Sustained release osmotically controlled pharmaceutical composition and method for preparing same

Abstract

A sustained-release osmotically controlled pharmaceutical composition is provided, comprising a core and a semipermeable membrane coated on the core. The core comprises a drug compartment, wherein the drug compartment comprises a first active ingredient, a first polymer, and a first osmogen, and the first active ingredient comprises lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof. The semipermeable membrane comprises a membrane body and at least one pore distributed throughout the membrane body.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 418,029, filed October 20, 2022, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to sustained-release osmotically controlled pharmaceutical compositions. In particular, the present disclosure relates to sustained-release osmotically controlled pharmaceutical compositions comprising lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof. [Background technology]

[0003] 2. Description of Related Art Latuda® (active pharmaceutical ingredient (API): lurasidone HCl) is a rapid-release (immediate-release) tablet in which lurasidone is rapidly released into the circulation, achieving a rapid onset of effect. However, because lurasidone is released rapidly into the blood, greater fluctuations in lurasidone plasma concentrations occur, raising safety concerns.

[0004] Although several types of sustained controlled release formulations are available, there are still many problems.

[0005] For example, CN110693843A provides a tablet manufactured using a hydrophilic gel matrix system. The API release mechanism in a hydrophilic gel matrix system is controlled by a hydrophilic polymer that forms a gel upon absorbing liquid. Therefore, the API diffuses out of the tablet over time as the gel erodes, achieving the goal of sustained controlled release. However, the API release from this formulation is relatively rapid initially, exhibiting a first-order release curve, and the release rate is affected by the API concentration. As the API concentration decreases, the release rate decreases. This means that the hydrophilic gel matrix system has limited effectiveness in reducing plasma concentration fluctuations. Furthermore, rapid disintegration of the tablet structure caused by agitation in the gastrointestinal tract during ingestion increases the risk of API burst release.

[0006] CN107998105A provides a pellet capsule formulation formed by an API-containing core, an isolation coating layer, an extended-release coating layer, and a protective coating layer. Because pellet capsules contain multiple layers, they require multiple, cumbersome manufacturing procedures. Furthermore, the manufacturing procedures are inflexible and the technical requirements are high, which can lead to increased lot-to-lot variation. In other words, pellet capsule formulations have several limitations.

[0007] Therefore, a method for avoiding the burst release of lurasidone and providing a sustained release pharmaceutical composition that can be easily manufactured with stable performance remains to be solved. Summary of the Invention

[0008] In one embodiment of the present disclosure, there is provided a sustained-release osmotically controlled pharmaceutical composition comprising: a core; and a semipermeable membrane coated on the core. The core comprises a drug compartment, wherein the drug compartment comprises a first active ingredient, a first polymer, and a first osmogen, and the first active ingredient comprises lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof. The semipermeable membrane comprises a membrane body and at least one pore distributed in the membrane body.

[0009] In some embodiments, the weight percentage of the first active ingredient is 2% to 30% based on 100% core weight.

[0010] In some embodiments, the weight percentage of the first polymer is between 5% and 80%, based on 100% core weight.

[0011] In some embodiments, the first polymer comprises poly(methyl methacrylate), microcrystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, poly(ethylene oxide), polyoxypropylene, polyvinylpyrrolidone, carbomer, sodium carboxymethyl starch, carboxymethyl cellulose, the sodium salt of carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, xanthan gum, or a combination thereof.

[0012] In some embodiments, the first osmogen comprises a water-soluble salt, a carbohydrate, a water-soluble amino acid, or a combination thereof, and the weight percentage of the first osmogen is 10% to 55% based on 100% core weight.

[0013] In some embodiments, the first osmogen comprises magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, sodium sulfate, sodium phosphate, potassium chloride, potassium phosphate, sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate, sodium carboxymethylcellulose, sucrose, sorbitol, mannitol, glucose, lactose, fructose, glycine, leucine, alanine, methionine, urea, or a combination thereof.

[0014] In some embodiments, the drug compartment further comprises an acidifying agent.

[0015] In some embodiments, the weight percentage of the semipermeable membrane is 1% to 45%, based on 100% of the core weight.

[0016] In some embodiments, the membrane body comprises cellulose acetate, ethyl cellulose, or a combination thereof.

[0017] In some embodiments, the core further comprises a push compartment, the push compartment comprising a second polymer and a second osmogen.

[0018] In some embodiments, the weight percentage of the second polymer is 15% to 55% based on 100% core weight, and the weight percentage of the second osmogen is 5% to 55% based on 100% core weight.

[0019] In some embodiments, the first percent dissolution of the first active ingredient is between 0% and 30% within 2 hours, and the second percent dissolution of the first active ingredient is between 30% and 100% within 10 hours, when assayed in McIlvaine buffer at pH 3.8.

[0020] In some embodiments, the sustained-release osmotic-controlled pharmaceutical composition further comprises a film coating coated on the semipermeable membrane.

[0021] In some embodiments, the weight percentage of the film coating is 2% to 25%, based on 100% weight of the core and semipermeable membrane.

[0022] In some embodiments, the film coating comprises a second active ingredient, the second active ingredient comprising lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof, wherein the weight percentage of the second active ingredient is 10% to 60% based on 100% by weight of the first active ingredient in the core.

[0023] In some embodiments, the percent dissolution of the first active ingredient and the second active ingredient is between 10% and 40% within 1 hour when assayed in McIlvaine buffer at pH 3.8.

[0024] In another aspect of the present disclosure, there is provided a method for preparing a sustained-release osmotically controlled pharmaceutical composition, the method comprising: mixing a first active ingredient, a first polymer, and a first osmogen to form a drug compartment mixture, wherein the first active ingredient comprises lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof; compressing and tableting the drug compartment mixture to form a core; mixing a membrane body material and a porogen in a solvent to form a membrane liquid; spraying the membrane liquid onto the core; and drying the membrane liquid to form a semipermeable membrane coated on the core.

