Kaliprazine-releasing preparation

Abstract

This patent discloses long-term injectable formulations and delivery systems of cariprazine and related salts and derivatives in the prevention and treatment of various psychotic disorders such as schizophrenia, mania, bipolar disorder, etc. The dosage form is either a microsphere, microparticle, nanoparticle drug delivery system, or device containing such a long-term injectable formulation of cariprazine and related salts and derivatives in a pharmaceutically acceptable carrier.

Description

Technical Field

[0001] The present invention relates to a cariprazine-releasing preparation.

Background Art

[0002] Cariprazine is a dopamine D2 and D3 receptor partial agonist and is used as an antipsychotic drug for schizophrenia, mania, and bipolar disorder. However, current drug delivery methods only have immediate-release oral preparations, which are inconvenient for these types of patients. Currently, there are no long-term preparations that provide extended drug release, ease of administration, and high patient compliance with microspheres or nanoparticle formulations or delivery systems of cariprazine. Therefore, there is a great need to develop long-acting formulations or sustained-release drug delivery systems that provide convenience and compliance.

[0003] It is widely accepted that zero-order release of the active ingredient from the formulation produces a stable and predictable pharmacokinetic profile. In a sustained drug delivery system, zero-order release allows the drug concentration to remain within the therapeutic range for a longer period. This is particularly beneficial for psychiatric patients because the reduced frequency of drug administration alleviates patient non-compliance, the defined pharmacokinetic profile reduces the risk of side effects, and the clinical response that requires treating the negative and positive symptoms of psychosis simultaneously with a delicate balance is improved.

[0004] However, examples of formulations exhibiting zero-order release characteristics are very rare. In most microsphere, microparticle, or nanoparticle formulations, the particle shell has a larger surface area, and matrix breakdown is faster in the initial and early stages of drug release, so the drug release profile is likely to be burst release and primary drug release. Furthermore, since the molecules of the active ingredient are usually smaller than the matrix components, drug release is accelerated in the early stages of dissolution as the smaller molecules diffuse across the matrix that is eroded upon contact with the dissolving medium. These two drug release mechanisms in polymer matrices constitute a "burst release" and increased release of the active ingredient in the early or primary stages of the drug release profile, thus resulting in undesirable spikes and unstable drug concentrations during treatment. [Overview of the project] [Problems that the invention aims to solve]

[0005] Currently available caliprazine is in the form of conventional solid formulations such as capsules, which, when mixed with gastric or intestinal fluid, are directly excreted into the gastrointestinal tract. Therefore, patients must continue to take capsules or tablets daily throughout the treatment period, which imposes difficulties on this specific group of patients. Furthermore, side effects such as abdominal pain, vomiting, diarrhea, nausea, and constipation occur. No one has reported a sustained-release microsphere or nanoparticle formulation or long-acting drug delivery system that allows for intramuscular (IM) administration of caliprazine, offers a longer duration of pharmacological effect, high convenience, and high patient compliance. Therefore, the first object of the present invention is to address the above needs in the art by providing a microparticle or nanoparticle formulation or drug delivery system for caliprazine and related salts and other derivative compounds.

[0006] Another object of the present invention is to provide a microparticle or nanoparticle formulation comprising caliprazine and related salts and other derivative compounds having a zero-order release profile, because zero-order release offers far more therapeutic advantages than primary release and other release types, as described above.

[0007] Another objective of the present invention is to avoid initial burst release and spikes in drug release during the initial stages.

[0008] Another object of the present invention is to provide dosage forms for the administration of caliprazine and related salts and other derivative compounds in microparticle and nanoparticle formulations in order to potentially avoid GI and other side effects.

[0009] Another object of the present invention is to provide a dosage form comprising such a drug-containing nanoparticle formulation.

[0010] Another object of the present invention is to provide such microspheres or microparticles, nanoparticles, that are suspended in a liquid or semi-solid carrier.

