Solid dispersion, preparation method, and pharmaceutical composition thereof

Abstract

The present invention provides a solid dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof and a carrier. The carrier material includes polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

Description

Technical Field

[0001] The present disclosure relates to solid dispersions, preparation methods, and pharmaceutical compositions containing solid dispersions. In particular, the present disclosure relates to solid dispersions containing lurasidone or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Lurasidone is an atypical antipsychotic drug and was approved for sale in 2010 under the trademark Latuda®. The approved indications are schizophrenia and bipolar I disorder. As a Biopharmaceutics Classification System (BCS) class II drug, lurasidone has high permeability and low water solubility characteristics, which are affected by pH. The solubility of lurasidone is much better in acidic media compared to lurasidone in neutral media.

[0003] Since Latuda® has a distinct food effect, Latuda® should be administered once daily with food. In particular, compared to the drug administered under fasting conditions, the maximum plasma concentration (Cmax) and the area under the curve (AUC) of Latuda® administered with food increase by 3-fold and 2-fold, respectively, indicating that the bioavailability of the drug is affected by food intake (referred to as the food effect).

[0004] For example, U.S. Patent US 11,090,272 B2 discloses that Latuda® is an immediate-release tablet. Latuda® dissolves in the stomach after administration. Since the solubility of lurasidone changes with pH, a large amount of lurasidone will precipitate in the intestine (neutral environment), and only a small portion of lurasidone will dissolve and be absorbed. After the patient eats food, the solubility of lurasidone is improved by the detergents secreted by the gastrointestinal tract to exhibit the food effect.

[0005] However, even when Latuda® is administered with food, the bioavailability of lurasidone is only 9-19%. Furthermore, there are calorie intake restrictions, requiring patients to consume more than 350 calories during administration, which reduces patient compliance.

[0006] Therefore, the question of how to provide a dosage form of lurasidone that increases its solubility in the gastrointestinal tract (including the neutral environment) in order to reduce the food effect remains to be resolved. [Overview of the project]

[0007] In one aspect of the present disclosure, a solid dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof and a carrier is provided. The carrier material includes polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

[0008] In some embodiments, the weight ratio of lurasidone or its pharmaceutically acceptable salt to the carrier is 3:1 to 1:30.

[0009] In some embodiments, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, and the weight percentage of the carrier is 25% to 97%.

[0010] In some embodiments, the carrier comprises a first carrier and a second carrier, the first carrier comprising polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose (HPC), copovidone, hypromellose acetate succinate (HPMCAS), or a combination thereof, and the second carrier comprising polyvinyl alcohol (PVA), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethyl cellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

[0011] In some embodiments, the weight ratio of lurasidone or a pharmaceutically acceptable salt to the first carrier and the second carrier is 3:1 to 1:30.

[0012] In some embodiments, the weight ratio of the first carrier to the second carrier is 1:10 to 10:1.

[0013] In some embodiments, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, and the weight percentages of the first and second carriers are 25% to 97%.

[0014] In some embodiments, the solid dispersion further comprises a surfactant, the surfactant comprising a glycerol ester, a polyoxyethylene ester, or a combination thereof.

[0015] In one aspect of this disclosure, a pharmaceutical composition comprising the above-described solid dispersion and an excipient is provided.

[0016] One aspect of the present disclosure provides a method for preparing a solid dispersion, comprising: mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier to form a mixture; spray-drying the mixture or melting the mixture and then cooling it, wherein the carrier comprises polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

[0017] In some embodiments, the mixing step includes mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier in an organic solvent to form a mixture.

[0018] In some embodiments, the melting step includes melting the mixture at a temperature of 80°C to 200°C by using a hot melting extruder.

[0019] In one aspect of the present disclosure, a solid dispersion is provided comprising lurasidone or a pharmaceutically acceptable salt thereof, a carrier, and a surfactant, wherein the surfactant comprises a glycerol ester, a polyoxyethylene ester, or a combination thereof.

[0020] In some embodiments, the weight ratio of lurasidone or its pharmaceutically acceptable salt to the carrier is 3:1 to 1:30.

[0021] In some embodiments, the weight ratio of lurasidone or its pharmaceutically acceptable salt to the surfactant is 1:0.1 to 1:30.

[0022] In some embodiments, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, the weight ratio of the carrier is 25% to 97%, and the weight ratio of the surfactant is 0.1% to 45%.

[0023] In some embodiments, the surfactant is a fatty acid glyceride, a polyoxyethylene fatty acid ester, or a combination thereof.

[0024] In some embodiments, the surfactant is a polyoxylglyceride.

[0025] In some embodiments, the carrier material includes polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

[0026] In some embodiments, the carrier includes a first carrier and a second carrier. The first carrier includes polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose (HPC), copovidone, hypromellose acetate succinate (HPMCAS), or a combination thereof. The second carrier includes polyvinyl alcohol (PVA), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethyl cellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or a combination thereof.