[0025] In some embodiments, the method further includes mixing a second polymer and a second osmogen to form a push compartment mixture, and compressing and tableting the drug compartment mixture includes: compressing the drug compartment mixture to form a drug compartment; mixing the push compartment mixture with the drug compartment to form a core mixture; and compressing and tableting the core mixture to form a core.

[0026] In some embodiments, the method further comprises the steps of: mixing film coating materials in an aqueous solution to form a film coating liquid; and spraying the film coating liquid onto the semipermeable membrane to form a film coating coated on the semipermeable membrane.

[0027] In another aspect of the present disclosure, there is provided a method for treating a psychiatric disorder, comprising administering to a subject suffering from the psychiatric disorder the sustained-release osmotic-controlled pharmaceutical composition described above. [Brief explanation of the drawings]

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

[0029] [Figure 1] FIG. 1 illustrates a flow chart of a method for preparing a sustained-release osmotic-controlled pharmaceutical composition according to some embodiments of the present disclosure.

[0030] [Figure 2A] FIG. 2A illustrates the release profiles of Examples 1-9 and the commercial product LATUDA in dissolution assays according to some embodiments of the present disclosure.

[0031] [Figure 2B] FIG. 2B illustrates the blood concentrations of LATUDA in beagle dogs while being fed Example 6 or LATUDA in some embodiments of the disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0032] In order to describe the present disclosure in detail and completely, embodiments and specific embodiments of the present disclosure accompanied by illustrative explanations are presented, but these are not the only modes for implementing or using the specific embodiments of the present disclosure. The embodiments disclosed herein may be combined with or substituted for each other in a suitable manner, and one embodiment may be added to another embodiment without further explanation. In the following description, many specific details will be set forth in order for the reader to fully understand the following embodiments. However, the embodiments of the present disclosure may be practiced without these specific details.

[0033] To illustrate the methods disclosed herein, a series of operations or steps are described below, but the order of the operations or steps is not intended to be limiting. For example, certain operations or steps may be performed in different orders and / or concurrently with other steps. Moreover, not all illustrated operations, steps, and / or features are required to practice embodiments of the present disclosure. Furthermore, each operation or step described herein may include multiple sub-steps or actions.

[0034] definition

[0035] As used herein, unless specifically indicated otherwise, "a" and "the" can mean singular or plural. It will be understood that the terms "comprise," "include," "have," and similar terms, as used herein, refer to stated features, regions, integers, steps, operations, elements, and / or components, but do not exclude other features, regions, integers, steps, operations, elements, components, and / or groups.

[0036] As used herein, "drug" or "active ingredient" refers to lurasidone or a pharmaceutically acceptable salt thereof, including, but not limited to, salts, esters, complexes, chelators, cage compounds, racemates, enantiomers, and the like.

[0037] As used herein, "water soluble" refers to a substance having a solubility in water of greater than 10 g / L (1 g / 100 mL), e.g., from 10 g / L to 100 g / L, e.g., 10 g / L, 20 g / L, 30 g / L, 40 g / L, 50 g / L, 60 g / L, 70 g / L, 80 g / L, 90 g / L, 100 g / L, or any value between any interval of the aforementioned values.

[0038] As used herein, "Cmax" refers to the maximum plasma / medium concentration of the active ingredient.

[0039] As used herein, "zero-order release" is characterized by the fact that the release rate of the active ingredient is not affected by the concentration of the active ingredient, and the active ingredient is generally released at a constant or near-constant rate. Zero-order release is shown as a linear segment in the dissolution curve, and the release rate at each point in the linear segment differs from the average rate of the linear segment by less than 1%, and the interval between two sampling points should not exceed 2 hours.

[0040] As used herein, "excipients" refer to pharmaceutical additives that have no pharmacological activity and are used in pharmaceutical compositions for different purposes and functions.

[0041] As used herein, "osmogen" refers to a material that provides an osmotic pressure differential that drives fluid in the environment into the sustained-release osmotically-controlled pharmaceutical composition.

[0042] As used herein, "pore" refers to the openings formed by the porogen that allow environmental fluid to enter the sustained-release osmotic-controlled pharmaceutical composition.

[0043] As used herein, "orifice" refers to an opening formed by manual action, laser, mechanical means or other suitable orifice-making methods to allow the active ingredient to be forced out of the sustained-release osmotic-controlled pharmaceutical composition.

[0044] As used herein, "immediate release" (IR) refers to the phenomenon whereby the active ingredient is completely released in 2 hours, 1 hour, 30 minutes or less.

[0045] Sustained release osmotically controlled pharmaceutical composition and method for preparing same

[0046] The main objective of the present disclosure is to provide a sustained-release osmotically controlled pharmaceutical composition in the form of a sustained-release osmotic pharmaceutical dosage form, which controls the release of lurasidone or a pharmaceutically acceptable salt thereof by osmotic pressure.It is noted that lurasidone is insoluble in water (e.g., its solubility in water is less than 0.1 mg / mL) and has a high dosage requirement in the administration regimen.Therefore, the essential difficulty in applying lurasidone in a sustained-release osmotically controlled pharmaceutical composition relates to a method for increasing the dissolution efficiency of the active ingredient while avoiding fluctuations in a stable release state.

