Pharmaceutical composition

Abstract

A pharmaceutical composition is provided that includes an active pharmaceutical ingredient (API), a polymer, and a solvent. The API includes cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof. The polymer includes polylactic acid (PLA), a lactic acid-glycolic acid copolymer (PLGA), polyglycolic acid (PGA), or a combination thereof. The invention also provides a preparation method of the pharmaceutical composition.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, and more particularly to a flowable pharmaceutical composition comprising cariprazine and serving as an in situ formed long-acting implant. Background Art

[0002] Cariprazine is a third-generation, orally active, potent antipsychotic. Cariprazine is a partial activator of dopamine D3 / D2 receptors and a partial activator of serotonin 5-HT1A receptors that prefers D3 receptors. It has two major active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Cariprazine was approved by the U.S. Food and Drug Administration (FDA) in 2015 and the European Medicines Agency (EMA) in 2017. Used to treat schizophrenia and bipolar disorder.

[0003] Currently, there are some disadvantages to once-daily oral cariprazine immediate-release capsules for the treatment of schizophrenia. Patients with schizophrenia often have poor compliance with treatment regimens. Once-daily oral dosing may lead to irregular or inconsistent treatment, which may lead to the risk and crisis of psychotic episodes and relapses.

[0004] Therefore, the development of antipsychotic drugs is aimed at better controlling schizophrenia. Treatments that do not require caregivers to pay attention to daily dosing and that maintain more stable blood levels of antipsychotic drugs are highly desirable. Summary of the invention

[0005] According to one embodiment of the present invention, a pharmaceutical composition is provided, comprising: an active pharmaceutical ingredient (API), a polymer, and a solvent. The active pharmaceutical ingredient comprises cariprazine, a pharmaceutically 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 pharmaceutically acceptable salt of cariprazine includes cariprazine hydrochloride (cariprazine HCl). In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride is 1:99 to 99:1. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride is 1:3 to 3:1 or 1:1 to 1:3. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride 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 the active pharmaceutical ingredient (API) in the pharmaceutical composition is 1% to 30%.

[0007] In some embodiments, in the lactic acid-glycolic acid copolymer (PLGA), the ratio of lactic acid to glycolic acid is 48:52 to 100:0. In some embodiments, the polymer comprises more than one lactic acid-glycolic acid copolymer (PLGA) having various lactic acid to glycolic acid ratios. In some embodiments, the concentration of the polymer in the pharmaceutical composition is 150 mg / ml to 1000 mg / ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is 340 mg / ml to 560 mg / ml. In some embodiments, the viscosity of the polymer is 0.1 dl / g to 0.7 dl / g.

[0008] In some embodiments, the solvent includes a water-soluble solvent or a partially water-soluble solvent. In some embodiments, the water-soluble solvent includes dimethyl-sulfoxide (DMSO), N-methylpyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water-soluble solvent includes benzylalcohol (BA).

[0009] In some embodiments, the weight ratio of the active pharmaceutical ingredient (API) to the polymer is 1:0.8 to 1:40. In some embodiments, the weight ratio of the active pharmaceutical ingredient (API) to the 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 the polymer to the solvent is 1:0.5 to 1:4. In some embodiments, the weight ratio of the polymer to the 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 the active pharmaceutical ingredient (API), polymer, and solvent is 1:0.8:0.4 to 1:40:160. In some embodiments, the weight ratio of active pharmaceutical ingredient (API), polymer, and solvent is 1:0.8:0.6 to 1:30:110 or 1:0.8:0.8 to 1:20:60 or 1:0.8:1.0 to 1:10:10 or 1:0.8:1.2 to 1:3:5 or 1:0.9:1.35 to 1:3:4.5.

[0010] In some embodiments, the release percentage of the pharmaceutical composition within the first 24 hours is less than 30%. In some embodiments, the sustained release of the pharmaceutical composition exceeds 14 days. In some embodiments, the pharmaceutical composition is stored at a temperature of 4°C to 25°C.

[0011] According to one embodiment of the present invention, a method for preparing a pharmaceutical composition is provided, comprising the following steps: dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution. The active pharmaceutical ingredient (API) includes cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof. Under continuous stirring, a polymer is dissolved in the solution. The polymer includes polylactic acid (PLA), poly(lactide-co-glycolide), PLGA, polyglycolic acid (PGA), or a combination thereof.