[0027] In one aspect of the present disclosure, a method for preparing a solid dispersion, comprising: mixing lurasidone or a pharmaceutically acceptable salt thereof, a carrier, and a surfactant to form a mixture; and spray-drying the mixture or melting the mixture and then cooling it, wherein the surfactant includes glycerol ester, polyoxyethylene ester, or a combination thereof.

Brief Description of the Drawings

[0028] To more clearly understand the above and other objects, features, advantages, and embodiments of the present disclosure, the description of the accompanying drawings is as follows.

[0029] [Figure 1] FIG. 1 illustrates a flowchart of a method for preparing a solid dispersion in some embodiments of the present disclosure.

[0030] [Figure 2]Figure 2 illustrates the release profiles of experimental groups 2-1 to 2-3 and the commercially available product, Latuda®, from dissolution tests in several embodiments of the present disclosure. [Modes for carrying out the invention]

[0031] To provide a detailed and complete description of this disclosure, embodiments and specific embodiments of this disclosure are presented with illustrative descriptions, but these are not the only types for implementing this disclosure or using specific embodiments. The embodiments disclosed herein may be combined or substituted for each other in a preferred manner, and other embodiments may be added to one embodiment without further description. In the following description, many specific details will be described in detail so as to enable the reader to fully understand the following embodiments. However, embodiments of this disclosure may be implemented without these specific details.

[0032] A series of operations or steps are described to illustrate the methods disclosed herein, but the order of the operations or steps is not to be considered limiting. For example, certain operations or steps may be performed in a different order and / or concurrently with other steps. Furthermore, not all of the exemplary operations, steps and / or features are required to perform the embodiments of this disclosure. In addition, each of the operations or steps described herein may include multiple substeps or actions.

[0033] definition

[0034] In this description, unless otherwise specified, “a” and “the” may mean singular or plural. It will be further understood that “comprise,” “include,” “have,” and similar terms, when used herein, refer to the features, regions, integers, steps, operations, elements, and / or components described, but do not exclude other features, regions, integers, steps, operations, elements, components, and / or groups.

[0035] As used herein, “active ingredient” means lurasidone or any pharmaceutically acceptable salt thereof, which includes, but is not limited to, salts, esters, complexes, chelating agents, cage compounds, racemates, enantiomers, and the like.

[0036] As used herein, "excipient" refers to a pharmaceutical additive used in a pharmaceutical composition for various purposes and functions, without having pharmacological activity.

[0037] As used herein, "immediate release" (IR) refers to the phenomenon in which the active ingredient is completely released within 2 hours, 1 hour, or 30 minutes or less.

[0038] As used herein, "oral dosage form" refers to a method of oral administration, such as a tablet.

[0039] Solid dispersion and method for preparing the same

[0040] Lurasidone is insoluble in water (for example, its solubility in water is less than 0.1 mg / mL), and its solubility increases in the gastrointestinal tract during food intake. Therefore, the timing of drug administration is usually limited to when food is consumed, which leads to decreased patient compliance.

[0041] The primary object of this disclosure is to provide a solid dispersion containing lurasidone or a pharmaceutically acceptable salt thereof (active pharmaceutical ingredient, API) that has improved solubility at least under neutral conditions, thereby reducing or eliminating food effects and increasing patient compliance. Surprisingly, the solid dispersion of the present invention achieves higher solubility of lurasidone or a pharmaceutically acceptable salt thereof by selecting a suitable carrier suitable for combination with lurasidone or a pharmaceutically acceptable salt thereof, dispersing the lurasidone or a pharmaceutically acceptable salt thereof in a carrier to form a solid dispersion, and maintaining the lurasidone or a pharmaceutically acceptable salt thereof in a non-crystalline form. Furthermore, a suitable surfactant for increasing the solubility of lurasidone or a pharmaceutically acceptable salt thereof is also provided in this disclosure.

[0042] By dispersing lurasidone or a pharmaceutically acceptable salt thereof in a carrier, the lurasidone or a pharmaceutically acceptable salt thereof exists in an amorphous form, achieving the objective of increasing solubility. The polymer chains of the carrier can be loosened by appropriately heating or dissolving them in the solvent during the preparation process, and thus lurasidone or a pharmaceutically acceptable salt thereof can be dispersed in the carrier. Therefore, appropriate temperature and solvent are often considered simultaneously so that lurasidone or a pharmaceutically acceptable salt thereof can be dispersed in the carrier in an amorphous form.

[0043] Please refer to Figure 1, which shows a flowchart of a method 100 for preparing a solid dispersion in some embodiments of the present disclosure, including steps S110 and S120.

[0044] First, referring to step S110, lurasidone or a pharmaceutically acceptable salt thereof is mixed with a carrier to form a mixture.