[0011] Additional objectives, advantages, and novel features of the present invention are partially described below, partially apparent to those skilled in the art through the following considerations, or can be acquired through the practice of the present invention. [Means for solving the problem]

[0012] In yet another aspect of the present invention, a method is provided for treating patients having symptoms that respond to the administration of an activator selected from caliprazine and its related salts and other derivatives, the method comprising intramuscular administration of such pharmaceutical formulations, i.e., microspheres, microparticles and nanoparticles, to the patient within the range of an effective administration regimen. Symptoms generally include schizophrenia, mania, bipolar disorder and other related disorders.

[0013] In frequently included embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of an activator selected from caliprazine, its salts, or derivatives thereof, including derivative salt forms; a biodegradable and biocompatible polymer comprising a polymer matrix material; and a nonionic water-soluble colloid, wherein the activator is ionically complexed with the biodegradable and biocompatible polymer, the activator is dispersed in the matrix material, and the composition is in the form of microparticles, microspheres, nanoparticles, or a combination thereof. Often, caliprazine, its salts, or derivatives thereof, including derivative salt forms, are present in the composition at concentrations between about 0.1% and about 80% wt / wt. In many cases, the biodegradable and biocompatible polymer is selected from the group consisting of polylactic acid, polyglycolic acid, the copolymers mentioned above, poly(aliphatic carboxylic acid), copolyoxalate, polycaprolactone, polydioxonone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, albumin, casein, lipids, and waxes. In many cases, the nonionic water-soluble colloid is selected from the group consisting of one or more of poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween80, Tween20, or Span. In many cases, the nonionic water-soluble colloid is selected from the group consisting of one or more of the following: poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween80, Tween20, or Span.In frequently occurring embodiments, the calipladine, its salts, or derivatives thereof, including derivative salt forms, are present in the composition at a concentration of about 0.1% to about 80% wt / wt, the biodegradable and biocompatible polymer is selected from the group consisting of polylactic acid, polyglycolic acid, the copolymers thereof, poly(aliphatic carboxylic acid), copolyoxalates, polycaprolactone, polydioxonone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, albumin, casein, lipids, and waxes, and the nonionic water-soluble colloid is poly(vinyl) The composition is selected from the group consisting of one or more of the following: (aerosols), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween80, Tween20, or Span, and comprises aggregates of microparticles, microspheres, nanoparticles, or combinations thereof, wherein the aggregate comprises one or more discrete groups of microparticles, microspheres, or nanoparticles, and each discrete group of microparticles, microspheres, or nanoparticles specifies an average diameter size different from that of any other of the two or more discrete groups of microparticles, microspheres, or nanoparticles. According to a frequently occurring embodiment of this disclosure, the microparticles, microspheres, nanoparticles, or combinations thereof exhibit a desired drug release profile. In many cases, the microparticles, microspheres, nanoparticles, or combinations thereof exhibit zero-order release characteristics.

[0014] In a common embodiment, the pharmaceutical composition comprises an aggregate of microparticles, microspheres, nanoparticles, or combinations thereof. In a common embodiment, the aggregate comprises an aggregate of microparticles, microspheres, or nanoparticles that defines an average diameter size. Often, the aggregate comprises two or more discrete groups of microparticles, microspheres, or nanoparticles, each discrete group of microparticles, microspheres, or nanoparticles defining an average diameter size different from that of any other of the two or more discrete groups of microparticles, microspheres, or nanoparticles.

[0015] In more frequently occurring embodiments, the biodegradable and biocompatible polymer includes poly(d,l-lactic acid-co-glycolic acid) and poly(d,l-lactic acid)(d,l-PLA) copolymers, poly(d,l-lactic acid-co-glycolide) copolymers, polylactic acid, polyglycolic acid, or combinations thereof. In many such embodiments, the copolymer is poly(d,l-lactide-co-glycolide), and the molar ratio of lactide to glycolide in the copolymer is between approximately 95:5 and approximately 5:95.