[0012] Embodiments are given in the following examples with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The present invention may be more fully understood by reading the following detailed description and examples and referring to the accompanying drawings, in which:

[0014] Figure 1 is a diagram showing release curves of a pharmaceutical composition with different solvents according to an embodiment of the present invention;

[0015] Figure 2 is a release profile of a pharmaceutical composition of polymers having different intrinsic viscosities according to an embodiment of the present invention;

[0016] Figure 3 is a graph showing the release profiles of the pharmaceutical composition of polymers having different lactic acid (L) / glycolic acid (G) ratios according to one embodiment of the present invention;

[0017] Figure 4 is a diagram showing release curves of pharmaceutical compositions having different weight ratios of poly(lactic acid-co-glycolic acid) (PLGA) according to an embodiment of the present invention;

[0018] Figure 5 is a diagram showing the release curve of a pharmaceutical composition of a poly(lactic acid-glycolic acid) copolymer (PLGA) having different terminal groups according to an embodiment of the present invention;

[0019] Figure 6 is a diagram showing release profiles of pharmaceutical compositions having different polymer to solvent ratios according to an embodiment of the present invention;

[0020] Figure 7 is a diagram showing release profiles of pharmaceutical compositions having different drug weight ratios according to an embodiment of the present invention;

[0021] Figure 8 is a diagram showing release profiles of pharmaceutical compositions having different weight ratios of cariprazine to polymer according to an embodiment of the present invention;

[0022] Fig. 9 is a diagram showing the release profile of a pharmaceutical composition having different cariprazine salt forms according to an embodiment of the present invention;

[0023] Fig.10 is a diagram showing a plasma concentration-time curve of cariprazine after subcutaneous administration of the pharmaceutical composition to rats according to an embodiment of the present invention; and

[0024] Fig.11 According to one embodiment of the present invention, rats orally Plasma concentration-time curve of cariprazine after administration. DETAILED DESCRIPTION OF THE INVENTION

[0026] According to one embodiment of the present invention, a pharmaceutical composition is provided, comprising: an active pharmaceutical ingredient (API), a polymer, and a solvent. The active pharmaceutical ingredient comprises cariprazine, a pharmaceutically 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.

[0027] In some embodiments, the pharmaceutical composition may be an injectable pharmaceutical composition. In some embodiments, the pharmaceutical composition may be an implant formed in situ after injection. In some embodiments, the pharmaceutical composition may provide extended release of an active pharmaceutical ingredient (API), for example, cariprazine. A depot is formed when in contact with water and body fluids, and is converted into a solid implant in situ, providing an extended release time of cariprazine. Once the pharmaceutical composition contacts aqueous body fluids, it solidifies to form a solid / semi-solid implant due to outward diffusion of the solvent. The drug release rate can be controlled by different polymer ratios.

[0028] In some embodiments, the pharmaceutically acceptable salt of cariprazine may include cariprazine hydrochloride (cariprazine HCl). In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride is about 1:99 to 99:1. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride is about 1:3 to 3:1 or 1:1 to 1:3. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine hydrochloride is about 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 the active pharmaceutical ingredient (API) in the pharmaceutical composition is about 1% to 30%. The weight ratio is expressed as the percentage of the weight of the active pharmaceutical ingredient (API) to the total weight of the pharmaceutical composition.

[0029] In some embodiments, the polymer may be a biodegradable and biocompatible polymer with controllable properties. The polymer is degraded by enzymes in the body. Therefore, the polymer is non-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 ester or carboxylic acid end-capped. In some embodiments, in the lactic acid-glycolic acid copolymer (PLGA), the ratio of lactic acid (lactide) to glycolic acid (glycolide) is approximately 48:52 to 100:0. Different monomer ratios in the lactic acid-glycolic acid copolymer (PLGA) result in different degradation times, for example, the higher the glycolic acid unit content, the shorter the time required for degradation. In some embodiments, the polymer may include more than one lactic acid-glycolic acid copolymer (PLGA) with various lactic acid and glycolic acid ratios. In some embodiments, the lactic acid and glycolic acid in the lactic acid-glycolic acid copolymer (PLGA) are mixed in a ratio of approximately 48:52 to 100:0. In some embodiments, the concentration of the polymer in the pharmaceutical composition is approximately 150 mg / ml to 1000 mg / ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is about 340 mg / ml to 560 mg / ml. In some embodiments, the viscosity of the polymer is about 0.1 dl / g to 0.7 dl / g. In some embodiments, the viscosity of the polymer is about 0.14 dl / g to 0.60 dl / g. In some embodiments, the viscosity of the polymer is about 0.14 dl / g to 0.24 dl / g. The intrinsic viscosity is measured by a viscometer at 25°C and a concentration of 0.1% (wt / v) in chloroform. The intrinsic viscosity is related to the molecular weight of the polymer. Polymers with higher molecular weights increase 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 54 kD. In some embodiments, the average molecular weight of the polymer is about 4 kD to 17 kD.

