhile, the 505 polymer was not suitable for use in the pharmaceutical composition because it could not be dissolved in NMP solvent. The accumulated percentage of cariprazine released on the first, 14th and 28th days was 1.00%, 46.00% and 91.66% for pharmaceutical composition 502H-TF8, 2.94%, 10.15% and 78.78% for pharmaceutical composition 503H-TF8, and 2.96%, 8.20% and 70.80% for pharmaceutical composition 504H-TF8, respectively. Compared with pharmaceutical composition 503H-TF8, the NMP solvent in pharmaceutical composition 502H-TF8 containing a PLGA polymer with a lower IV may cause the NMP solvent to disperse more slowly, resulting in a slower initial release rate of cariprazine. In contrast, pharmaceutical composition 502H-TF8 containing a PLGA polymer with a lower IV showed a high release profile because its degradation rate was faster than that containing a PLGA polymer with a higher IV. In addition, pharmaceutical compositions containing PLGA polymers with lower intrinsic viscosity have a lower solution viscosity, making them easier to inject.

[0040] Example 4 Study on different lactide (L) / glycolide (G) ratios in polymers

[0041] Poly(lactide-glycolide) (PLGA) polymers are copolymers with different ratios of lactide (L) and glycolide (G) (L / G ratio). In this example, the effect of different L / G ratios in the polymers used in the pharmaceutical composition on the in vitro release of cariprazine was investigated. In this example, the pharmaceutical composition was as follows:

[0042] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in NMP solvent, and then dissolving different model numbers of PLGA polymers, such as 502H, 653H, 752H and 202H, respectively. The pharmaceutical compositions with different ratios of lactide and glycolide in the polymers were named B-502H-TF8-N, B-653H-TF8-N, B-752H-TF8-N, B-202H-TF8-N, respectively, and the combinations of polymers with different weights were named B-502H / 752H-TF8-N(1:1) and B-502H / 752H-TF8-N(1:3), as shown in Table 4.

[0043] [Table 4]

[0044] The results showed that the release rate of cariprazine from pharmaceutical compositions with higher L / G ratio was slower than that with lower L / G ratio. Figure 3 shows the release profile of pharmaceutical compositions with different L / G ratios in polymer according to this embodiment. As shown in Figure 3, the cumulative release rate of pharmaceutical composition with 502H PLGA polymer on 1st day, 14th day and 28th day was 1.00%, 46.00% and 91.66%, respectively. The cumulative release rate of pharmaceutical composition with 752H PLGA polymer on 1st day, 14th day and 28th day was 1.70%, 6.50% and 34.30%, respectively. In other groups, the cumulative release rate of pharmaceutical composition with 653H PLGA polymer on 1st day, 14th day and 28th day was 3.51%, 10.49% and 31.71%, respectively. The cumulative release rates of the pharmaceutical composition with 202H PLGA polymer on days 1, 14 and 28 were 3.58%, 9.90% and 11.95%, respectively. Thus, due to the presence of hydrophobic groups in the PLGA polymer, the implants formed from the pharmaceutical composition with the polymer with a higher L / G ratio degraded at a slower rate, which in turn led to a slower rate of water absorption and diffusion.

[0045] To investigate the effect of different weight ratios of PLGA polymer combinations on the release of cariprazine, pharmaceutical compositions were prepared using a combination of 752H PLGA polymer and 502H PLGA polymer. Figure 4 shows the release profiles of pharmaceutical compositions with different weight ratios of PLGA polymers according to this example. As shown in Figure 4, the release profiles of cariprazine from pharmaceutical compositions having different weight ratios of PLGA polymer combinations were between those having only 502H PLGA polymer and those having only 752H PLGA polymer. The cumulative release rate of cariprazine from pharmaceutical compositions B-502H-TF8-N, B-502H / 752H-TF8-N (1:1), B-502H / 752H-TF8-N (1:3) and B-752H-TF8-N exceeded 10.0% on days 10, 14, 14 and 21, respectively, and the cumulative release rate of cariprazine reached approximately 80.0% on days 28, 35, 42 and 56, respectively.