[0047] Surprisingly, the sustained-release osmotically controlled pharmaceutical composition achieves sustained controlled release through the application of an osmogen and a polymer in the core (e.g., the drug compartment, or a combination of the drug compartment and the push compartment) and a semipermeable membrane. The mechanism of the sustained-release osmotically controlled pharmaceutical composition is that when the environmental fluid diffuses into the core due to the osmotic pressure caused by the osmogen, the polymer swells to form a three-dimensional structure, and the active ingredient dispersed in the polymer is dissolved by the environmental fluid and slowly released through diffusion. Meanwhile, the three-dimensional structure formed by the polymer can act as a barrier to delay the diffusion of the active ingredient. On the other hand, the semipermeable membrane acts as a barrier that allows the environmental fluid to pass through and control the release of the active ingredient.

[0048] It should be emphasized that the active ingredient in the sustained-release osmotically controlled pharmaceutical composition is released at a zero-order rate for at least 4 hours through an osmotically controlled mechanism without being affected by the environment, and the plateau of the dissolution percentage of the active ingredient is higher than 50%. Therefore, the sustained-release osmotically controlled pharmaceutical composition of the present disclosure can not only stably provide a desired amount of the active ingredient, but also significantly reduce Cmax, avoid fluctuations of the active ingredient, and prolong the release of the active ingredient (e.g., more than 4 hours), thereby reducing the occurrence of side effects and increasing patient compliance.

[0049] That is, the sustained-release osmotic controlled pharmaceutical composition of the present disclosure balances the need to prevent fluctuations in the plasma concentration of the active ingredient with the need for higher release efficiency of the active ingredient through formulation design and selection of appropriate materials.

[0050] Please refer to Figure 1. Figure 1 shows a flowchart of a method 100 for preparing a sustained-release osmotic-controlled pharmaceutical composition in some embodiments of the present disclosure, which includes steps S110, S120, S130, S140, and S150. It should be emphasized that compared with the capsule formulation described in CN107998105A, method 100 is simpler and the amount between lots can be relatively stable.

[0051] First, referring to step S110, a first active ingredient, a first polymer, and a first osmogen are mixed to form a drug compartment mixture, where the first active ingredient comprises lurasidone, a pharmaceutically acceptable salt of lurasidone, or a combination thereof.

[0052] In some embodiments, the first polymer comprises poly(methyl methacrylate), microcrystalline cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, poly(ethylene oxide), polyoxypropylene, polyvinylpyrrolidone, carbomer, sodium carboxymethyl starch, carboxymethyl cellulose, sodium salt of carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, xanthan gum, or a combination thereof. As the fluid in the environment diffuses into the sustained-release osmotic-controlled pharmaceutical composition, the first polymer expands, delaying the release of the first active ingredient.

[0053] In some embodiments, the first osmogen comprises a water-soluble salt, a carbohydrate, a water-soluble amino acid, or a combination thereof. In some embodiments, the first osmogen comprises magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, sodium sulfate, sodium phosphate, potassium chloride, potassium phosphate, sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate, sodium carboxymethylcellulose, sucrose, sorbitol, mannitol, glucose, lactose, fructose, glycine, leucine, alanine, methionine, urea, or a combination thereof. In some embodiments, some materials can serve as both the first polymer and the first osmogen. Thus, the barrier (caused by the first polymer) that delays the release of the first active ingredient and the diffusion of liquid in the environment (caused by the first osmogen) can be adjusted by selecting an appropriate material that simultaneously functions as the first polymer and the first osmogen.

[0054] In some embodiments, the weight ratio of the first active ingredient to the first polymer is 1:1.5 to 1:7, e.g., 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or any value within any of the intervals described above. In some embodiments, the weight ratio of the first active ingredient to the first osmogen is 1:0.6 to 1:5, e.g., 1:0.6, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, or any value within any of the intervals described above. If the weight ratio is too low, the release percentage of the first active ingredient decreases. If the weight ratio is too high, the release content of the first active ingredient increases, increasing the risk of fluctuations in the plasma concentration of the first active ingredient.

[0055] In some embodiments, step S110 further includes mixing the first polymer, the first osmogen, and the first active ingredient with an adhesive, a lubricant (e.g., magnesium stearate), a preservative, a filler, an acidifying agent, a coloring agent, or a combination thereof. For example, HPMC (hypromellose) can act as an adhesive to aid in adhesion of the first polymer, the first osmogen, and the first active ingredient. In some embodiments, the acidifying agent provides an acidic microenvironment to aid in dissolution of the first active ingredient. The acidifying agent can include, for example, citric acid, succinic acid, tartaric acid, or a combination thereof.

[0056] In some embodiments, magnesium stearate may be added last to achieve better lubrication efficiency.

[0057] In some embodiments, the method 100 further comprises mixing a second polymer and a second osmogen to form a push compartment mixture. The candidate materials for the second polymer and the second osmogen are similar to those for the first polymer and the first osmogen, respectively, and therefore will not be repeated here.

[0058] Now, see step S120, where the drug segment mixture is compressed and tableted to form the core.

[0059] In some embodiments, step S120 includes compressing the drug compartment mixture to form a drug compartment; mixing the push compartment mixture with the drug compartment to form a core mixture; and compressing and tableting the core mixture to form a core. It should be emphasized that the step of mixing the push compartment mixture with the drug compartment after compressing the drug compartment mixture can provide a core having two layers, with the drug compartment overlapping the push compartment. Thus, while the sustained-release osmotic-controlled pharmaceutical composition absorbs fluid in the environment, the push compartment expands and pushes the first active ingredient in the drug compartment out of the sustained-release osmotic-controlled pharmaceutical composition through an orifice in the portion of the semipermeable membrane adjacent to the drug compartment, thereby increasing the release content of the first active ingredient. In one embodiment, selecting poly(ethylene oxide) to serve as the second polymer in the push compartment, compared to xanthan gum, provides a higher push force and achieves a higher release of the first active ingredient (i.e., a higher plateau in a dissolution assay).