[0030] The solvent is used for injection into any living body. The requirement of the solvent is that it is not easy to cause toxicity. The solvent is biocompatible and will not cause tissue necrosis or irritation at the injection site. For implants formed in situ, when exposed to body fluids, the solvent should diffuse rapidly from the polymer solution to the surrounding tissue. Solvent diffusion causes polymer precipitation, and the implant preparation effectively causes the encapsulated active ingredient to be continuously released. 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 dimethyl-sulfoxide (DMSO), N-methyl pyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water miscible solvent may include benzylalcohol (BA).

[0031] In the pharmaceutical composition, the weight ratio of the active pharmaceutical ingredient (API) to the polymer also helps control the initial release of the active pharmaceutical ingredient (API) from the implant. In some embodiments, the weight ratio of the active pharmaceutical ingredient (API) to the polymer is about 1:0.8 to 1:40. In another embodiment, the weight ratio of the active pharmaceutical ingredient (API) to the polymer is about 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 the polymer to the solvent is about 1:0.5 to 1:4. In some embodiments, the weight ratio of the polymer to the solvent is about 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 the active pharmaceutical ingredient (API), polymer, and solvent is about 1:0.8:0.4 to 1:40: 160. In some embodiments, the weight ratio of the active pharmaceutical ingredient (API), polymer, and solvent is about 1:0.8:0.6 to 1:30:110 or 1:0.8:0.8 to 1:20:60 or 1:0.8:1.0 to 1:10:10 or 1:0.8:1.2 to 1:3:5 or 1:0.9:1.35 to 1:3:4.5.

[0032] In some embodiments, the pharmaceutical composition may further include an excipient. In some embodiments, the excipient may be, for example, an antioxidant.

[0033] In some embodiments, the percentage of release of the pharmaceutical composition in the first 24 hours may be less than about 30%. In some embodiments, the percentage of release of the pharmaceutical composition in the first 24 hours may be less than about 25%. In some embodiments, the percentage of release of the pharmaceutical composition in the first 24 hours may be less than about 20%. In some embodiments, the percentage of release of the pharmaceutical composition in the first 24 hours may be less than about 15%. In some embodiments, the percentage of release 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 exceed 14 days or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 20 days or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 25 days or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 28 days or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 30 days or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 1.5 months or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 3 months or more. In some embodiments, the sustained release of the pharmaceutical composition may exceed 6 months or more. In some embodiments, the pharmaceutical composition is stored at a temperature of about 4°C to 25°C.

[0034] According to one embodiment of the present invention, a method for preparing a pharmaceutical composition is provided, comprising the following steps: dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution. The active pharmaceutical ingredient (API) includes cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof. Under continuous stirring, a polymer is dissolved in the solution. The polymer includes polylactic acid (PLA), poly(lactide-co-glycolide), PLGA, polyglycolic acid (PGA), or a combination thereof.

[0035] According to one embodiment of the present invention, a method for preparing a pharmaceutical composition is provided, comprising the following steps: dissolving a polymer in a solvent under continuous stirring to form a solution, and dispersing an active pharmaceutical ingredient (API) in the solution.

[0036] Example 1

[0037] Preparation of pharmaceutical composition and drug release method

[0038] The pharmaceutical composition is prepared as follows. First, cariprazine or a pharmaceutically acceptable salt thereof is dispersed in a solvent selected from dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or benzyl alcohol (BA) to form a suspension. Subsequently, different types of lactic acid-glycolic acid copolymer (PLGA) (models: 502H, 503H, 653H, 752H, and 752S) are selected and dissolved in the suspension under continuous stirring for 10 minutes. The mixture solution is placed overnight until the lactic acid-glycolic acid copolymer (PLGA) is completely dissolved.

[0039] To measure the drug release profile of cariprazine, 50 mg of the pharmaceutical composition was injected into a glass vial containing 10 mL of acetate buffer, capped and placed in a shaking incubator at 37° C., 100 rpm to form a medium. At a predetermined time point (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 the 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 described in Table 1.