[0016] Methods for producing sustained-release microparticles and nanoparticles are also intended in accordance with this disclosure. Such methods often include the steps of: dissolving one activator and one or more biodegradable / biocompatible polymers in a solvent having low solubility in water and a boiling point below 100°C to form an organic phase; quenching the organic phase with an aqueous solution of a nonionic water-soluble colloidal polymer to form a quenched composition; homogenizing the quenched composition to form an emulsion; and removing the solvent from the emulsion to form microparticles, microspheres, or nanoparticles, wherein the activator is selected from the group consisting of calipladine, its salts, or derivatives thereof, including derivative salt forms. Often, such methods include one solvent for both the biodegradable / biocompatible polymer and the active ingredient, or a blend of different solvents, one of which is the solvent for the biodegradable / biocompatible polymer and the other is the solvent for the activator. Also often, the solvent for the biodegradable / biocompatible polymer is a poorly water-soluble solvent. In most cases, the concentration of the nonionic water-soluble hydrophilic colloid in the process medium is approximately 0.1% to approximately 50% w / w.

[0017] According to a particular intended embodiment, the solvent for the biodegradable and biocompatible polymer has a solubility of 10% to 100% for the biodegradable and biocompatible polymer.

[0018] In further embodiments, the intended method often further includes the step of contacting the microparticles, microspheres, or nanoparticles with a second quench solution. Also often, such a method includes the step of washing the microparticles, microspheres, or nanoparticles with a washing solution containing a C1-C4 aliphatic alcohol. Also often, such a method includes the step of drying the microparticles, microspheres, or nanoparticles at a temperature of about 10°C to about 50°C. Also often, such a method includes the step of freeze-drying the microparticles, microspheres, or nanoparticles in a freeze-dryer or freeze-drier. The intended method may include all of the sub-selections / combinations of the further steps described above. Often, according to the intended method, the organic phase is combined with the aqueous phase before the solvent is removed. Often, the emulsion is prepared by a homogenizer, mixer, or microfluidizer.

[0019] These and other embodiments, features, and advantages will become apparent to those skilled in the art upon further detailed description of various exemplary embodiments of the present disclosure, in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0020] [Figure 1] This graph shows the standard calibration and regression equation for caliprazine solution. [Figure 2] This graph shows the drug release profile from caliprazine microparticles. [Figure 3] This graph shows the kinetics of drug release from caliprazine microparticles. [Modes for carrying out the invention]

[0021] The present invention features a pharmaceutical dosage form that provides a long-acting microsphere drug delivery system or formulation of cariprazine and related salts and other derivatives. The sustained drug delivery system of cariprazine and related salts and other derivatives can be administered intramuscularly to patients periodically, thus providing long-term pharmacological effects, convenience, and high patient compliance.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published publications, and other publications mentioned herein are incorporated by reference in their entirety. If the definitions set forth in this section conflict with the definitions set forth in patents, applications, published publications, and other publications incorporated herein by reference, or are otherwise inconsistent, the definitions set forth in this section shall prevail over the definitions incorporated herein by reference.

[0023] As used herein, "a" or "an" means "at least one" or "one or more".

[0024] As used herein, the term "and / or" may mean "and", "or", "exclusive - or", "one", "part but not all", "neither", and / or "both".

[0025] To clarify the following explanation, the following definitions are provided: "Microparticles," "microspheres," or "nanoparticles" mean solid particles containing an activator dispersed or dissolved within a biodegradable, biocompatible polymer that functions as a particle matrix. "Limited water solubility" means having solubility in water in the range of approximately 0.1 to approximately 25% by weight at 20°C. "Halogenated hydrocarbons" mean halogenated organic solvents, i.e., C1-C4 halogenated alkanes, such as methylene chloride, chloroform, methyl chloride, carbon tetrachloride, ethylene dichloride, ethylene chloride, 2,2,2-trichloroethane, etc. "Biodegradable" means a substance that should be broken down by bodily processes and become easily disposed of in the body, and should not accumulate in the body. Furthermore, the biodegradation products should preferably be biocompatible. "Biocompatible" means a material that is non-toxic to the human body, pharmaceutically acceptable, non-carcinogenic, and does not significantly induce inflammation in bodily tissues. "Weight %" or "% by weight" means parts by weight relative to total parts by weight. "Zero-order release" means that the increase in drug concentration in the dissolving medium over a set time interval is constant.