[0060] In some embodiments, before step S120, method 100 further includes a step of granulating the drug compartment mixture, such as adding an organic solvent (e.g., ethanol) to the drug compartment mixture, sieving the drug compartment mixture to obtain drug compartment particles, and drying the drug compartment particles. For example, the drug compartment particles are dried at 40°C to 60°C for 20 to 40 minutes. Through the method of granulating the drug compartment mixture, the particle size of the drug compartment particles can become more uniform and well-distributed, thereby increasing the uniformity and flowability and increasing the release stability of the first active ingredient. In some embodiments, before mixing the push compartment mixture with the drug compartment, method 100 further includes a step of granulating the push compartment mixture in a manner similar to that of granulating the drug compartment mixture to further increase the flowability of the push compartment mixture and stabilize the weight of the core mixture during the subsequent compression and tableting steps.

[0061] It is noted that the percent release of the first active ingredient can be controlled by the weight percentage of the materials in the core, such as the first active ingredient, first polymer, first osmogen, second polymer, and second osmogen.

[0062] In some embodiments, the weight percent of the first active ingredient is 2% to 30%, for example, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or any value between any of the above values, based on 100% core weight. If the weight percent of the first active ingredient is too low, the barrier provided by the polymer (e.g., the first polymer, or the combination of the first polymer and the second polymer) is too high, limiting the release efficiency of the first active ingredient. If the weight percent of the first active ingredient is too high, the risk of fluctuations in the plasma concentration of the first active ingredient increases.

[0063] In some embodiments, the weight percentage of the first polymer is 5% to 80%, for example, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or any value between any of the above values, based on 100% core weight. Generally, if the weight percentage of the first polymer is too low, the barrier provided by the first polymer is insufficient, increasing the risk of fluctuations in the plasma concentration of the first active ingredient. If the weight percentage of the first polymer is too high, the barrier provided by the first polymer is too high, limiting the release efficiency of the first active ingredient. In some preferred embodiments, the weight percentage of the first polymer is 10% to 80%, based on 100% core weight.

[0064] In some embodiments, the weight percentage of the first osmogen is 10% to 55%, for example, 10%, 20%, 30%, 40%, 50%, 55%, or any value between any of the above values, based on 100% core weight. Generally, if the weight percentage of the first osmogen is too low, the pressure provided by the first osmogen is insufficient, limiting the release efficiency of the first active ingredient. If the weight percentage of the first osmogen is too high, the pressure provided by the first osmogen is too high, increasing the risk of fluctuations in the plasma concentration of the first active ingredient.

[0065] In some embodiments, the weight percentage of the second polymer is 15% to 55%, e.g., 15%, 20%, 30%, 45%, 50%, 55%, or any value between any of the intervals mentioned above, based on 100% core weight. In some embodiments, the weight percentage of the second osmogen is 5% to 55%, e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or any value between any of the intervals mentioned above, based on 100% core weight. In some preferred embodiments, the weight percentage of the second osmogen is 5% to 15%, based on 100% core weight. After the environmental fluid diffuses into the sustained-release osmotically controlled pharmaceutical composition, the push compartment expands and provides a force to the drug compartment. Therefore, if the weight percentage of the second polymer or the second osmogen is too low, the force provided by the push compartment will be insufficient, limiting the release efficiency of the first active ingredient. If the weight percentage of the second polymer or second osmogen is too high, the force provided by the push compartment will be too high, increasing the risk of fluctuations in the first active ingredient plasma concentration.

[0066] In some embodiments, the weight percentage of the combination of the first polymer and the second polymer is 30% to 80%, for example, 30%, 40%, 50%, 60%, 70%, 80%, or any value between the above values, based on 100% core weight. Generally, if the weight percentage of the combination of the first polymer and the second polymer is too low, the barrier provided by the first polymer and the second polymer is insufficient, increasing the risk of fluctuations in the plasma concentration of the first active ingredient. Furthermore, if the weight percentage of the combination of the first polymer and the second polymer is too low to meet the desired dosage requirements of the active ingredient, the volume of the sustained-release osmotic-controlled pharmaceutical composition may be too large to administer. If the weight percentage of the combination of the first polymer and the second polymer is too high, the barrier provided by the first polymer and the second polymer is too high, limiting the release efficiency of the first active ingredient.

[0067] The film body material and the porogen are mixed in a solvent to form a film solution, see step S130.

[0068] In some embodiments, the membrane body material primarily forms a semipermeable membrane, wherein the membrane body material comprises cellulose acetate, ethyl cellulose, or a combination thereof. In some embodiments, a porogen is used to form pores in the semipermeable membrane, allowing environmental fluid to flow into the sustained-release osmotic-controlled pharmaceutical composition. The porogen comprises hydroxypropyl cellulose, hypromellose, glycerin, propylene glycol, polyethylene glycol, sucrose, mannitol, lactose, sodium chloride, or a combination thereof. In some embodiments, the solvent comprises a dual solvent system for dissolving the membrane body material and the porogen. For example, the dual solvent system is a combination of an aqueous phase solvent (e.g., water) and an organic solvent (e.g., acetone).

[0069] In some embodiments, step S130 includes mixing the membrane body material, the porogen, and a plasticizer in a solvent, where the plasticizer is used to increase the strength of the semipermeable membrane. In some embodiments, the plasticizer includes triethyl citrate, propylene glycol, polysorbate 80, polyethylene glycol, polyoxymethylene, polyethylene oxide, sorbitan ester, triacetyl glyceride, diethyl phthalate, mineral oil, trisebacic acid, glycerin, or a combination thereof.