[0040] Table 1

[0041] Method Parameters illustrate wavelength 215nm Injection volume 20μL flow 1.0mL / min Analysis time 13 minutes (Cariprazine retention time: about 10 minutes) Mobile phase Solution (pH 6.5): acetonitrile (ACN) = 4:6 column YMC triart C18, 4.6*250mm, 5μm (YM6-3) Column temperature 35℃ Sample temperature 20℃ Thinner and needle wash Acetonitrile (ACN): methanol: water = 7:2:1

[0042] Example 2

[0043] Research on solvents suitable for pharmaceutical compositions

[0044] In the present invention, solvents suitable for use in pharmaceutical compositions are first evaluated. It is known that the solubility of a polymer in a solvent can affect the formation of a pharmaceutical composition and the release of cariprazine from the pharmaceutical composition. Therefore, the solubility of a polymer in a solvent is evaluated to find a range suitable for use in a pharmaceutical composition.

[0045] The pharmaceutical composition in this example is as follows.

[0046] The pharmaceutical composition comprising cariprazine is a solution formed by dispersing cariprazine in a water-soluble solvent, a partially water-soluble solvent, or a non-water-soluble solvent. Subsequently, lactic acid-glycolic acid copolymer (PLGA) (model: 502H) is dissolved in the solution. Water-soluble solvents, for example, N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO) belong to a fast phase inversion system and a highly polar solvent. Partially water-soluble solvents, for example, benzyl alcohol (BA) belong to a slow conversion system. Non-water-soluble solvents, for example, benzyl benzoate (BB) belong to non-polar solvents. Pharmaceutical compositions with different solvents are named TF8-BB, TF8-BA, TF8-N, and TF8-D, as shown in Table 2.

[0047] Table 2

[0048]

[0049]

[0050] The results showed that benzyl benzoate (BB) was not a suitable solvent for the pharmaceutical composition due to the poor solubility of PLGA in the solvent. However, the implant formed by the pharmaceutical composition (TF8-BA) containing benzyl alcohol (BA) solvent was quite soft and easy to change shape. Figure 1 The release curves of the pharmaceutical compositions with different solvents according to this example are shown. Figure 1 As shown, the release curve of cariprazine from the pharmaceutical composition (TF8-D) with dimethyl sulfoxide (DMSO) solvent is similar to the release curve of the pharmaceutical composition (TF8-N) with N-methylpyrrolidone (NMP) solvent. In addition, the cumulative release percentage of cariprazine released by TF8-D and TF8-N within 1 day is less than 10%. Since the pharmaceutical compositions TF8-N and TF8-D show slower drug release within 14 days, N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO) solvents are more suitable for use in pharmaceutical compositions than benzyl alcohol (BA) solvents. The results show that the release of cariprazine is closely related to the properties of the solvent.

[0051] Example 3

[0052] Study on polymers with different intrinsic viscosities

[0053] The pharmaceutical composition in this example is as follows.

[0054] The pharmaceutical composition containing cariprazine is prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving lactic acid-glycolic acid copolymer (PLGA) with different intrinsic viscosities (IV). The models of lactic acid-glycolic acid copolymer (PLGA) are 502H, 503H, 504H, and 505, wherein the intrinsic viscosity (IV) of 502H polymer is the lowest and the intrinsic viscosity (IV) of 505 polymer is the highest. The pharmaceutical compositions with different lactic acid-glycolic acid copolymers (PLGA) are named 502H-TF8, 503H-TF8, 504H-TF8, and 505-TF8, and are shown in Table 3.

[0055] Table 3

[0056]

[0057]

[0058] Figure 2The release curves of the pharmaceutical compositions of polymers with different intrinsic viscosities according to the examples are shown. The results show that the release rate of cariprazine in the pharmaceutical composition of lactic acid-glycolic acid copolymer (PLGA) with a lower intrinsic viscosity (IV) (the pharmaceutical composition named 502H-TF8) is faster than that in the pharmaceutical composition of lactic acid-glycolic acid copolymer (PLGA) with a higher intrinsic viscosity (IV) (the pharmaceutical compositions named 503H-TF8 and 504H-TF8), and can last for 14 days. However, since the 505 polymer cannot be dissolved in the N-methylpyrrolidone (NMP) solvent, the 505 polymer is not suitable for use in the pharmaceutical composition. The cumulative release percentages of cariprazine in the pharmaceutical composition 502H-TF8 on the 1st day, the 14th day, and the 28th day are 1.00%, 46.00%, and 91.66%, respectively. The cumulative release percentages of cariprazine in pharmaceutical composition 503H-TF8 on day 1, day 14, and day 28 were 2.94%, 10.15%, and 78.78%, respectively. The cumulative release percentages of cariprazine in pharmaceutical composition 504H-TF8 on day 1, day 14, and day 28 were 2.96%, 8.20%, and 70.80%, respectively. Compared with pharmaceutical composition 503H-TF8, pharmaceutical composition 502H-TF8 containing lactic acid-glycolic acid copolymer (PLGA) with a lower intrinsic viscosity (IV) resulted in slower diffusion of N-methylpyrrolidone (NMP) solvent and reduced the initial release rate of cariprazine. However, pharmaceutical composition 502H-TF8 containing lactic acid-glycolic acid copolymer (PLGA) with a lower intrinsic viscosity (IV) showed a faster release curve because its degradation rate was faster than that of the pharmaceutical composition containing lactic acid-glycolic acid copolymer (PLGA) with a higher intrinsic viscosity (IV). In addition, the solution viscosity of the pharmaceutical composition including poly(lactic acid-glycolic acid) (PLGA) having a lower intrinsic viscosity is less and easier to inject.

