Patent Application
20230372331
The disclosure relates to a pharmaceutical composition, and relates to a flowable pharmaceutical composition comprising cariprazine for in-situ forming long-acting implants.
Cariprazine is a third-generation, orally active, and potent antipsychotic drug. It acts as dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist with two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Cariprazine (Vraylar®) was approved for the treatment of schizophrenia and bipolar disorder by the Food and Drug Administration (FDA) in 2015 and the European Medicines Agency (EMA) in 2017.
Currently, there are some disadvantages when administrating cariprazine for schizophrenia treatment with once-daily oral immediate release capsules. Schizophrenic patients usually exhibit poor adherence to treatment regimens. A therapy that includes a once-daily oral dosage can lead to irregular or inconsistent treatment, thereby risking the recurrence of psychotic episodes and crisis.
Therefore, antipsychotic drugs have evolved in order to offer better control of schizophrenia. The treatment without the need of caregivers to pay attention to daily administration and a more stable plasma concentration level in the patient after taking antipsychotic drugs are both desirable.
In accordance with one embodiment of the 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 pharmaceutically acceptable salt of cariprazine, or a mixture thereof. The polymer comprises poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof.
In some embodiments, the pharmaceutically acceptable salt of cariprazine comprises cariprazine HCl. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from 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 HCl is from 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 HCl is from 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 API in the pharmaceutical composition is from 1% to 30%.
In some embodiments, in PLGA, the ratio of lactide to glycolide is from 48:52 to 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 from 150 mg/ml to 1000 mg/ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is from 340 mg/ml to 560 mg/ml. In some embodiments, the viscosity of the polymer is from 0.1 dl/g to 0.7 dl/g.
In some embodiments, the solvent comprises water miscible solvent or partially water miscible solvent. In some embodiments, the water miscible solvent comprises dimethyl-sulfoxide (DMSO), N-methyl pyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water miscible solvent comprises benzyl alcohol (BA).
In some embodiments, the weight ratio of the API to the polymer is from 1:0.8 to 1:40. In some embodiments, the weight ratio of the API to the polymer is from 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 from 1:0.5 to 1:4. In some embodiments, the weight ratio of the polymer to the solvent is from 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 among the API, the polymer and the solvent is from 1:0.8:0.4 to 1:40:160. In some embodiments, the weight ratio among the API, the polymer and the solvent is from 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.
In some embodiments, the release percentage of the pharmaceutical composition is lower than 30% in the first 24 hours. In some embodiments, the release of the pharmaceutical composition is sustained for more than 14 days. In some embodiments, the pharmaceutical composition is stored at the temperature of 4° C. to 25° C. for use.
In accordance with one embodiment of the disclosure, a method for preparing a pharmaceutical composition is provided. The preparation method comprises the following steps. An active pharmaceutical ingredient (API) is dispersed in a solvent to form a solution. The API comprises cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof. A polymer is dissolved in the solution under continuous stirring. The polymer comprises poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof.
A detailed description is given in the following embodiments with reference to the accompanying drawings.
The invention can be more fully understood by reading the subsequent detailed description and examples with references made to the accompanying drawings, wherein:
In accordance with one embodiment of the 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 pharmaceutically acceptable salt of cariprazine, or a mixture thereof. The polymer comprises poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof.
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 upon injection. In some embodiments, the pharmaceutical composition may provide an extended release of API, for example, cariprazine. The depot is formed when contacts with water and physiological fluids and transforms in situ into the solid implant thereby providing an extended release of cariprazine for prolonged periods of time. Once the pharmaceutical composition contacts the aqueous body fluids, it solidifies to form a solid/semi-solid implant due to the solvent diffusing out. The drug release rate may be controlled by different polymer ratio.
In some embodiments, the pharmaceutically acceptable salt of cariprazine may comprise cariprazine HCl. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from about 1:99 to about 99:1. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from about 1:1 to about 1:3. In some embodiments, in the mixture of cariprazine and the pharmaceutically acceptable salt of cariprazine, the weight ratio of cariprazine to cariprazine HCl is from 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 from about 1% to about 30%. The weight ratio is expressed as the percentage of the weight of API in total pharmaceutical composition weight.