[0070] In some embodiments, the weight percentage of the membrane body material and porogen in the membrane solution is 2.5% to 7.5%, for example, 2.5%, 5%, 7.5%, or any value between any of the intervals mentioned above. If the weight percentage is too low, the subsequent steps (spraying and drying) must be performed more times, thereby extending the time required for the subsequent steps. If the weight percentage is too high, it is difficult to control the appropriate amount of membrane body material and porogen to coat on the core in the subsequent steps.

[0071] Spray the membrane liquid onto the core, see step S140.

[0072] Referring to step S150, the membrane liquid is dried to form a semipermeable membrane coated on the core, where pores are formed by the porogen and distributed throughout the membrane body, allowing environmental fluids to diffuse into the drug compartment and push compartment.

[0073] In some embodiments, after step S150, the membrane solution is further dried at a temperature of 40°C to 50°C (e.g., 40°C, 45°C, 50°C, or any value between any of the intervals mentioned above) for 40 to 60 hours (e.g., 40 hours, 45 hours, 50 hours, 55 hours, 60 hours, or any value between any of the intervals mentioned above). If the temperature is too low or the time is too short, residual solvent will remain outside the sustained-release osmotic controlled pharmaceutical composition. If the temperature is too high or the time is too long, the state of the first polymer or the second polymer may change.

[0074] In some embodiments, the weight percentage of the semipermeable membrane is 1% to 45%, for example, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or any value between any of the above values, based on 100% core weight. In some preferred embodiments, the weight percentage of the semipermeable membrane is 1% to 40%, based on 100% core weight. If the weight percentage is too low, the dissolution rate of the first component will be too high (i.e., the zero-order release slope will be too high), increasing the risk of fluctuations in the first active component. If the weight percentage is too high, the dissolution rate of the first component will be too low (i.e., the zero-order release slope will be too low), resulting in insufficient release efficiency.

[0075] According to steps S110 to S150, a sustained-release osmotic-controlled pharmaceutical composition is provided, comprising a core and a semipermeable membrane coated on the core, wherein the core may comprise only a drug compartment, or may comprise a drug compartment and a push compartment, depending on clinical needs.

[0076] In some embodiments, the first percent dissolution of the first active ingredient, when assayed in McIlvaine buffer at pH 3.8, is 0% to 30%, e.g., 0%, 5%, 10%, 15%, 20%, 25%, 30%, or any value between any of the intervals recited above, within 2 hours. In some embodiments, the second percent dissolution of the first active ingredient, when assayed in McIlvaine buffer at pH 3.8, is 30% to 100%, e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any value between any of the intervals recited above, within 10 hours. The dissolution rate of the first active ingredient can maintain a zero-order release rate for at least 4 hours, thereby avoiding fluctuations in the plasma concentration of the first active ingredient.

[0077] In some other embodiments, to maintain the delivery of the first active ingredient at an initial release state (e.g., a release state within 4 hours), method 100 further includes mixing a film-coating material in an aqueous solution to form a film-coating solution, and spraying the film-coating solution onto the semipermeable membrane to form a film coating coated on the semipermeable membrane. In some embodiments, method 100 further includes drying the film-coating solution after spraying the film-coating solution onto the semipermeable membrane, similar to step S150.

[0078] In some embodiments, the film coating material comprises a second active ingredient and a film material, where the second active ingredient is the same as the first active ingredient. In some embodiments, the film material comprises hypromellose.

[0079] In some embodiments, the weight percentage of the film coating is 2% to 25%, e.g., 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, or any value between any of the intervals mentioned above, based on 100% weight of the core and semipermeable membrane. In some embodiments, the weight percentage of the second active ingredient is 10% to 60%, e.g., 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or any value between any of the intervals mentioned above, based on 100% weight of the first active ingredient in the core. If the weight percentage is too low, the release percentage of the active ingredients (first active ingredient and second active ingredient) will be limited. If the weight percentage is too high, the risk of fluctuations in active ingredient plasma concentration will increase.

[0080] In some embodiments, the weight percentage of the second active ingredient and film material in the film-coating solution is 5% to 15%, for example, 5%, 10%, 15%, or any value between any of the above values. If the weight percentage is too low, the subsequent step (spraying) must be performed more frequently, thereby extending the time required for the subsequent step. If the weight percentage is too high, it is difficult to control the appropriate amount of the second active ingredient and film material.

[0081] In some embodiments, method 100 further comprises forming at least one orifice by manual action, laser, mechanical means, or other suitable orifice-making method, hi some embodiments, the orifice is formed in a portion of the semipermeable membrane adjacent to the drug compartment to allow for the extrusion of the first active ingredient out of the sustained-release osmotic-controlled pharmaceutical composition.

[0082] In some embodiments, when the sustained-release osmotic-controlled pharmaceutical composition with a film coating is assayed in McIlvaine buffer at pH 3.8, the percent dissolution of the active ingredients (first active ingredient and second active ingredient) is 10% to 40%, e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, or any value between any of the intervals mentioned above, within 1 hour. The percent dissolution of the active ingredients within 1 hour can be adjusted according to the weight percent of the second active ingredient or the weight ratio of the second active ingredient to the film material.

[0083] Methods for Treatment

[0084] In another aspect of the present disclosure, there is provided a method for treating a psychiatric disorder, comprising administering the sustained-release osmotic-controlled pharmaceutical composition described above to a subject suffering from the psychiatric disorder. In some embodiments, the psychiatric disorder comprises schizophrenia, bipolar disorder, autism, depression, or a combination thereof.

[0085] In another aspect of the present disclosure, there is provided the use of the sustained-release osmotically controlled pharmaceutical composition described above in the manufacture of a medicament for treating a psychiatric disorder.