[0045] In some embodiments, step S110 comprises mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier in an organic solvent to form a mixture, wherein lurasidone or a pharmaceutically acceptable salt thereof and the carrier are uniformly distributed in the organic solvent. In some embodiments, the organic solvent includes dichloromethane, methanol, ethanol, dimethyl sulfoxide (DMSO), acetone, chloroform, isopropanol, or a combination thereof. In some other embodiments, step S110 comprises mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier in water.

[0046] In some embodiments, the carrier material includes polyvinyl acetate phthalate (PVAP), polyvinyl alcohol (PVA), cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose (HPC), povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), or combinations thereof. It should be noted that the carrier material is selected after confirmation by field testing (e.g., dissolution testing). Compared with other common carrier materials not selected in this disclosure, the carrier material increases at least the solubility of lurasidone or its pharmaceutically acceptable salts, and the storage stability of the solid dispersion, or both.

[0047] In some embodiments, the carrier comprises a first carrier and a second carrier, the first carrier comprising polyvinyl acetate phthalate, polyvinyl alcohol, cellulose acetate phthalate, mesoporous silica, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl cellulose, copovidone, hypromellose acetate succinate, or a combination thereof, and the second carrier comprising polyvinyl alcohol, mesoporous silica, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose, povidone, copovidone, ethyl cellulose, polyoxyethylene glycol, hypromellose acetate succinate, hypromellose phthalate, or a combination thereof. In some embodiments, the first and second carriers are different; that is, the carrier comprises at least two of the above-mentioned materials. It is noteworthy that, compared to a single material, the solid dispersions of the present invention containing at least two different carriers may achieve better solubility of lurasidone or its pharmaceutically acceptable salts in a neutral medium, or increased Cmax (maximum plasma concentration) and AUC (area under the curve) in in vivo studies. In some embodiments, carriers containing PVAP or PVA and mesoporous silica in the solid dispersion may achieve better solubility compared to other materials. Furthermore, carriers containing PVAP may further increase the storage stability of lurasidone or its pharmaceutically acceptable salts.

[0048] In some embodiments, the weight ratio of lurasidone or its pharmaceutically acceptable salt to the carrier (first carrier and second carrier) is 3:1 to 1:30, for example, 3:1, 2:1, 1:1, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, or any value within any interval of the above values. If the weight ratio of lurasidone or its pharmaceutically acceptable salt is too low, a large amount of solid dispersion will be required in the manufacture of the pharmaceutical composition containing it. If the weight ratio of lurasidone or its pharmaceutically acceptable salt is too high, the dispersion efficiency of lurasidone or its pharmaceutically acceptable salt will decrease, thereby reducing the release efficiency of lurasidone or its pharmaceutically acceptable salt during administration.

[0049] In some embodiments, the weight ratio of the first carrier to the second carrier is 1:10 to 10:1, for example, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or any value between any intervals of the above values.

[0050] In some embodiments, step S110 comprises mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier and a surfactant to form a mixture, wherein the surfactant includes glycol esters, polyoxyethylene esters, or a combination thereof. It should be noted that since the surfactant must be combined with lurasidone or a pharmaceutically acceptable salt thereof and the aforementioned method (spray-drying step, or melting and cooling step), the surfactant should be selected after being confirmed by field testing (e.g., dissolution test).

[0051] The miscibility of lurasidone or its pharmaceutically acceptable salts can be increased through the addition of selected surfactants, and the recrystallization effect of lurasidone or its pharmaceutically acceptable salts can be reduced. In addition, surfactants can also improve the dissolution rate of lurasidone or its pharmaceutically acceptable salts, and the wetting properties of the solid dispersion, thereby increasing the bioavailability of the solid dispersion and avoiding precipitation.

[0052] In some embodiments, the surfactant includes glycerol esters, polyoxyethylene esters, or a combination thereof. In some embodiments, the surfactant includes fatty acid glycerides, polyoxyethylene fatty acid esters, or a combination thereof. Preferably, the surfactant is a combination of fatty acid glycerides and polyoxyethylene fatty acid esters. Preferably, the surfactant is a polyoxylglyceride. In some embodiments, the polyoxylglyceride includes caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, stearoyl polyoxylglyceride, or a combination thereof.

[0053] In some embodiments, the weight ratio of lurasidone or its pharmaceutically acceptable salt to the surfactant is 1:0.1 to 1:30, for example, 1:0.1, 1:0.5, 1:1, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, or any value within any interval of the above values. If the weight ratio of lurasidone or its pharmaceutically acceptable salt is too high, the dispersion efficiency of lurasidone or its pharmaceutically acceptable salt decreases, thereby reducing the release efficiency of lurasidone or its pharmaceutically acceptable salt during administration. If the weight ratio of lurasidone or its pharmaceutically acceptable salt is too low, a large amount of solid dispersion will be required in the manufacture of the pharmaceutical composition containing lurasidone or its pharmaceutically acceptable salt.