[0046] Example 5 Study of different end groups of PLGA polymer

[0047] In this example, the pharmaceutical compositions were as follows:

[0048] Pharmaceutical compositions containing cariprazine HCl were prepared by dispersing cariprazine in NMP solvent, and then dissolving PLGA polymers with different end groups. The model numbers of the PLGA polymers were 752H and 752S. The 752H polymer had a carboxylic acid end group, and the 752S polymer had an ester end group. The pharmaceutical compositions with different PLGA polymers were named C-752H-TF8 and C-752S-TF8, and are shown in Table 5.

[0049] [Table 5]

[0050] Figure 5 shows the release profiles of the pharmaceutical compositions with different end groups of PLGA polymers according to this embodiment. As shown in Figure 5, the initial drug release of cariprazine HCl from the pharmaceutical composition with PLGA polymer having ester end groups was lower than 30% at 24 hours and lasted for about 56 days. However, as shown in Figure 5, both the pharmaceutical compositions with PLGA polymer having carboxylic acid end groups or ester end groups could produce sustained release profiles of cariprazine HCl.

[0051] Example 6 Study of different polymer to solvent weight ratios

[0052] In this example, the pharmaceutical compositions were as follows:

[0053] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in NMP solvent and then dissolving 502H PLGA polymer. The weight ratios of polymer to solvent were 1:0.65, 1:0.8, 1:2, 1:4, and 1:9. The pharmaceutical compositions with different weight ratios of polymer to solvent were named TF15, TF16, TF17, TF18, and TF19 and are shown in Table 6.

[0054] [Table 6]

[0055] It was shown that pharmaceutical composition TF19 with a polymer to solvent weight ratio of 1:9 could not form an implant. The total formulation of each pharmaceutical composition in Table 6 was 500 mg, which is about 0.5 ml. This result showed that the concentration of polymer in the pharmaceutical composition to form an implant should be in the range of 174 mg / ml to 528 mg / ml. Figure 6 shows the release profiles of pharmaceutical compositions with different polymer to solvent ratios according to this embodiment. As shown in Figure 6, the cumulative release rate of cariprazine released from the pharmaceutical composition decreased with increasing polymer to solvent weight ratio. The cumulative release rate of cariprazine in 24 hours was below 10% for all pharmaceutical compositions. In addition, it was shown that a polymer to solvent weight ratio in the pharmaceutical composition ranging from 1:0.65 to 1:4 resulted in a sustained release profile of cariprazine.

[0056] Example 7 Study of different weight ratios of cariprazine in pharmaceutical compositions

[0057] In this example, the pharmaceutical compositions were as follows:

[0058] A pharmaceutical composition containing cariprazine was prepared by dispersing cariprazine in NMP solvent and then dissolving PLGA polymer model number 502H. The weight ratio of cariprazine in the pharmaceutical composition was 1-30% (w / w). The weight ratio of cariprazine was calculated from the weight of cariprazine and the total weight of the pharmaceutical composition. The pharmaceutical composition is shown in Table 7.

[0059] [Table 7]

[0060] Figure 7 shows the release profiles of the pharmaceutical compositions according to this embodiment, each having a different weight ratio of the drug in the pharmaceutical composition. As shown in Figure 7, pharmaceutical composition TF14 showed sustained release of cariprazine for about 49 days. A high weight ratio of cariprazine in the pharmaceutical composition leads to a smaller injection amount and higher patient compliance. There was no obvious difference in the release of cariprazine during the first 7 days between the pharmaceutical compositions containing different weight ratios of cariprazine ranging from 1% to 30%.

[0061] Example 8 Study of different weight ratios of cariprazine to polymer

[0062] In this example, the pharmaceutical compositions were as follows:

[0063] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in NMP solvent and then dissolving PLGA polymer 502H. The weight ratio of cariprazine to polymer was 1:0.9 to 1:39.6. The weight ratio was calculated from the weight of cariprazine and the weight of polymer. The pharmaceutical compositions with different weight ratios of cariprazine to polymer were named TF6, TF13 and TF14 and shown in Table 8.

[0064] [Table 8]

[0065] 8 shows the release profiles of the pharmaceutical compositions having different weight ratios of cariprazine to polymer according to this example. It was shown that the release of cariprazine from the pharmaceutical compositions having weight ratios of cariprazine to polymer ranging from 1:0.9 to 1:39.6 was sustained for 28 to 49 days.