[0086] In some embodiments, the pharmaceutical agent is in the form of a tablet, capsule, or enteric formulation.

[0087] In some embodiments, the pharmaceutical preparation comprises excipients, such as fillers, disintegrants, adhesives, surfactants, flavoring agents, coloring agents, and lubricants.

[0088] It should be understood that the above-described embodiments and the following examples are offered by way of illustration and not by way of limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from this description.

[0089] I. Methods for Preparing Sustained-Release Osmotically Controlled Pharmaceutical Compositions

[0090] To clarify the appropriate blending ratios and materials for the sustained-release osmotic controlled pharmaceutical composition, Examples 1 to 9 are provided, and the methods for preparing Examples 1 to 9 are described below in order.

[0091] Example 1

[0092] 1. Granulation of the drug compartment

[0093] (1) According to Table 1, mix all ingredients except magnesium stearate until uniform.

[0094] (2) For granulation, add an appropriate amount of alcohol and then pass the wet granules through a 20 mesh sieve.

[0095] (3) The material in the fluidized bed is dried at 50°C for 30 minutes, and then the dry granules are screened through a 20 mesh sieve to form particles.

[0096] (4) The particles obtained in (3) above are uniformly mixed with magnesium stearate to obtain drug compartment particles.

[0097] 2. Granulation of the push compartment

[0098] (1) According to Table 1, mix all ingredients except magnesium stearate until uniform.

[0099] (2) For granulation, add an appropriate amount of alcohol and then pass the wet granules through a 20 mesh sieve.

[0100] (3) The material in the fluidized bed is dried at 50°C for 30 minutes, and then the dried granules are screened through a 20 mesh sieve to form particles.

[0101] (4) The particles obtained in (3) above are uniformly mixed with magnesium stearate to obtain push compartment particles.

[0102] 3. Compression and Tableting

[0103] (1) Using a tableting device, compress the drug compartment particles into a shape.

[0104] (2) The push compartment particles are added onto the compressed drug compartment particles, and then the compressed drug compartment particles and the push compartment particles are pressed in a tablet machine to form a core having two layers including the drug compartment and the push compartment, followed by a semipermeable membrane coating procedure.

[0105] 4. Coating of semipermeable membrane

[0106] (1) The materials in Table 2 were dissolved in a dual solvent system of acetone and water to form a 5% (w / w) membrane solution, where the weight ratio of acetone to water was 95:5.

[0107] (2) Spray the membrane solution onto the core (with two layers) obtained by point 3 above, and increase the weight of the semipermeable membrane according to Table 2, where the formula percentage in Table 2 is based on 100% core weight.

[0108] (3) The semipermeable membrane-coated tablets are dried in an oven at 45°C for 48 hours.

[0109] 5. Formation of an orifice through a semipermeable membrane

[0110] An orifice through the semipermeable membrane of the tablet obtained according to point 4 above was formed using a laser, where the orifice was formed in the portion of the semipermeable membrane adjacent to the drug compartment.

[0111] [Table 1]

[0112] Note 1: POLYOX™ WSR N80 has a molecular weight of 2x10 5g / mol of poly(ethylene oxide).

[0113] Note 2: POLYOX™ WSR 303 has a molecular weight of 7x10 6 g / mol of poly(ethylene oxide).

[0114] [Table 2]

[0115] Example 2

[0116] The preparation method of Example 2 basically followed that of Example 1, where the core formulation was shown in Table 3 and the semipermeable membrane formulation was shown in Table 4.

[0117] [Table 3]

[0118] [Table 4]

[0119] Example 3

[0120] The preparation method of Example 3 basically followed that of Example 1, where the core formulation was shown in Table 5 and the semipermeable membrane formulation was shown in Table 6.

[0121] Additionally, Example 3 further included a procedure for preparing a film coating after the orifice was formed in the tablet. The film coating contained lurasidone or a pharmaceutically acceptable salt thereof. The film coating formulation is shown in Table 7, where the formulation percentages in Table 7 are based on 100% weight of the semipermeable membrane-coated tablet.

[0122] 1. Film coating formation

[0123] (1) Prepare a 10% (w / w) film coating solution according to the formulation in Table 7, including the steps of: (1) dissolving hypromellose in water; then adding lurasidone HCl; and stirring the film coating solution uniformly.

[0124] (2) Sift the film coating solution through a 100 mesh sieve.

[0125] (3) After forming an orifice by laser, spray the film coating liquid onto the tablet, and then increase the weight of the film coating liquid according to Table 7.

[0126] [Table 5]

[0127] [Table 6]

[0128] [Table 7]

[0129] Example 4

[0130] The method for preparing Example 4 essentially followed that of Example 1, where the core formulation was shown in Table 8 and the semipermeable membrane formulation was shown in Table 9.

[0131] [Table 8]

[0132] [Table 9]

[0133] Example 5

[0134] The method for preparing Example 5 essentially followed that of Example 1, where the core formulation was shown in Table 10 and the semipermeable membrane formulation was shown in Table 11.

[0135] [Table 10]

[0136] [Table 11]

[0137] Example 6

[0138] The method for preparing Example 6 essentially followed that of Example 1, where the core formulation was shown in Table 12 and the semipermeable membrane formulation was shown in Table 13.

[0139] [Table 12]

[0140] [Table 13]

[0141] Example 7

[0142] The preparation of Example 7 is described below, the core formulation is shown in Table 14, and the semipermeable membrane formulation is shown in Table 15.

[0143] 1. Core Granulation

[0144] (1) Mix all ingredients except magnesium stearate according to Table 14.

[0145] (2) For granulation, add an appropriate amount of alcohol and then pass the wet granules through a 20 mesh sieve.