[0054] Furthermore, referring to step S120, the mixture is spray-dried or the mixture is melted and then cooled (e.g., hot-melt extrusion (HME)).

[0055] In some embodiments, before spray drying, the mixture is dissolved in a spray-drying solution (e.g., dichloromethane, methanol, ethanol, dimethyl sulfoxide (DMSO), acetone, chloroform, isopropanol, water, or any combination thereof) in which lurasidone or a pharmaceutically acceptable salt thereof is dispersed amorphously among the carriers. It should be emphasized that, in the spray-drying step, since lurasidone or a pharmaceutically acceptable salt thereof, as well as each of the carriers and surfactants, have individual solubility in the spray-drying solution, the selected materials for the carriers and surfactants must be combined with the solubility of lurasidone or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, after dissolving the mixture in a spray-drying solution, the spray-drying solution containing the mixture is atomized by airbrushing in a dry room, where, during atomization, the spray-drying solution comes into contact with hot, dry gas and then rapidly evaporates to obtain dry particles of the mixture. In some embodiments, the inlet or outlet temperature is 35°C to 200°C (e.g., 35°C, 45°C, 50°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, or any value between any intervals of the above values), where the inlet temperature is higher than the outlet temperature. If the temperature is too high, the structure of lurasidone or its pharmaceutically acceptable salt, carrier, or surfactant may be destroyed. If the temperature is too low, an excess residue of the spray-drying solution remains.

[0057] During the melting and cooling steps, each lurasidone or its pharmaceutically acceptable salt, as well as the carrier and surfactant, has its own working temperature range during melting and cooling; therefore, the selected materials for the carrier and surfactant must be matched to the working temperature of the lurasidone or its pharmaceutically acceptable salt.

[0058] In some embodiments, the melting and cooling steps include vacuum compression modeling (VCM) or hot melt extrusion (HME).

[0059] In particular, HME is a continuous process. During the process, the mixture is melted or softened through heat and pressure, and the molten mixture is uniformly mixed. The molten mixture is then extruded through an outlet mold hole at the end of the machine and cooled to form an extruded product. The heating temperature is often higher than the glass transition temperature (Tg) of the components of the mixture, and sometimes higher than the melting point of lurasidone or its pharmaceutically acceptable salt, so that all components can be mixed at the molecular level. Thus, lurasidone or its pharmaceutically acceptable salt can be uniformly dispersed in the carrier through the melting step. Furthermore, the extruded product may be cooled by air cooling, water cooling, etc., to form a solid dispersion.

[0060] In some embodiments, the melting step includes melting the mixture at a temperature of 80°C to 200°C (e.g., 80°C, 90°C, 100°C, 200°C, or any value between any intervals of the above values) by using a hot melt extruder. If the melting temperature is too high, the structure of lurasidone or its pharmaceutically acceptable salts, carriers, or surfactants may be destroyed. If the melting temperature is too low, the distribution of lurasidone or its pharmaceutically acceptable salts will be uneven. In some embodiments, the cooling step includes cooling the mixture at a temperature of 20°C to 30°C (e.g., 20°C, 25°C, 30°C, or any value between any intervals of the above values) to form a solid dispersion.

[0061] After step 120, a solid dispersion is then provided.

[0062] In some embodiments, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, e.g., 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or any value between any intervals of the above values, and the weight percentage of carriers (first carrier and second carrier) is 25% to 97%, e.g., 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or any value between any intervals of the above values, based on 100% of the weight percentage of the solid dispersion. If the weight percentage of lurasidone or its pharmaceutically acceptable salt is too high, or if the weight percentage of the carrier is too low, the dispersion efficiency of lurasidone or its pharmaceutically acceptable salt decreases, thereby reducing the release efficiency of lurasidone or its pharmaceutically acceptable salt during administration. If the weight percentage of lurasidone or its pharmaceutically acceptable salt is too low, or if the weight percentage of the carrier is too high, a large amount of solid dispersion will be required in the manufacture of pharmaceutical compositions containing lurasidone or its pharmaceutically acceptable salt.

[0063] In some embodiments, if the solid dispersion contains a surfactant, the weight percentage of the surfactant is 0.1% to 45%, based on 100% of the weight percentage of the solid dispersion, for example, 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or any value within any interval of the above values. If the weight percentage of the surfactant is too low, the dispersion efficiency of lurasidone or its pharmaceutically acceptable salt is reduced, thereby reducing the release efficiency of lurasidone or its pharmaceutically acceptable salt during administration. If the weight percentage of the surfactant is too high, the weight percentage of lurasidone or its pharmaceutically acceptable salt may be too low, which would require a large amount of solid dispersion in the manufacture of the pharmaceutical composition.