[0066] Example 9 Study of different cariprazine salt forms used in pharmaceutical compositions

[0067] In this example, the pharmaceutical compositions were as follows:

[0068] Pharmaceutical compositions were prepared by dispersing cariprazine in base and HCl forms in NMP solvent, followed by dissolving PLGA polymer model number 752H, respectively. The pharmaceutical compositions with different salt forms of cariprazine are shown in Table 9 and named as B-752H-TF8-N, C-752H-TF8-N, B / C-752H-TF8-N(1:3) and B / C-752H-TF8-N(1:1).

[0069] [Table 9]

[0070] Figure 9 shows the release profile of the pharmaceutical composition with different forms of cariprazine salt according to this embodiment. As shown in Figure 9, the cumulative release rate of cariprazine HCl in the pharmaceutical composition in 24 hours was about 25%, which showed a faster release profile than the pharmaceutical composition containing cariprazine base. The difference in drug solubility of cariprazine HCl and cariprazine base may be the cause of affecting the release of cariprazine in the pharmaceutical composition. Cariprazine HCl has a higher solubility in acetic acid medium than cariprazine base. The release profile of cariprazine in the pharmaceutical composition having the combination of cariprazine base and cariprazine HCl was located between pharmaceutical compositions B-752H-TF8-N and C-752H-TF8-N.

[0071] Example 10 Stability of pharmaceutical compositions

[0072] In this example, the pharmaceutical compositions were as follows:

[0073] A pharmaceutical composition containing cariprazine was prepared by dispersing cariprazine in NMP solvent and then dissolving PLGA polymer 502H. The pharmaceutical composition was named TF20 and shown in Table 10. The dissolution test in the stability study was performed by acceleration dissolution method.

[0074] [Table 10]

[0075] Table 11 shows the stability study of pharmaceutical composition TF20 stored at 4°C, and Table 12 shows the stability study of pharmaceutical composition TF20 stored at room temperature (25°C). It is known that pharmaceutical compositions used for injection are usually stored at 4°C. However, the results show that the pharmaceutical composition of the present invention stored at room temperature (25°C) is still stable. Both the pharmaceutical compositions stored at 4°C and 25°C respectively meet the quality standard. In other words, the pharmaceutical composition of the present invention can be stored at room temperature, which can reduce the production cost.

[0076] [Table 11]

[0077] [Table 12]

[0078] Example 11 Pharmacokinetic study of pharmaceutical compositions in rats

[0079] The pharmaceutical composition was subcutaneously injected into 3 to 5 Wistar rats with an average body weight of 250 g. Approximately 75 mg / kg of cariprazine was subcutaneously injected into the dorsal thoracic region using a syringe with a 20G needle. The pharmaceutical composition is shown in Table 13. The drug plasma concentration after subcutaneous administration was evaluated. Plasma concentrations were obtained periodically at each time point from 0, 0.15, 0.21, 1 day, 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, and 56 days after injection, as well as plasma concentrations at 63 days, 70 days, 77 days, and 84 days, which are shown in Figure 10.

[0080] [Table 13]

[0081] Figure 10 shows the plasma concentration-time curve of cariprazine after subcutaneous administration of the pharmaceutical composition to rats according to one embodiment of this example. The pharmacokinetic (PK) parameters were calculated by WinNonlin software and shown in Table 14. It was found that the PK profile was related to the L / G ratio. The higher the L / G ratio in the pharmaceutical composition, the slower the release rate and the higher the maximum plasma concentration (C max However, polymers with different intrinsic viscosities have a lower T max (C max The time to reach 100 mg / kg / day was similar. In addition, the pharmaceutical compositions with different solvents (e.g., NMP or DMSO) had similar release profiles of cariprazine. Different solvents used in the pharmaceutical compositions, such as NMP and DMSO, were not the main cause of affecting the release of cariprazine. Different end group polymers used in the pharmaceutical compositions, such as 752H and 752S, were not the main cause of affecting the drug absorption in vivo. The results showed that the pharmaceutical compositions of the present invention had no burst release during 24 hours. The release of cariprazine from the pharmaceutical compositions can be sustained for longer than 14 days. More preferably, the release of cariprazine from the pharmaceutical compositions can be sustained for longer than 30 days, even longer than 3 months.