[0059] Example 4

[0060] Study on different lactic acid (L) / glycolic acid (G) ratios in polymers

[0061] Lactic acid-glycolic acid copolymer (PLGA) is a copolymer with different ratios of lactic acid (L) to glycolic acid (G) (L / G ratio). This example studies the effect of using polymers with different L / G ratios in a pharmaceutical composition on the in vitro release of cariprazine. The pharmaceutical composition in this example is as follows.

[0062] The pharmaceutical composition containing cariprazine is prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving different types of lactic acid-glycolic acid copolymer (PLGA), for example, 502H, 653H, 752H, and 202H. The pharmaceutical compositions of polymers with different ratios of lactic acid to glycolic acid are named B-502H-TF8-N, B-653H-TF8-N, B-752H-TF8-N, and B-202H-TF8-N. Different weight combinations of different polymer types are named B-502H / 752H-TF8-N (1:1) and B-502H / 752H-TF8-N (1:3), as shown in Table 4.

[0063] Table 4

[0064]

[0065] The results showed that the release rate of cariprazine in the pharmaceutical composition with a higher L / G ratio was slower than that in the pharmaceutical composition with a lower L / G ratio. Figure 3 The release profiles of the pharmaceutical compositions of polymers having different L / G ratios according to the examples are shown. Figure 3 As shown, the cumulative release percentages of the pharmaceutical composition containing 502H lactic acid-glycolic acid copolymer (PLGA) on the first day, the 14th day, and the 28th day were 1.00%, 46.00%, and 91.66%, respectively. The cumulative release percentages of the pharmaceutical composition containing 752H lactic acid-glycolic acid copolymer (PLGA) on the first day, the 14th day, and the 28th day were 1.70%, 6.50%, and 34.30%, respectively. In another group, the cumulative release percentages of the pharmaceutical composition containing 653H lactic acid-glycolic acid copolymer (PLGA) on the first day, the 14th day, and the 28th day were 3.51%, 10.49%, and 31.71%, respectively. The cumulative release percentages of the pharmaceutical composition containing 202H lactic acid-glycolic acid copolymer (PLGA) on the first day, the 14th day, and the 28th day were 3.58%, 9.90%, and 11.95%, respectively. Therefore, implants formed from pharmaceutical compositions having a higher L / G ratio polymer will degrade more slowly due to the presence of hydrophobic groups in PLGA, which further results in slower absorption and diffusion of water.

[0066] To investigate the effects of different weight ratios of PLGA combinations on the release of cariprazine, a pharmaceutical composition was prepared by combining 752H PLGA and 502H PLGA. Figure 4The release curves of the pharmaceutical compositions of the poly(lactic acid-glycolic acid) copolymer (PLGA) according to the examples are shown. Figure 4 As shown, the release curves of cariprazine from the pharmaceutical compositions with different weight ratios of lactic acid-glycolic acid copolymer (PLGA) combinations are between the pharmaceutical compositions with only 502H lactic acid-glycolic acid copolymer (PLGA) or 752H lactic acid-glycolic acid copolymer (PLGA). The cumulative release percentages of cariprazine released from the 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. The cumulative release percentages of cariprazine approached 80.0% on days 28, 35, 42, and 56, respectively.

[0067] Example 5

[0068] Study on different end groups of poly(lactic acid-co-glycolic acid) (PLGA)

[0069] The pharmaceutical composition in this example is as follows.