In some embodiments, the polymer may be a biodegradable and biocompatible controlled polymer. The polymer is degraded by body enzyme. As a result, the polymer is not toxic to patient, will not accumulate in the human body and will not induce inflammatory responses. The end groups of the polymer may be end-capped with esters or carboxylic acid. In some embodiments, in PLGA, the ratio of lactide to glycolide is from about 48:52 to about 100:0. The different monomer ratios in PLGA cause different time of degradation, for example, the higher content of glycolide units, the lower time required for degradation. In some embodiments, the polymer may comprise more than one PLGA with various ratios of lactide to glycolide. In some embodiment, lactide and glycolide in PLGA are mixed in a ratio from about 48:52 to about 100:0. In some embodiments, the concentration of the polymer in the pharmaceutical composition is from about 150 mg/ml to about 1000 mg/ml. In some embodiments, the concentration of the polymer in the pharmaceutical composition is from about 340 mg/ml to about 560 mg/ml. In some embodiments, the viscosity of the polymer is from about 0.1 dl/g to about 0.7 dl/g. In some embodiments, the viscosity of the polymer is from about 0.14 dl/g to about 0.60 dl/g. In some embodiments, the viscosity of the polymer is from about 0.14 dl/g to about 0.24 dl/g. Inherent viscosity is measured in chloroform at 25° C., at a concentration of 0.1% wt/v by viscometer. The inherent viscosity is related to polymer molecular weight. The polymers with higher molecular weight will increase the viscosity of liquid in which they dissolved. In some embodiments, the average molecular weight of the polymer is from about 4 kD to about 54 kD. In some embodiments, the average molecular weight of the polymer is from about 4 kD to about 17 kD.
Solvent is used for the injection into any living body. The needs of solvent are susceptible not to cause toxicity. Solvent is biocompatible, not to cause tissue necrosis or irritation at the injection site. For the in-situ forming implant, the solvent should diffuse quickly from the polymeric solution toward surrounding tissues when exposed to body fluids. Solvent diffusion leads to polymer precipitate, and the implant formulation effectively leads to sustained release of active ingredient encapsulated. In some embodiment, the solubility of polymer in solvent is more than 1%. In some embodiments, the solvent may comprise water miscible solvent or partially water miscible solvent. In some embodiments, the water miscible solvent may comprise dimethyl-sulfoxide (DMSO), N-methyl pyrrolidone (NMP), or a combination thereof. In some embodiments, the partially water miscible solvent may comprise benzyl alcohol (BA).
The weight ratio of API to polymer in the pharmaceutical composition may also contribute to control the initial release of API from the implant. In some embodiments, the weight ratio of the API to the polymer is from about 1:0.8 to about 1:40. In another embodiments, the weight ratio of the API to the polymer is from 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 from about 1:0.5 to about 1:4. In some embodiments, the weight ratio of the polymer to the solvent is from 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 among the API, the polymer and the solvent is from about 1:0.8:0.4 to about 1:40:160. In some embodiments, the weight ratio among the API, the polymer and the solvent is from 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.
In some embodiment, the pharmaceutical composition may further comprise an excipient. In some embodiment, the excipient may be, for example, an antioxidant.
In some embodiments, the release percentage of the pharmaceutical composition may be lower than about 30% in the first 24 hours. In some embodiments, the release percentage of the pharmaceutical composition may be lower than about 25% in the first 24 hours. In some embodiments, the release percentage of the pharmaceutical composition may be lower than about 20% in the first 24 hours. In some embodiments, the release percentage of the pharmaceutical composition may be lower than about 15% in the first 24 hours. In some embodiments, the release percentage of the pharmaceutical composition may be lower than about 10% in the first 24 hours. In some embodiments, the sustained release of the pharmaceutical composition may be more than 14 days. In some embodiments, the sustained release of the pharmaceutical composition may be more than 20 days. In some embodiments, the sustained release of the pharmaceutical composition may be more than 25 days. In some embodiments, the sustained release of the pharmaceutical composition may be more than 28 days. In some embodiments, the sustained release of the pharmaceutical composition may be more than 30 days. In some embodiments, the sustained release of the pharmaceutical composition may be more than 1.5 months. In some embodiments, the sustained release of the pharmaceutical composition may be more than 3 months. In some embodiments, the sustained release of the pharmaceutical composition may be more than 6 months. In some embodiments, the pharmaceutical composition is stored from about 4° C. to about 25° C. for use.
In accordance with one embodiment of the disclosure, a method for preparing a pharmaceutical composition is provided. The preparation method comprises the following steps. An active pharmaceutical ingredient (API) is dispersed in a solvent to form a solution. The API comprises cariprazine, a pharmaceutically acceptable salt of cariprazine, or a mixture thereof. A polymer is dissolved in the solution under continuous stirring. The polymer comprises poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(glycolic acid) (PGA), or a combination thereof.