[0064] In some embodiments, the solubility of a solid dispersion in a pH 6.0 medium containing 0.01% to 0.25% sodium dodecyl sulfate (SDS), e.g., 0.01% SDS, is more than one time greater than two times greater than the solubility of lurasidone or its pharmaceutically acceptable salts. The solubility in a pH 6.0 medium containing 0.01% to 0.25% SDS, e.g., 0.01% SDS, over 5 to 60 minutes is more than one time greater than two times greater than the control group of lurasidone tablets (Latuda®).

[0065] In some embodiments, the AUC of lurasidone or a pharmaceutically acceptable salt during administration of a solid dispersion to fasted rats is more than 1 time higher than that of lurasidone HCl, or even 1.5 to 4 times higher. In some embodiments, the Cmax of lurasidone or a pharmaceutically acceptable salt in rats during administration of a solid dispersion to fasted rats is more than 1 time higher than that of lurasidone HCl, or even 1.5 to 9 times higher. That is, the solid dispersion achieves superior bioavailability compared to lurasidone HCl.

[0066] Pharmaceutical composition

[0067] Pharmaceutical compositions comprising solid dispersions are also provided in some embodiments of this disclosure.

[0068] In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, the solid dosage form includes powder, granules, fine granules, tablets, or capsules.

[0069] In some embodiments, the pharmaceutical composition further comprises at least one excipient, such as a filler, surfactant, disintegrant, lubricant, or a combination thereof. In some embodiments, the filler includes poly(methyl methacrylate), microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly(ethylene oxide), polyoxypropylene, polyvinylpyrrolidone, carbomer, sodium carboxymethyl starch, carboxymethylcellulose and its sodium salts, cross-linked sodium carboxymethylcellulose, xanthan gum, lactose, starch, mannitol, pregelatinized starch, corn starch, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, or a combination thereof. In some embodiments, the surfactant includes sodium lauryl sulfate, quaternary ammonium compounds, lecithin, fatty acid glycerides, polyoxyethylene esters, polyoxylglycerides, sorbitan fatty acid esters, polysorbates, or a combination thereof. In some embodiments, the disintegrant includes croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, starch, pregelatinized starch, or any combination thereof. In some embodiments, the lubricant includes magnesium stearate, colloidal silicon dioxide, stearic acid, talc, glyceryl behenate, hydrogenated castor oil, sodium stearyl fumarate, or a combination thereof.

[0070] In some embodiments, the solubility of the pharmaceutical composition in a pH 6.0 medium containing 0.01% to 0.25% SDS, e.g., 0.01% SDS, over 10 to 75 minutes is more than 1-fold higher, or even 2 to 4-fold higher, than that of the control group of lurasidone tablets (Latuda®).

[0071] treatment method

[0072] In another aspect of this disclosure, a method for treating a mental disorder is provided, comprising administering the above-described solid dispersion or pharmaceutical composition to a subject suffering from a mental disorder. In some embodiments, the mental disorder includes schizophrenia, bipolar disorder, autism, depression, or a combination thereof.

[0073] Another aspect of this disclosure provides the use of the above-described solid dispersion or the above-described pharmaceutical composition in the manufacture of a drug for treating a mental disorder. In some embodiments, the mental disorder includes schizophrenia, bipolar disorder, autism, depression, or a combination thereof. [Examples]

[0074] It should be understood that the embodiments described above and the following embodiments are provided for illustrative purposes only and not for limitation. A variety of variations and modifications within the scope of the invention will become apparent to those skilled in the art from this description.

[0075] Example 1 - Solid dispersion

[0076] Example 1.1 - Preparation method (spray drying)

[0077] The following is a method for preparing a solid dispersion containing lurasidone by solvent evaporation using spray drying.

[0078] Step 1: Prepare the spray-drying solution according to the ratios listed in Table 1.

[0079] Step 2: Batch weigh the pre-mixture of the active ingredient (lurasidone or lurasidone HCl) and carrier (and optionally a surfactant) according to the formulations in Tables 2 to 6.

[0080] In step 3, the pre-mixture measured in step 2 is added to the spray-drying solution in step 1 to form the mixture.

[0081] Step 4: Stir the mixture from Step 3 until clear, then spray dry it using a spray dryer (Mini Spray Dryer B-290 (Buechi)).

[0082] The granules obtained in Step 5 and Step 4 (spray drying) were sieved through a 60-mesh sieve to form solid dispersions of experimental groups 1 to 21, respectively.

[0083] [Table 1]

[0084] [Table 2]

[0085] [Table 3]

[0086] [Table 4]

[0087] [Table 5]

[0088] [Table 6]

[0089] [Table 7]

[0090] Example 1.2 - Preparation Method (Hot Melt Extrusion (HME))

[0091] The hot-melt extrusion method for preparing a solid dispersion containing lurasidone is as follows:

[0092] Step 1: The active ingredient (lurasidone), carrier, and surfactant are batch weighed according to Tables 8 and 9, and then each group is uniformly blended to obtain a mixture.

[0093] In step 2, the mixture obtained in step 1 is placed in a hot melt extruder (Pharma mini HME, Thermo) and then melted to obtain a hot melt extruded product. The hot melt extrusion parameters are shown in Table 10.