[0146] (3) The material in the fluidized bed is dried at 50°C for 30 minutes, and then the dried granules are screened through a 20 mesh sieve to form particles.

[0147] (4) The particles obtained in (3) above are uniformly mixed with magnesium stearate to obtain drug compartment particles.

[0148] 2. Compression and Tableting

[0149] Using a tableting machine, the particles obtained in point 1 above are compressed into a shape, which is then treated with a semipermeable membrane coating.

[0150] 3. Coating of semipermeable membrane

[0151] (1) The materials in Table 15 were dissolved in a dual solvent system of acetone and water to form a 5% (w / w) membrane solution, where the weight ratio of acetone to water was 95:5.

[0152] (2) Spray the membrane liquid onto the core obtained by point 2 above, and increase the weight of the semipermeable membrane according to Table 15, where the formula percentage in Table 15 is based on 100% core weight.

[0153] (3) The semipermeable membrane-coated tablets are dried in an oven at 45°C for 48 hours.

[0154] 4. Formation of an orifice through a semipermeable membrane

[0155] An orifice is formed through the semipermeable membrane of the tablet obtained according to point 3 above using a laser.

[0156] [Table 14]

[0157] [Table 15]

[0158] Example 8

[0159] The method for preparing Example 8 essentially followed that of Example 3, where the core formulation was shown in Table 16, the semipermeable membrane formulation was shown in Table 17, and the film coating formulation was shown in Table 18.

[0160] [Table 16]

[0161] [Table 17]

[0162] [Table 18]

[0163] Example 9

[0164] The method for preparing Example 9 essentially followed Example 1, where the core formulation was shown in Table 19 and the semipermeable membrane formulation was shown in Table 20.

[0165] [Table 19]

[0166] [Table 20]

[0167] Note 3: Ethocel 100 FP is a type of ethyl cellulose.

[0168] Note 4: HPMC E5LV is a type of hypromellose.

[0169] II. Lysis Assay

[0170] Dissolution assays comparing Examples 1-9 with the commercial product (LATUDA®) were performed in 900 mL of McIlvaine buffer (0.025 M citric acid solution + 0.05 M NaHPO) at pH 3.8 using the paddle method at a rotation speed of 50 rpm, with sampling times of 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours. The results of the dissolution assays are shown in Figure 2A.

[0171] Figure 2A shows that the release time of the active ingredient (lurasidone HCl) is extended in Examples 1-9 compared to LATUDA®. In particular, compared to LATUDA®, which shows 100% release of the active ingredient within just 1 hour, the percent dissolution of the active ingredient in Examples 1-9 was 0%-50% within 2 hours and 30%-100% within 10 hours.

[0172] Furthermore, it was observed that the sustained-release osmotic-controlled pharmaceutical compositions with a push compartment (Examples 1-6 and 8-9) exhibited a higher plateau compared to the sustained-release osmotic-controlled pharmaceutical composition without a push compartment (Example 7), i.e., the push compartment increases the release content of the active ingredient.

[0173] Furthermore, it was observed that the sustained-release osmotic-controlled pharmaceutical compositions with film coating (Examples 3 and 8) showed increased release of the active ingredient within 2 hours compared to the sustained-release osmotic-controlled pharmaceutical compositions without film coating (Examples 1-2, 4-7 and 9).

[0174] Furthermore, with reference to Examples 1 and 5, the material of one of the push compartments (Example 1: poly(ethylene oxide); Example 5: xanthan gum) and the weight percentage of the semipermeable membrane (Example 1: 3.43%; Example 5: 6.86%) are different. Compared to Example 1, Example 5 has a higher weight percentage of semipermeable membrane, which exhibits a decreased release slope (slower release rate), and xanthan gum was selected instead of poly(ethylene oxide) in Example 1, which was observed to exhibit a lower plateau.

[0175] With reference to Example 2 and Example 8, the formulation of the semipermeable membrane (for example, 40% in Example 2; 6.57% in Example 8) and whether or not the film coating is applied (Example 2: no film coating; Example 8: film coating) are different. Compared with Example 2, Example 8 has a lower weight percentage of the semipermeable membrane, which shows a higher release slope (higher release rate), and it was observed that the film coating increases the initial release of the active ingredient.

[0176] With reference to Example 8 and Example 9, the main differences were the formulation of the semipermeable membrane (for example, the membrane body of Example 8 was cellulose acetate, while that of the other examples was ethyl cellulose (Ethocel 100 FP), and the weight ratio of the membrane body to the porogen of Example 8 was higher than that of Example 9), and whether the film coating was coated or not (Example 8: film coating; Example 9: no film coating). Compared with Example 9, in Example 8, cellulose acetate was selected to act as the membrane body instead of ethyl cellulose in Example 9, and the weight ratio of the membrane body to the porogen was higher, which showed a decreased release slope (slower release rate), and it was observed that the film coating increased the immediate release of the active ingredient.

[0177] According to Figure 2A, the dissolution profile of Example 6 effectively delayed the release of lurasidone and showed a profile that was favorably suited to the desired dose, and Example 6 was selected to carry out subsequent animal studies.

[0178] III. Animal research

[0179] The diffusion of the sustained-release osmotic-controlled pharmaceutical composition prepared according to Example 6 and LATUDA® was studied in a single-dose parallel test in two beagle dogs. Each group was administered a 40 mg tablet of Example 6 or LATUDA® within 20-30 minutes after a meal, and sampling time points were 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 18, 24, 36, and 48 hours. The blood concentrations of lurasidone HCl in the two groups are shown in Figure 2B.