In some embodiments, another method for preparing a pharmaceutical composition is provided. The preparation method includes the following steps. A polymer is dissolved in a solvent under continuous stirring to form a solution. An active pharmaceutical ingredient (API) is dispersed in the solution.
Preparation of Pharmaceutical Composition and Drug Release Method
The pharmaceutical composition was prepared as follows. First, cariprazine or its pharmaceutically acceptable salt was dispersed in solvent selected from dimethyl-sulfoxide (DMSO), N-methyl-pyrrolidone (NMP) or benzyl alcohol (BA) to form a suspension solution. Subsequently, PLGA polymer selected from 502H, 503H, 653H, 752H and 752S was dissolved in the suspension solution under continuous stirring for 10 min. The mixture of solution was put overnight until PLGA polymer dissolved completely.
To measure the drug release profile of cariprazine, 50 mg of pharmaceutical composition was injected into 10 mL acetate buffer in a glass vial, capped and placed inside an incubator shaker at 37° C., 100 rpm to form a medium. At predetermined time points (t=1, 2, 4, 7, 10, 14, 21 and 28 days), medium was collected to measure the release of cariprazine. At each time point, 2 mL of medium was collected and replaced with 2 mL fresh acetate buffer to form a dissolution sample. The dissolution sample was analyzed by High Performance Liquid Chromatography (HPLC) under the condition described in Table 1.
Study of Solvent Suitable for Using in Pharmaceutical Composition
In the present invention, solvent suitable for using in pharmaceutical composition was first to be estimated. It was known that the solubility of polymer in solvent could affect the formation of pharmaceutical composition and the release of cariprazine from the pharmaceutical composition. As a result, the solubility of polymer in solvent was estimated to find a suitable range for using in pharmaceutical composition.
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical composition comprising cariprazine was prepared by dispersing cariprazine in the water miscible solvent, partially water miscible solvent or water un-miscible solvent respectively to form a solution, and subsequently dissolving PLGA (model: 502H) polymer in the solution. Water miscible solvent such as NMP and DMSO belonged to fast phase inversion system and highly polar solvents. Partially water-miscible solvent such as benzyl alcohol (BA) belonged to slow inverting system. Water un-miscible solvent such as benzyl benzoate (BB) belonged to non-polar solvent. The pharmaceutical compositions with different solvents were named TF8-BB, TF8-BA, TF8-N and TF8-D and showed in Table 2.
The results showed that BB solvent was not a suitable solvent for pharmaceutical compositions because PLGA polymer couldn't dissolve well in BB solvent. However, pharmaceutical composition with BA solvent (TF8-BA) formed an implant which was very soft and easy to change shape.
Study of Polymers with Different Inherent Viscosities
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine were prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving PLGA polymer with different inherent viscosity (IV). The models of PLGA polymer were 502H, 503H, 504H and 505, wherein the 502H polymer had the lowest IV and the 505 polymer had the highest IV. The pharmaceutical compositions with different PLGA polymers were named 502H-TF8, 503H-TF8, 504H-TF8, and 505-TF8 and showed in Table 3.
Study of Different Lactide (L)/Glycolide (G) Ratio in Polymers
Poly (lactide-glycolide) (PLGA) polymers are copolymers with different ratios of lactide(L) to glycolide(G) (L/G ratio). This example investigated influence of different L/G ratio in polymers used in pharmaceutical compositions on the in vitro release of cariprazine. In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine were prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving different models of PLGA polymers such as 502H, 653H, 752H and 202H, respectively. The pharmaceutical compositions with different ratios of lactide to glycolide in polymers were named B-502H-TF8-N, B-653H-TF8-N, B-752H-TF8-N, B-202H-TF8-N, and different weight combinations of polymer types were named B-502H/752H-TF8-N(1:1) and B-502H/752H-TF8-N(1:3) and showed in Table 4.
The result showed that release rate of cariprazine from the pharmaceutical compositions with higher L/G ratio was slower than those with lower L/G ratio.
To investigate the influence of the different weight ratio of PLGA polymer combination on the release of cariprazine. The pharmaceutical compositions were prepared with the combination of 752H PLGA polymer and 502H PLGA polymer.