[0094] Step 3: For solidification, the hot-melt extruded product is cooled to room temperature (e.g., 25°C) by air cooling. After solidification, the solidified product is crushed and then sieved through a 60-mesh sieve to obtain a solid dispersion (experimental groups 22-28, respectively).

[0095] [Table 8]

[0096] [Table 9]

[0097] [Table 10]

[0098] Example 1.3 - Dissolution and Storage Test

[0099] 1.3.1-Dissolution Test 1

[0100] Solubility tests were performed on experimental groups 1 to 28, the control group lurasidone HCl, and lurasidone, which were manufactured by spray drying or hot melt extrusion. The solubility of each experimental group and the control group lurasidone HCl and lurasidone was analyzed. The solubility tests were performed using the paddle method in 500 mL of pH 6.0 + 0.01% SDS medium at a rotation speed of 100 rpm and a sampling time of 60 minutes. The results are shown in Table 11.

[0101] [Table 11]

[0102] As shown in Table 11, the solubility of each experimental group at 60 minutes in a medium of pH 6.0 + 0.01% SDS was higher than that of the control group (containing only lurasidone or lurasidone HCl), and the solubility of most experimental groups was more than twice that of the control group. In other words, the solid dispersions of the experimental groups have improved solubility of lurasidone.

[0103] Furthermore, it is noteworthy that experimental groups containing surfactants (e.g., experimental groups 2-5, 13, 19) or experimental groups containing other specific carriers and surfactants (e.g., experimental groups 6-9) exhibit higher solubility compared to experimental groups 1 and 20 (lurasidone + PVAP, or lurasidone HCl + PVAP).

[0104] Furthermore, it is noteworthy that in experimental groups 22 and 23, solubility increased (from 1.0 g / mL to 9.5 g / mL) as the carrier (PVAP) concentration increased (from 33.3% to 71.4%).

[0105] Example 1.3.2 - Dissolution Test 2 (Carrier Comparison: PVAP vs. Crospovidone)

[0106] To compare the applicability of carriers suitable for solid dispersions containing lurasidone, solid dispersions of comparison group 1 (containing crospovidone, a common carrier component) were prepared according to the weight ratios in Example 1.2 (HME) and Table 12, and their solubility was tested according to the method described in Example 1.3.1. The comparison results are also listed in Table 12.

[0107] [Table 12]

[0108] Table 12 shows that the solubility of comparison group 1 (active ingredient lurasidone; carrier crospovidone) is essentially similar to that of lurasidone HCl. Relatively, the solubility of experimental group 20 (active ingredient lurasidone; carrier PVAP) is significantly higher than that of lurasidone HCl and comparison group 1 (carrier crospovidone). In other words, solid dispersions containing PVAP acting as a carrier can achieve superior solubility.

[0109] Furthermore, it should be noted that in the preparation method of comparative group 1, the mixture containing crospovidone easily clogs the hot-melt extruder, making extrusion difficult, which makes it difficult to obtain a solid dispersion.

[0110] Therefore, it should be emphasized that not all common carrier components can be used in solid dispersions containing lurasidone, and whether a carrier is suitable for solid dispersions containing lurasidone or lurasidone salts can only be confirmed after field testing.

[0111] Example 1.3.3 - Storage Stability (Carrier: PVAP)

[0112] To observe the storage stability of experimental groups containing different carriers or surfactants, experimental groups 14 (without PAVP) and 16 (with PAVP), which have similar solubility (experimental group 14: 39.8 μg / mL, experimental group 16: 35.2 μg / mL), were selected for storage testing. Specifically, experimental groups 14 and 16 were placed at 25°C for 30 days, and then analyzed by X-ray diffraction (XRD) to observe changes in crystal structure.

[0113] XRD results show that after 30 days of storage, experimental group 14 (without PAVP) exhibits recrystallization problems, while experimental group 16 (with PAVP) maintains an amorphous state after 30 days. Therefore, solid dispersions containing PAVP, which acts as a carrier, exhibit superior storage stability.

[0114] Example 1.3.4 - Dissolution Test 3 (Surfactant Comparison: Surfactant: Lauroyl Polyoxyl-32 Glyceride (Gelucire 44 / 14) vs. Sodium Lauryl Sulfate (SLS))

[0115] To compare the applicability of surfactants suitable for solid dispersions containing lurasidone, comparison groups 2-1 to 2-4 (comparison groups 2-1 and 2-3 contain no surfactant; comparison groups 2-2 and 2-4 contain SLS, a common surfactant component) were prepared according to Example 1.1 (spray drying) or Example 1.2 (HME) and the weight ratios in Table 13 or Table 14, and their solubility was tested according to the method described above in Example 1.3.1. The comparison results are also listed in Tables 13 and 14.