[0070] The pharmaceutical composition containing cariprazine hydrochloride (cariprazine HCl) is prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving lactic acid-glycolic acid copolymer (PLGA) with different end groups. The models of lactic acid-glycolic acid copolymer (PLGA) are 752H and 752S, wherein the 752H polymer has a carboxyl end group and the 752S polymer has an ester end group. The pharmaceutical compositions with different lactic acid-glycolic acid copolymers (PLGA) are named C-752H-TF8 and C-752S-TF8 and are shown in Table 5.

[0071] Table 5

[0072]

[0073] Figure 5 The release curves of the pharmaceutical compositions of the lactic acid-glycolic acid copolymer (PLGA) with different terminal groups according to the examples are shown. Figure 5 As shown in Figure 2, the initial drug release of cariprazine hydrochloride from a pharmaceutical composition of poly(lactic-co-glycolic acid) (PLGA) having ester end groups was less than 30% at 24 hours and lasted for about 56 days. Figure 5 As shown, the pharmaceutical compositions comprising poly(lactic acid-glycolic acid) (PLGA) having carboxyl terminal groups or ester terminal groups can all result in the sustained release characteristics of cariprazine hydrochloride.

[0074] Example 6

[0075] Study of different weight ratios of polymer to solvent

[0076] The pharmaceutical composition in this example is as follows.

[0077] Pharmaceutical compositions containing cariprazine were prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving 502H lactic acid-co-glycolic acid (PLGA). The weight ratio of polymer to solvent was 1:0.65, 1:0.8, 1:2, 1:4, and 1:9. Pharmaceutical compositions with different polymer to solvent weight ratios were named TF15, TF16, TF17, TF18, and TF19 and are shown in Table 6.

[0078] Table 6

[0079]

[0080] The results showed that the pharmaceutical composition TF19 with a polymer to solvent weight ratio of 1:9 could not form an implant. Each dosage form of the pharmaceutical composition in Table 6 totaled 500 mg, which is about 0.5 ml. The results showed that the polymer concentration in the pharmaceutical composition for forming an implant should be between 174 mg / ml and 528 mg / ml. Figure 6 The release curves of the pharmaceutical compositions with different polymer to solvent ratios according to the examples are shown. Figure 6 As shown, the cumulative release percentage of cariprazine released from the pharmaceutical composition decreases with the increase of the weight ratio of polymer to solvent. The cumulative release percentage of cariprazine in all pharmaceutical compositions at 24 hours is less than 10%. In addition, Figure 6 It was shown that the pharmaceutical compositions having a polymer to solvent weight ratio ranging from 1:0.65 to 1:4 formed a sustained release profile of cariprazine.

[0081] Example 7

[0082] Study on different weight ratios of cariprazine in pharmaceutical compositions

[0083] The pharmaceutical composition in this example is as follows.

[0084] The pharmaceutical composition containing cariprazine is prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving 502H lactic acid-glycolic acid copolymer (PLGA). The weight ratio of cariprazine in the pharmaceutical composition is between 1-30% (w / w). The weight ratio of cariprazine is calculated by the weight of cariprazine and the weight of the total pharmaceutical composition. The pharmaceutical composition is shown in Table 7.

[0085] Table 7

[0086]

[0087] Figure 7 The release curves of the pharmaceutical compositions according to the different drug weight ratios of the examples are shown. Figure 7 As shown, pharmaceutical composition TF14 shows sustained release of cariprazine for about 49 days. High weight ratio cariprazine loaded in the pharmaceutical composition leads to smaller injection amount and better patient compliance. In pharmaceutical compositions with different cariprazine weight ratios (between 1% and 30%), there is no significant difference in the release amount of cariprazine in the first 7 days.

[0088] Example 8

[0089] Study on different weight ratios of cariprazine and polymer

[0090] The pharmaceutical composition in this example is as follows.

[0091] The pharmaceutical composition comprising cariprazine was prepared by dispersing cariprazine in N-methylpyrrolidone (NMP) solvent and then dissolving 502H lactic acid-glycolic acid copolymer (PLGA). The weight ratio of cariprazine to polymer was 1:0.9 to 1:39.6. The weight ratio was calculated by the weight of cariprazine to the weight of polymer. The pharmaceutical compositions with different cariprazine to polymer weight ratios were named TF6, TF13, and TF14, as shown in Table 8.

[0092] Table 8

[0093]

[0094]

[0095] Figure 8 The release curves of the pharmaceutical compositions with different cariprazine to polymer weight ratios according to the examples are shown. The results show that the release of cariprazine from the pharmaceutical compositions with cariprazine to polymer weight ratios ranging from 1:0.9 to 1:39.6 can last for 28 to 49 days.