[0082] [Table 14]

[0083] Additionally, six rats were orally administered Vraylar® at a repeated oral dose of 0.27 mg / kg for 5 days as a control group. Blood samples were collected into tubes from the tail vein at 0.16, 0.5, 1, 2, 3, 5, 7, 10, and 24 hours on days 1 and 5, and at 1 and 3 hours on days 2 to 4 after oral administration. All blood samples were immediately centrifuged after collection to obtain plasma and then stored at -80°C until analysis. Plasma cariprazine extraction was performed by protein precipitation and analyzed by LC-MS / MS.

[0084] 11 shows the plasma concentration-time curve of cariprazine after oral administration of Vraylar® to rats according to one embodiment of this example. Pharmacokinetic (PK) parameters were calculated using WinNonlin software and are shown in Table 15. As shown in Table 15, the half-life (T 1 / 2 ) is 4.5 hours, and the half-life (T 1 / 2 ) ranged from 4.4 to 37.0 days.

[0085] [Table 15]

[0086] The results showed that the pharmaceutical composition of the present invention can realize a longer sustained release of cariprazine than the oral dosage form of cariprazine, and also showed that the pharmaceutical composition of the present invention can reduce the fluctuation of the plasma cariprazine concentration, and the release of cariprazine from the pharmaceutical composition can be sustained for at least 84 days.

[0087] While the present invention has been described by way of example and in terms of a preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiment. On the contrary, it is intended to cover various modifications and similar arrangements (as would be apparent to those skilled in the art). Thus, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.

Claims

1. 1. A pharmaceutical composition comprising: an active pharmaceutical ingredient (API) comprising cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof; a polymer comprising polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof; A solvent; 23. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable salt of cariprazine comprises cariprazine HCl.

3. 3. The pharmaceutical composition of claim 2, wherein in said mixture of cariprazine and said pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from 1:99 to 99:

1.

4. 3. The pharmaceutical composition of claim 2, wherein in said mixture of cariprazine and said pharma- ceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from 1:1 to 1:

3.

5. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of said API in said pharmaceutical composition is from 1% to 30%.

6. 2. The pharmaceutical composition of claim 1, wherein the ratio of lactide to glycolide in the PLGA is from 48:52 to 100:

0.

7. 7. The pharmaceutical composition of claim 6, wherein the polymer comprises more than one PLGA having various ratios of lactide and glycolide.

8. 2. The pharmaceutical composition of claim 1, wherein the concentration of the polymer in the pharmaceutical composition is from 150 mg / ml to 1000 mg / ml.

9. 2. The pharmaceutical composition of claim 1, wherein the concentration of said polymer in said pharmaceutical composition is from 340 mg / ml to 560 mg / ml.

10. 2. The pharmaceutical composition of claim 1, wherein the viscosity of the polymer is from 0.1 dl / g to 0.7 dl / g.

11. The pharmaceutical composition of claim 1 , wherein the solvent comprises a water-miscible or partially water-miscible solvent.

12. 12. The pharmaceutical composition of claim 11, wherein the water-miscible solvent comprises dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), or a combination thereof.

13. 12. The pharmaceutical composition of claim 11, wherein the partially water-miscible solvent comprises benzyl alcohol (BA).

14. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of said API to said polymer is 1:0.8 to 1:

40.

15. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of said polymer to said solvent is from 1:0.5 to 1:

4.

16. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of said API, said polymer and said solvent is from 1:0.8:0.4 to 1:40:

160.

17. 2. The pharmaceutical composition of claim 1, wherein the release rate of said pharmaceutical composition in the first 24 hours is less than 30%.

18. 2. The pharmaceutical composition of claim 1, wherein the sustained release of the pharmaceutical composition is for more than 14 days.

19. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is stored and used at a temperature between 4°C and 25°C.

20. 1. A method of making a pharmaceutical composition comprising the steps of: Dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution, said API comprising cariprazine, a pharma- ceutically acceptable salt of cariprazine, or a mixture thereof; dissolving a polymer in the solution under continuous stirring, the polymer comprising polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), polyglycolic acid (PGA), or a combination thereof; A method of making a pharmaceutical composition comprising:

Images