[0026] The process of the present invention involves using a solvent to produce biodegradable, biocompatible microparticles and nanoparticles containing at least one biological activator. Preferred solvent systems are one solvent or a blend of at least two solvents. Particularly preferred solvents are solvent blends containing at least two solvents. The first solvent component of the solvent blend is a poor solvent for the activator but a good solvent for the biodegradable, biocompatible polymer used herein. The second solvent component of the solvent blend is a good solvent for the activator. The activator is dissolved or dispersed in the solvent. The polymer matrix material is added to the agent-containing medium in an amount that provides a product with a desired amount of supported activator. Optionally, all components of the microparticle and nanoparticle products may be blended together in the solvent blend medium.

[0027] An ideal solvent blend for encapsulating activators should have high solubility for polymer encapsulants at 20°C, generally at least about 5% by weight, preferably at least about 20% by weight. While the upper limit of solubility is not critical, if the encapsulated polymer makes up more than about 50% by weight of the solution, the solution may become too viscous and difficult to handle effectively and conveniently.

[0028] The solvent system is substantially miscible with the continuous-phase process medium and any quenching solution, usually water or aqueous, but preferably has limited solubility in them. If the solvent system is infinitely soluble in the process medium, microparticles and nanoparticles may not be able to form between the emulsion phases; however, if the solubility of the solvent system in the extractable quenching medium is too low, a large amount of quenching medium may be required. Generally, solvent solubility of about 0.1 to about 30% in the process medium and any quenching medium is acceptable for use as specified herein.

[0029] Additional considerations when selecting the components of the solvent blend of the present invention are the boiling point (i.e., the ease with which the solvent can be evaporated to form the final product if desired) and the specific gravity (the tendency for discontinuities or oil phases to float during emulsification and quenching). Finally, the solvent system should be low in toxicity.

[0030] The polymer matrix materials of microparticles and nanoparticles prepared by the process of the present invention are biocompatible and biodegradable. The matrix material should be biodegradable in the sense that it should be broken down into products that can be easily disposed of in the body by internal processes and should not be accumulated in the body. The biodegradation products should also be biocompatible with the body, as should any residual solvents that may remain in the microparticles.

[0031] Preferred examples of polymer matrix materials include polyglycolic acid, poly(d,l-lactic acid), poly(l-lactic acid), the aforementioned copolymers, etc. Various commercially available poly(lactide-co-glycolide) materials (PLGA) can be used in the method of the present invention. For example, poly(d,l-lactic acid-co-glycolic acid) is commercially available from Evonik (Birmingham, Alabama). Suitable commercially available products from Evonik or other suppliers include 50:50, 65:35DL, 75:25DL, 85:15DL poly(d,l-lactic acid-co-glycolic acid) and poly(d,l-lactic acid) (d,l-PLA). These copolymers are available in a wide range of molecular weights and lactic acid-to-glycolic acid ratios.

[0032] The most preferred polymer for use in carrying out the present invention is the copolymer poly(d,l-lactide-co-glycolide). The molar ratio of lactide to glycolide in such a copolymer is preferably in the range of about 85:15 to about 15:85.

[0033] The present invention is broader than the shelf life problem caused by residual solvents and addresses a more general solution of washing products containing specific viscous solvents with a washing solution comprising water and a water-miscible solvent for the viscous solvent(s) in the product. The washing step affects the drug release rate from the microparticles. Residual solvents in the microparticles can also be removed by processes such as evaporation, filtration, and freeze-drying. In these processes, the solvent is preferably low-boiling point and volatile, which facilitates the easy and complete removal of the residual solvent.

[0034] The molecular weight should be high enough to allow for the formation of a sufficient polymer matrix or coating. Typically, a sufficient molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 to 200,000 daltons. The molecular weight of the polymer is also important in terms of its effect on the biodegradation rate of the polymer. Drugs can be released from microparticles and nanoparticles by erosion and diffusion processes.

[0035] The formulations prepared by the process of the present invention contain an activator dispersed in a microparticle and nanoparticle polymer matrix material. The amount of such agent incorporated into the microparticles and nanoparticles is typically in the range of about 1 wt% to about 90 wt%, preferably 20 to 50 wt%.