[0096] Example 9

[0097] Study on different cariprazine salt forms in pharmaceutical compositions

[0098] The pharmaceutical composition in this example is as follows.

[0099] The cariprazine base and hydrochloride form were separately dispersed in N-methylpyrrolidone (NMP) solvent and then dissolved in 752H lactic acid-glycolic acid copolymer (PLGA) to prepare the pharmaceutical composition. The pharmaceutical compositions with different cariprazine salt forms are disclosed in Table 9 and are named B-752H-TF8-N, C-752H-TF8-N, B / C-752H-TF8-N (1:3), and B / C-752H-TF8-N (1:1).

[0100] Table 9

[0101]

[0102] Fig. 9 Shows the release profiles of the pharmaceutical compositions having different cariprazine salt forms according to the examples. Fig. 9 As shown, at 24 hours, the cumulative release percentage of cariprazine hydrochloride released from the pharmaceutical composition was about 25%, and it showed a faster release curve than the pharmaceutical composition containing cariprazine base. The different drug solubility of cariprazine hydrochloride and cariprazine base may be the reason affecting the release of cariprazine in the pharmaceutical composition. The solubility of cariprazine hydrochloride in acetate medium is higher than that of cariprazine base. The release curve of cariprazine in the pharmaceutical composition with a combination of cariprazine base and cariprazine hydrochloride falls between the pharmaceutical compositions B-752H-TF8-N and C-752H-TF8-N.

[0103] Example 10

[0104] Stability of pharmaceutical compositions

[0105] The pharmaceutical composition in this example is as follows.

[0106] Cariprazine was dispersed in N-methylpyrrolidone (NMP) solvent and then 502H lactic acid-glycolic acid copolymer (PLGA) was dissolved to prepare a pharmaceutical composition containing cariprazine. The pharmaceutical composition was named TF20, as shown in Table 10. The dissolution test in this stability study was performed using an accelerated dissolution method.

[0107] Table 10

[0108]

[0109] Table 11 shows the stability study of the pharmaceutical composition TF20 stored at 4°C, and Table 12 shows the stability study of the pharmaceutical composition TF20 stored at room temperature (25°C). It is known that pharmaceutical compositions for injection are usually stored at 4°C. However, the results show that the pharmaceutical composition of the present invention can remain stable when stored at room temperature (25°C). The pharmaceutical compositions stored at 4°C and 25°C, respectively, meet the quality specifications. That is, the pharmaceutical composition of the present invention can be stored at room temperature, reducing the manufacturing cost.

[0110] Table 11

[0111]

[0112] Table 12

[0113]

[0114] Embodiment 11

[0115] Pharmacokinetic study of drug composition in rats

[0116] The drug composition was injected subcutaneously into 3 to 5 Wistar rats with an average weight of 250 g. About 75 mg / kg of cariprazine was injected subcutaneously into the dorsal thorax using a syringe with a 20G needle. The drug composition is shown in Table 13. The drug plasma concentration after subcutaneous administration was evaluated. After injection, plasma concentrations were obtained at 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 regularly up to 56 days, 63 days, 70 days, 77 days, and 84 days, respectively, and were shown in Table 13. Fig.10 middle.

[0117] Table 13

[0118]

[0119]

[0120] Fig.10 The plasma concentration-time curve of cariprazine after subcutaneous administration of the pharmaceutical composition to rats according to the example is shown. The pharmacokinetic (PK) parameters were calculated by WinNonlin software, as shown in Table 14. It was found that the PK curve was related to the L / G ratio. The pharmaceutical composition with a higher L / G ratio resulted in a slower release rate and a lower maximum plasma concentration (C max However, polymers with different intrinsic viscosities showed similar Tmax (reaching C maxtime). In addition, pharmaceutical compositions with different solvents (e.g., N-methylpyrrolidone (NMP) or dimethyl sulfoxide (DMSO)) show similar cariprazine release curves. Different solvents used in the pharmaceutical composition, e.g., N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO) are not the main reasons affecting the release of cariprazine. Different end group polymers used in the pharmaceutical composition, e.g., 752H and 752S are not the main reasons affecting the absorption of the drug in vivo. The results show that the pharmaceutical composition of the present invention has no burst release within 24 hours. The release of cariprazine from the pharmaceutical composition can last for more than 14 days. More preferably, the release of cariprazine from the pharmaceutical composition can last for more than 30 days, or even more than 3 months.