[0180] FIG. 2B shows that compared with LATUDA®, the Cmax of the sustained-release osmotic-controlled pharmaceutical composition of the present disclosure (e.g., Example 6) was clearly reduced, and the concentration curve was relatively flat with no obvious peak, indicating that the sustained-release osmotic-controlled pharmaceutical composition exhibited the effect of stabilizing the drug concentration in the blood.

[0181] Although the present disclosure has been disclosed in the above embodiments, it is not intended to limit the present disclosure, and it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present disclosure. The scope of protection of the present disclosure is subject to the definition of the scope of the claims.

Claims

1. a core comprising a drug compartment, the drug compartment comprising a first active ingredient, a first polymer, and a first osmogen, the first active ingredient comprising lurasidone, a pharmaceutically acceptable salt of said lurasidone, or a combination thereof; a semipermeable membrane coated on the core, the semipermeable membrane comprising a membrane body and at least one pore distributed in the membrane body; 1. A sustained release osmotically controlled pharmaceutical composition comprising:

2. 2. The sustained release osmotic controlled pharmaceutical composition of claim 1, wherein the weight percentage of the first active ingredient is 2% to 30% based on 100% weight of the core.

3. 2. The sustained release osmotic controlled pharmaceutical composition of claim 1, wherein the weight percentage of the first polymer is 5% to 80% based on 100% of the weight of the core.

4. 2. The sustained-release osmotic controlled pharmaceutical composition of claim 1, wherein the first polymer comprises poly(methyl methacrylate), microcrystalline cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, poly(ethylene oxide), polyoxypropylene, polyvinylpyrrolidone, carbomer, sodium carboxymethyl starch, carboxymethyl cellulose, sodium salt of carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, xanthan gum, or a combination thereof.

5. 2. The sustained release osmotically controlled pharmaceutical composition of claim 1, wherein the first osmogen comprises a water-soluble salt, a carbohydrate, a water-soluble amino acid, or a combination thereof, and the weight percentage of the first osmogen is 10% to 55% based on 100% of the weight of the core.

6. 10. The sustained-release osmotic controlled pharmaceutical composition of claim 1, wherein the first osmogen comprises magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, sodium sulfate, sodium phosphate, potassium chloride, potassium phosphate, sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate, sodium carboxymethylcellulose, hypromellose, sucrose, sorbitol, mannitol, glucose, lactose, fructose, glycine, leucine, alanine, methionine, urea, or a combination thereof.

7. 10. The sustained release osmotic controlled pharmaceutical composition of claim 1, wherein the drug compartment further comprises an acidifying agent.

8. 2. The sustained-release osmotic-controlled pharmaceutical composition of claim 1, wherein the weight percentage of the semipermeable membrane is 1% to 45% based on 100% of the weight of the core.

9. 2. The sustained-release osmotic-controlled pharmaceutical composition of claim 1, wherein the membrane body comprises cellulose acetate, ethyl cellulose, or a combination thereof.

10. 10. The sustained release osmotic controlled pharmaceutical composition of claim 1, wherein the core further comprises a push compartment, the push compartment comprising a second polymer and a second osmogen.

11. 11. The sustained release osmotic controlled pharmaceutical composition of claim 10, wherein the weight percentage of the second polymer is 15% to 55% based on 100% weight of the core, and the weight percentage of the second osmogen is 5% to 55% based on 100% weight of the core.

12. 2. The sustained release osmotic controlled pharmaceutical composition of claim 1, wherein a first percent dissolution of the first active ingredient is between 0% and 30% within 2 hours and a second percent dissolution of the first active ingredient is between 30% and 100% within 10 hours when assayed in McIlvaine buffer at pH 3.

8.

13. 10. The sustained-release osmotic-controlled pharmaceutical composition of claim 1, further comprising a film coating coated on the semipermeable membrane.

14. 14. The sustained release osmotic controlled pharmaceutical composition of claim 13, wherein the weight percentage of the film coating is 2% to 25%, based on 100% of the weight of the core and the semipermeable membrane.

15. 14. The sustained-release osmotic controlled pharmaceutical composition of claim 13, wherein the film coating comprises a second active ingredient, the second active ingredient comprising lurasidone, a pharmaceutically acceptable salt of the lurasidone, or a combination thereof, and the weight percentage of the second active ingredient is 10% to 60% based on 100% by weight of the first active ingredient in the core.

16. 16. The sustained release osmotic controlled pharmaceutical composition of claim 15, wherein the percent dissolution of the first active ingredient and the second active ingredient is 10% to 40% within 1 hour when assayed in McIlvaine buffer at pH 3.

8.

17. 1. A method for preparing a sustained-release osmotic-controlled pharmaceutical composition, comprising: mixing a first active ingredient, a first polymer, and a first osmogen to form a drug compartment mixture, wherein the first active ingredient comprises lurasidone, a pharmaceutically acceptable salt of the lurasidone, or a combination thereof; compressing and tableting the drug segment mixture to form a core; mixing a film body material and a porogen in a solvent to form a film solution; spraying the coating liquid onto the core; drying the membrane solution to form a semipermeable membrane coated on the core; A method comprising:

18. mixing a second polymer and a second osmogen to form a push compartment mixture; further comprising compressing and tableting the drug segment mixture; compressing the drug segment mixture to form a drug segment; mixing the push compartment mixture with the drug compartment to form a core mixture; compressing and tableting the core mixture to form a core; 18. The method of claim 17, comprising:

19. mixing film coating materials in an aqueous solution to form a film coating solution; spraying the film coating solution onto the semipermeable membrane to form a film coating on the semipermeable membrane; 18. The method of claim 17, further comprising:

20. 10. A method for treating a psychiatric disorder, comprising administering the sustained-release osmotic-controlled pharmaceutical composition of claim 1 to a subject suffering from the psychiatric disorder.

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