[0036] In carrying out the process of the present invention, it is preferable that the encapsulated polymer is essentially 100% dissolved in the solvent or solvent blend at the time the solution is emulsified. The activator may be dispersed or dissolved in the solvent or solvent blend at the time it is added to the continuous phase process medium.

[0037] To achieve zero-order release, it is preferable that the activator (i.e., caliprazine) complexes with the encapsulated polymer during the dissolution process in a suitable solvent. For example, a free base of caliprazine or an equivalent process resulting in a free base (e.g., liquid-liquid extraction) can be used in the formulation or dissolution process to enable thorough complexing of the activator and the encapsulated polymer. Strong interactions between the activator and the encapsulated polymer are important to minimize the diffusion of the activator during matrix erosion. For example, ionic interactions can be used to trap the activator, caliprazine, in the polymer matrix, thereby preventing diffusion and preventing "burst release." The solvent used in the dissolution / complexing process should be one that is not readily soluble in water. Complexation should be carried out in a hydrophobic environment to allow for complete interaction between the activator and the encapsulated polymer. It is also desirable that the solvent be easily removed during quenching or evaporation.

[0038] Microparticles and nanoparticles can be mixed by size or type to deliver activators to patients in a multi-step manner, and / or to deliver different activators to patients at different times, or to deliver a mixture of activators to patients simultaneously. For example, secondary antibiotics, vaccines, or any desired activator in the form of microparticles or nanoparticles or in a conventional unencapsulated form can be blended with a primary activator and delivered to the patient.

[0039] Emulsions are created by high-speed homogenization, static mixing, in-line homogenization, microfluidization, and sonification. Microparticles and nanoparticles can also be created using biemulsions.

[0040] Typically, hydrophilic colloids are added to continuous-phase process media to prevent aggregation of solvent microdroplets and control the size of solvent microdroplets in the emulsion. Examples of compounds that can be used as hydrophilic colloids include, but are not limited to, poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween 80, Tween 20, and Span. The concentration of the hydrophilic colloid in the process medium should be sufficient to stabilize the emulsion and will affect the final size of microparticles and nanoparticles. Generally, the concentration of the hydrophilic colloid in the process medium is about 0.1% to about 10% by weight relative to the process medium, depending on the hydrophilic colloid, discontinuous or oil-phase solvent system, and the process medium used. A preferred combination of dispersion media is an aqueous solution of poly(vinyl alcohol) in a concentration of 0.1 to 10% by weight, more preferably 0.5 to 2% by weight.

[0041] Not all hydrophilic colloids are suitable for the production of microparticles or nanoparticles with zero-order release properties. Nonionic polymers with high water solubility are preferred. Ionic colloids typically charge microparticles or nanoparticles, which can lead to static electricity in powder products and make handling and filling into vials difficult. Charged particles are generally undesirable as injectables and can also cause burst release of drugs due to drug molecules attracted to the particle surface. The water solubility of hydrophilic colloid polymers creates a concentration gradient throughout the microparticles or nanoparticles during the emulsification and curing process because more of the polymer is embedded in the outer shell of the particles and less towards the hydrophobic core. The hydrophilic colloid gradient throughout the microparticles / nanoparticles is important for zero-order release because erosion of the particle outer shell that occurs early in dissolution reduces the amount of hydrophilic colloid available to accelerate drug release compared to the hydrophobic colloid encapsulated and uniformly dispersed within the polymer particles, potentially leading to primary or other types of drug release. Poly(vinyl alcohol) is a preferred example for creating such zero-order emission microparticles / nanoparticles, but other nonionic water-soluble polymers are obvious choices for those skilled in the art who are teaching the present invention.

[0042] Emulsions can be formed by mechanical stirring of the mixed phase or by adding droplets of a discontinuous phase containing the activator and wall-forming material to a continuous phase process medium. The temperature during emulsion formation is not particularly important, but it can affect the size and quality of microparticles and nanoparticles, as well as the solubility of the activator in the continuous phase. The dispersion process can be carried out at any temperature that maintains stable operating conditions, preferably about 20°C to about 60°C, depending on the selected activator and excipients.