[0116] [Table 13]

[0117] [Table 14]

[0118] Tables 13 and 14 show that experimental groups 10 and 25 (with lauroyl polyoxyl-32 glyceride (Gelucire 44 / 14) as the surfactant) exhibit higher solubility compared to comparison groups 2-1 to 2-4 (without surfactant or with SLS surfactant). In other words, solid dispersions containing lauroyl polyoxyl-32 glyceride acting as a surfactant have superior solubility.

[0119] Therefore, it should be noted that not all common surfactant components can be used in solid dispersions containing lurasidone, and suitable carriers for solid dispersions containing lurasidone or lurasidone salts can only be confirmed after field testing.

[0120] Example 1.4 - Animal Test

[0121] Lurasidone HCl was used as the control group, and experimental groups 14-17, 22, and 28 were used as test groups. The pharmacokinetics of each group were evaluated in male Sprague-Dawley rats.

[0122] In particular, the control group and experimental groups 14-17, 22, and 28 were administered to rats under fasting conditions, with the drug being either 10 mg / kg lurasidone HCl or 10 mg / kg lurasidone HCl containing an equivalent amount of lurasidone. Each experimental group consisted of three rats, and the sampling times for analyzing pharmacokinetic results were 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours, which are shown in Table 15.

[0123] [Table 15]

[0124] Table 15 shows that the maximum plasma concentration (Cmax) and area under the curve (AUC) of lurasidone in each experimental group were higher than those of lurasidone HCl without solid dispersion, indicating that the solid dispersions in the experimental groups containing selected carriers and surfactants may achieve higher absorption efficiency. Therefore, the food effect of lurasidone may be reduced or eliminated.

[0125] Furthermore, experimental group 28 (carrier: PVA + mesoporous silica) had a relatively high AUC (highest C) despite having a solubility of only 1.2 μg / mL (the third lowest solubility among the 28 experimental groups) as shown in Table 11. max It should be noted that it also exhibits the second highest AUC. Therefore, this combination of PVA and mesoporous silica may achieve unexpectedly superior absorption efficiency in animal studies.

[0126] Example 2 - Pharmaceutical Composition

[0127] 2.1-Preparation method

[0128] Experimental groups 2-1 to 2-3 (prepared according to experimental groups 2, 13, and 14, respectively)

[0129] The solid dispersions of the experimental group described above are prepared into pharmaceutical compositions. The formulations are shown in Table 16, which represent solid oral dosage forms. The preparation method is as follows.

[0130] 1. Manufacturing of tablet cores

[0131] (1) Blend the materials other than magnesium stearate to form a mixture according to the formulations in Table 16 (tablet core).

[0132] (2) Sift the mixture in step (1) using a 30-mesh sieve.

[0133] (3) Blend the mixture from step (2) again.

[0134] (4) Blend the mixture from step (3) with magnesium stearate to form core granules.

[0135] (5) By using a tableting device, the core granules in step (4) are pressed to form a tablet core.

[0136] 2. Manufacturing of the outer film

[0137] (1) Dissolve the outer membrane material from Table 16 in water to form a 15% (w / w) concentration membrane solution.

[0138] (2) The membrane solution is sprayed onto the tablet core obtained in the above step.

[0139] (3) Based on the formulations listed in Table 16, the weight of the membrane is increased to form a film-coated tablet. The formulation ratios of the outer membranes listed in Table 16 are relative to the total weight of the tablet.

[0140] (4) The film-coated tablets obtained in step (3) are dried in a film coating apparatus at 45°C for 15 minutes.

[0141] [Table 16]

[0142] 2.2-Dissolution Test

[0143] Dissolution tests were performed for experimental groups 2-1 to 2-3 to analyze the solubility of each pharmaceutical composition in the experimental groups and the commercially available product (product name: Latuda®). The dissolution tests were performed using the paddle method in 900 ml of a medium with a pH of 6.0 + 0.01% SDS, where the rotation speed was 100 rpm for the first 60 minutes and 150 rpm from 60 to 75 minutes, and the sampling times were 0, 5, 10, 15, 20, 30, 60, and 75 minutes, respectively. The results are shown in Table 17 and Figure 2.

[0144] [Table 17]

[0145] Table 17 and Figure 2 show that, compared to commercially available products, experimental groups 2-2 and 2-3 exhibited higher dissolution rates from 10 minutes to 75 minutes, and experimental group 2-1 exhibited higher dissolution rates from 20 minutes to 75 minutes. It is noteworthy that, in this disclosure, pharmaceutical compositions prepared with specific carriers and specific surfactants exhibit dissolution efficiencies similar to or even better than those of commercially available products.

[0146] While this disclosure is disclosed in embodiments described above, it is not intended to limit the disclosure, and those skilled in the art will understand that a variety of variations and modifications can be made without departing from the spirit and scope of this disclosure. The scope of protection of this disclosure is subject to the definition of the claims.