[0121] Table 14

[0122] Pharmaceutical composition <![CDATA[T 1 / 2 (day)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[T max (day)]]> <![CDATA[AUC all (day*ng / mL)]]> C-752H-TF8-N 14.5 52.5 0.13 788.7 C-752S-TF20-N 14.1 59.2 0.13 661.7 B-752H-TF8-N 10.2 25.2 28 933.2 B-502H-TF8-N 7.0 39.1 14 925.8 B-503H-TF8-N 37.0 24.0 14 727.1 B-752H-TF8-D 4.4 24.9 28 720.6

[0123] In addition, six rats were orally administered 0.27 mg / kg The drug was administered for 5 consecutive days as a control group. After oral administration, blood samples were collected from the tail vein in tubes at 0.16, 0.5, 1, 2, 3, 5, 7, 10, and 24 hours on the first and fifth days, and at 1 and 3 hours on the second to fourth days. After collection, all blood samples were immediately centrifuged to obtain plasma and stored at -80°C before analysis. Cariprazine in plasma was extracted by protein precipitation and analyzed by LC-MS / MS.

[0124] Fig.11 According to the example, rats were given The plasma concentration-time curve of cariprazine after oral administration of . The pharmacokinetic (PK) parameters were calculated by WinNonlin software and are shown in Table 15. As shown in Table 15, The half-life (T 1 / 2 ) is 4.5 hours, wherein the half-life (T 1 / 2 ) is 4.4 days to 37.0 days.

[0125] Table 15

[0126]

[0127] The results show that the pharmaceutical composition of the present invention can provide a longer sustained release time than the oral dosage form of cariprazine. The results also show that the pharmaceutical composition of the present invention can reduce the fluctuation of the plasma concentration of cariprazine, and the release of cariprazine from the pharmaceutical composition can last for at least 84 days.

[0128] Although the present invention has been described using examples and embodiments, it should be understood that the present invention is not limited to the disclosed embodiments. On the contrary, for those with ordinary knowledge in the art, the present invention should cover a variety of modifications and similar configurations. Therefore, the scope of the patent application should be interpreted in the broadest sense to include all modifications and similar configurations.

Claims

1. A pharmaceutical composition comprising: Active pharmaceutical ingredients (API) including cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof; A polymer including poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof; and Solvent.

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

3. The pharmaceutical composition of claim 2, wherein in the mixture of the cariprazine and the pharmaceutically acceptable salt of the cariprazine, the weight ratio of the cariprazine to the cariprazine hydrochloride is 1:99 to 99:

1.

4. The pharmaceutical composition of claim 2, wherein in the mixture of the cariprazine and the pharmaceutically acceptable salt of the cariprazine, the weight ratio of the cariprazine to the cariprazine hydrochloride is 1:1 to 1:

3.

5. The pharmaceutical composition of claim 1, wherein the weight ratio of the active pharmaceutical ingredient (API) in the pharmaceutical composition is 1% to 30%. 6 . The pharmaceutical composition of claim 1 , wherein in the poly(lactic acid-glycolic acid) copolymer (PLGA), the ratio of lactide to glycolide is 48:52 to 100:

0.

7. The pharmaceutical composition of claim 6, wherein the polymer comprises one or more poly(lactic acid-glycolic acid) (PLGA) having various ratios of lactic acid to glycolic acid.

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

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

10. The pharmaceutical composition of claim 1, wherein the polymer has a viscosity of 0.1 dl / g to 0.7 dl / g.

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

12. The pharmaceutical composition of claim 11, wherein the water-soluble solvent comprises dimethyl-sulfoxide (DMSO), N-methyl pyrrolidone (NMP), or a combination thereof.

13. The pharmaceutical composition of claim 11, wherein the partially water-soluble solvent comprises benzylalcohol (BA).

14. The pharmaceutical composition of claim 1, wherein the weight ratio of the active pharmaceutical ingredient (API) to the polymer is 1:0.8 to 1:

40.

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

4.

16. The pharmaceutical composition of claim 1, wherein the weight ratio of the active pharmaceutical ingredient (API), the polymer, and the solvent is 1:0.8:0.4 to 1:40:

160.

17. The pharmaceutical composition of claim 1, wherein the percentage of release of the pharmaceutical composition within the first 24 hours is less than 30%.

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

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

20. A method for preparing a pharmaceutical composition, comprising: Dispersing an active pharmaceutical ingredient (API) in a solvent to form a solution, wherein the active pharmaceutical ingredient (API) comprises cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof; as well as Under continuous stirring, a polymer is dissolved in the solution, wherein the polymer includes poly(lacticacid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof.

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