[0043] In practice, the organic phase and the aqueous phase are mixed using a static mixer, homogenizer, or microfluidizer to form an emulsion. The resulting emulsion contains microparticles and nanoparticles containing activators encapsulated within the polymer matrix material.

[0044] Next, the microparticles and nanoparticles are stirred in the tank, and the organic solvent is removed by evaporation under atmospheric pressure or vacuum. The solvent evaporation process typically takes 12 to 24 hours or more at atmospheric pressure. The evaporation process is usually faster under vacuum. Care must be taken to prevent liquid from overflowing into the vacuum piping.

[0045] The microparticles and nanoparticles may be stirred in a tank containing the quench solution to remove most of the organic solvent from them and form hardened microparticles. The extraction medium removes most of the solvent from the microparticles and nanoparticles but does not dissolve them. During extraction, the extraction medium containing dissolved solvent may optionally be removed and replaced with fresh extraction medium.

[0046] After the quench step is complete, the microparticles and nanoparticles can be isolated as described above and then, optionally, dried by exposure to air or by other conventional drying techniques, such as vacuum drying, drying on a desiccant, or freeze-drying. This process is very efficient for encapsulating the activator, as it yields a core load of up to about 80% by weight, preferably up to about 30% by weight.

[0047] Both temperature and the amount of solvent spikes can be adjusted to beneficially contribute to the final desired product characteristics, namely, highly porous, fast-release microparticles and nanoparticles, or slow-release microparticles and nanoparticles with low porosity.

[0048] The quenching solution can be ordinary water, an aqueous solution, or another suitable liquid, and its volume, amount, and type depend on the solvent used in the emulsion phase. The quenching solution is preferably water. Depending on the solvent system, the quenching volume can vary from about 2 times to about 20 times the saturation volume. Furthermore, it is convenient to describe the required quenching volume relative to the batch size (microparticle and nanoparticle products). This ratio can vary from about 0.1 to about 10 liters of quenching volume per gram of generated microparticles.

[0049] After the solvent evaporation step or quenching step, the microparticles and nanoparticles are isolated from the aqueous quenching solution by any convenient separation means—the fluid may be decanted from the microparticles, or the microparticle suspension may be filtered, for example, using a sieve column. Various other combinations of separation techniques such as filtration, ultrafiltration, centrifugation, and ultracentrifugation may be used if desired. Filtration is preferred.

[0050] The filtered microparticles and nanoparticles are subjected to the washing step of the present invention to further reduce the level of residual solvent(s) therein, preferably to a level in the range of about 0.1 to about 2.0%. At times, high levels of residual solvent in microparticles and nanoparticles can be sufficient to accelerate the degradation process and thereby reduce the shelf life. Degradation of microparticles and nanoparticles can occur, for example, by undesirable hydrolysis of hydrolyzable linkages of the matrix polymer by basic surfactants. Therefore, the washing step(s) of the present invention is used to reduce the residual benzyl alcohol or other solvent content in microparticles and nanoparticles and to delay the degradation process.

[0051] As described above, the cleaning solution contains only water, or preferably water and a solvent miscible with water, the solvent being a good solvent for residual solvent in microparticles. Here, it is preferable to use a C1-C4 aliphatic alcohol in the cleaning solution, as in the preferred process of the present invention. These alcohols are methanol, ethanol, propanol, butanol, and their isomers. The most preferred alcohol is ethanol. The concentration of alcohol in the cleaning solution may be varied depending on the circumstances.

[0052] The temperature of the cleaning solution is also important for the efficiency of the cleaning process. Generally, raising the temperature shortens the time required to clean and reduce any remaining residues to the desired level. On the other hand, if the temperature is too high, it may approach or exceed the softening temperature of the matrix polymer of the microparticles, potentially leading to problems such as aggregation and stickiness. Conversely, if the temperature is too low, the matrix material may become too hard, slowing down the extraction rate of residues and potentially making the process prohibitively expensive. Preferably, the temperature used is room temperature, i.e., in the range of about 10°C to about 30°C. When water alone is used as the cleaning solvent, it is used at a high temperature, i.e., above room temperature, preferably in the range of about 25°C to about 40°C.