Claims

1. Lurasidone or a pharmaceutically acceptable salt thereof, Carrier and Includes, The carrier material includes polyvinyl acetate phthalate, polyvinyl alcohol, cellulose acetate phthalate, mesoporous silica, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose, povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate, hypromellose phthalate, or a combination thereof. Solid dispersion.

2. The solid dispersion according to claim 1, wherein the weight ratio of lurasidone or a pharmaceutically acceptable salt thereof to the carrier is 3:1 to 1:

30.

3. The solid dispersion according to claim 1, wherein, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, and the weight percentage of the carrier is 25% to 97%.

4. The carrier includes a first carrier and a second carrier, The first carrier comprises the polyvinyl acetate phthalate, the polyvinyl alcohol, the cellulose acetate phthalate, the mesoporous silica, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the hydroxypropyl cellulose, the copovidone, the hypromellose acetate succinate, or a combination thereof. The second carrier comprises the polyvinyl alcohol, the mesoporous silica, the hydroxypropyl methylcellulose, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the acrylic resin, the hydroxypropyl cellulose, the povidone, the copovidone, the ethylcellulose, the polyoxyethylene glycol, the hypromellose acetate succinate, the hypromellose phthalate, or a combination thereof. The solid dispersion according to claim 1.

5. The solid dispersion according to claim 4, wherein the weight ratio of lurasidone or a pharmaceutically acceptable salt thereof to the first carrier and the second carrier is 3:1 to 1:

30.

6. The solid dispersion according to claim 4, wherein the weight ratio of the first carrier to the second carrier is 1:10 to 10:

1.

7. The solid dispersion according to claim 4, wherein, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, and the weight percentages of the first carrier and the second carrier are 25% to 97%.

8. The solid dispersion according to claim 1, further comprising a surfactant, wherein the surfactant further comprises a glycerol ester, a polyoxyethylene ester, or a combination thereof.

9. The solid dispersion according to claim 1 and Excipients and A pharmaceutical composition containing the above.

10. A method for preparing a solid dispersion, which includes: Mixing lurasidone or a pharmaceutically acceptable salt thereof with a carrier to form a mixture, The mixture is spray-dried, or The mixture is melted and then cooled. Includes, The carrier includes polyvinyl acetate phthalate, polyvinyl alcohol, cellulose acetate phthalate, mesoporous silica, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose, povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate, hypromellose phthalate, or a combination thereof. Preparation method.

11. The preparation method according to claim 10, wherein the mixing step comprises mixing the lurasidone or a pharmaceutically acceptable salt thereof with the carrier in an organic solvent to form the mixture.

12. The preparation method according to claim 10, wherein the melting step includes melting the mixture at a temperature of 80°C to 200°C by using a hot melt extruder.

13. Lurasidone or a pharmaceutically acceptable salt thereof, Carrier and, Surfactants and Includes, The surfactant includes glycerol ester, polyoxyethylene ester, or a combination thereof. Solid dispersion.

14. The solid dispersion according to claim 13, wherein the weight ratio of lurasidone or a pharmaceutically acceptable salt thereof to the carrier is 3:1 to 1:

30.

15. The solid dispersion according to claim 13, wherein the weight ratio of lurasidone or a pharmaceutically acceptable salt thereof to the surfactant is 1:0.1 to 1:

30.

16. The solid dispersion according to claim 13, wherein, based on 100% by weight of the solid dispersion, the weight percentage of lurasidone or a pharmaceutically acceptable salt thereof is 3% to 75%, the weight ratio of the carrier is 25% to 97%, and the weight ratio of the surfactant is 0.1% to 45%.

17. The solid dispersion according to claim 13, wherein the surfactant is a fatty acid glyceride, a polyoxyethylene fatty acid ester, or a combination thereof.

18. The solid dispersion according to claim 17, wherein the surfactant is a polyoxylglyceride.

19. The solid dispersion according to claim 13, wherein the carrier material comprises polyvinyl acetate phthalate, polyvinyl alcohol, cellulose acetate phthalate (CAP), mesoporous silica, hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, acrylic resin, hydroxypropyl cellulose, povidone, copovidone, ethylcellulose, polyoxyethylene glycol, hypromellose acetate succinate, hypromellose phthalate, or a combination thereof.

20. The carrier includes a first carrier and a second carrier, The first carrier comprises the polyvinyl acetate phthalate, the polyvinyl alcohol, the cellulose acetate phthalate, the mesoporous silica, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the hydroxypropyl cellulose, the copovidone, the hypromellose acetate succinate, or a combination thereof. The second carrier comprises the polyvinyl alcohol, the mesoporous silica, the hydroxypropyl methylcellulose, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the acrylic resin, the hydroxypropyl cellulose, the povidone, the copovidone, the ethylcellulose, the polyoxyethylene glycol, the hypromellose acetate succinate, the hypromellose phthalate, or a combination thereof. The solid dispersion according to claim 19.

Images