Study of Different End Group of PLGA Polymers
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine HCl were prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving PLGA polymer with different end group. The models of PLGA polymers were 752H and 752S, wherein the 752H polymer had carboxylic end group and the 752S polymer had ester end group. The pharmaceutical compositions with different PLGA polymers were named C-752H-TF8 and C-752S-TF8 and showed in Table 5.
Study of Different Weight Ratio of Polymer to Solvent
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine were prepared by dispersing cariprazine in the NMP solvent and subsequently 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 showed in Table 6.
It was showed that the pharmaceutical composition TF19 with weight ratio of polymer to solvent 1:9 couldn't form an implant. Since each of the formulation of pharmaceutical composition in Table 6 is summed up to 500 mg, and which is about 0.5 ml. The result showed concentration of polymer in pharmaceutical composition to form an implant should be within 174 mg/ml to 528 mg/ml.
Study of Different Weight Ratio of Cariprazine in the Pharmaceutical Compositions
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine were prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving PLGA polymer model 502H. The weight ratios of cariprazine in the pharmaceutical compositions were between 1-30% (w/w). The weight ratio of cariprazine was calculated by the weight of cariprazine to the weight of total pharmaceutical composition. The pharmaceutical compositions were shown in Table 7.
30%
Study of Different Weight Ratios of Cariprazine to Polymer
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions comprising cariprazine were prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving PLGA polymer 502H. The weight ratios of cariprazine to polymer were 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 weight ratios of cariprazine to polymer were named TF6, TF13 and TF14 and showed in Table 8.
Study of Different Cariprazine Salt Forms Used in Pharmaceutical Compositions
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical compositions were prepared by dispersing cariprazine base and HCl form in the NMP solvent and subsequently dissolving PLGA polymer model 752H, respectively. Pharmaceutical compositions with different salt forms of cariprazine were illustrated in Table 9 and were named B-752H-TF8-N, C-752H-TF8-N, B/C-752H-TF8-N (1:3) and B/C-752H-TF8-N(1:1).
Stability of Pharmaceutical Compositions
In the present example, the pharmaceutical compositions were as follows.
The pharmaceutical composition comprising cariprazine was prepared by dispersing cariprazine in the NMP solvent and subsequently dissolving PLGA polymer 502H. The pharmaceutical composition was named TF20 and showed in Table 10. The test of dissolution in this stability study was conduct by acceleration dissolution method.
Table 11 showed stability investigation of pharmaceutical composition TF20 stored at 4° C., and table 12 showed stability investigation of pharmaceutical composition TF20 stored at room temperature (25° C.). It was known that the pharmaceutical composition for injection usually stored at 4° C. However, the results showed the pharmaceutical compositions of the present invention stored at room temperature (25° C.) remained steady. Both pharmaceutical compositions stored at 4° C. and 25° C. respectively meet quality specification. That is, pharmaceutical compositions of the present invention could be stored at room temperature and lead to reduce of cost of manufacture.
Rat Pharmacokinetics Studies of Pharmaceutical Compositions
The pharmaceutical compositions were injected subcutaneous to 3 to 5 Wistar Rats with average weight of 250 g. About 75 mg/kg cariprazine was injected subcutaneous in the dorsal thoracic using a syringe with a 20G needle. The pharmaceutical compositions were shown in Table 13. Drug plasma concentration after subcutaneous administration was evaluated. After injection, plasma concentration 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 periodically up to 56 days, 63, 70, 77, and 84 days, respectively and shown in
In addition, six rats orally administered 5-day repeated oral dose 0.27 mg/kg of Vraylar® as control group. Blood samples were collected in tubes from the tail vein at 0.16, 0.5, 1, 2, 3, 5, 7, 10, and 24 hours on the first & fifth day and 1 and 3 hr on the second to fourth day after oral administration. After collection, all blood samples were immediately centrifuged to obtain plasma, and then stored at −80° C. before analysis. Plasma cariprazine extraction was performed by protein precipitation and analyzed by LC-MS/MS.
The result showed that the pharmaceutical composition of present invention could provide longer sustain release than the oral dosage form of cariprazine. The results also showed that the pharmaceutical composition of the present invention could lead to less fluctuation of cariprazine concentration in plasma, and cariprazine released from the pharmaceutical composition could be sustained for at least 84 days.
While the invention has been described by way of example and in terms of the preferred embodiments, it should be understood that the invention is not limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications and similar arrangements (as would be apparent to those skilled in the art). Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.
| Number | Date | Country | |
|---|---|---|---|
| 63343143 | May 2022 | US |