[0053] Typically, it is desirable to employ one or more washing steps, usually two or three. After each such step, the microparticles and nanoparticles are separated from the washing solution by known separation methods, such as filtration, decantation, or centrifugation. Filtration is preferred.

[0054] After each separation step, the microparticles and nanoparticles may be, if desired, fully or partially dried using conventional drying methods at a temperature substantially similar to that of the previous washing solution. The use of dry compressed air at a temperature in the range of about 10°C to about 30°C has been found to be particularly useful and convenient, and is preferred. Microparticle and nanoparticle products typically consist of spherical particles, although sometimes the microparticles may have an irregular shape. The size of the microparticles and nanoparticles may vary in the range of submicrons to millimeters in diameter. Preferably, microparticles of 1 to 500 microns and nanoparticles of 1 to 1000 nm are prepared so that the administration of microparticles to the patient can be carried out with a standard gauge needle. Preferably, the drug-carrying microparticles and nanoparticles are distributed to the patient in a single dose, releasing the drug to the patient in a constant or pulsed manner, eliminating the need for repeated injections.

[0055] Kalipalazine-containing microparticles and nanoparticles are obtained and stored as dry materials. Before administration to a patient, the dry microparticles and nanoparticles can be suspended in an acceptable pharmaceutical liquid vehicle, such as a 2.5 wt% solution of carboxymethylcellulose, and the suspension is then injected into the body.

[0056] Microparticles and nanoparticles may be mixed by size or type to deliver the activator to the patient in a multi-step manner, and / or to deliver different activators to the patient at different times, or to deliver a mixture of activators to the patient simultaneously. For example, a secondary antibiotic, vaccine, or any desired activator in microparticle and nanoparticle form or conventional unencapsulated form may be blended with a primary activator and delivered to the patient.

[0057] Those skilled in the art will understand that, in addition to caliprazine which can be incorporated into microparticles and nanoparticles, any of a number of activators may be prepared by the process of the present invention. For materials that do not have groups detrimental to the integrity of the matrix polymer, the additional washing step(s) of the present invention may be demonstrated to be beneficial, for example, in controlling the in vivo release characteristics of the activator or reducing undesirable or possibly harmful solvents.

[0058] The following examples further illustrate the materials and methods used in carrying out the present invention. These examples are not intended to limit the present invention in any way.

[0059] Example 1. Preparation of calipladine microparticles by solvent evaporation method 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine were dissolved in 2 mL of DCM. The resulting solution was added to 20 mL of 1.0% PVA solution. The mixture was homogenized using three different rates to obtain an emulsion. The emulsion was stirred using a magnetic stirrer for 12 hours to evaporate the DCM solvent. The weight and homogenization rates are shown in Table 1.

[0060] [Table 1]

[0061] Example 2. Calibration curve of standard solution Standard caliprazine was weighed, and a series of standard solutions of different concentrations were prepared. These solutions were measured at a wavelength of 254 nm using an ultraviolet spectrophotometer. The concentration and absorbance results are shown in Table 2. The regression equation is Y = 0.0154X - 0.0055, where Y is absorbance and X is drug concentration. The standard calibration curve is shown in Figure 1.

[0062] [Table 2]

[0063] Example 3. Measurement of drug loading rate in caliprazine microparticles The drug loading rate is determined as follows. For sample 1, the absorbance at 254 nm was measured as 0.4080. By substituting this absorbance into the regression equation Y = 0.0154X - 0.0055, the concentration is calculated to be 26.85 μg / ml. Multiplying the calculated concentration by the dilution factor of 25 and then by 19 mL yields 12.75 mg. This result represents the amount of unencapsulated caliprazine in the solution. Since the total amount of drug is 33.6 mg, 20.85 mg is encapsulated in the PLGA polymer. The total amount of PLGA is 70.8 mg, so the drug loading rate to the microparticles is 20.85 / (20.85 + 70.8) = 22.75%. The drug loading rates for samples 2 and 3 were calculated in the same way and are shown in Table 3.

[0064] [Table 3]

[0065] Example 4. Drug release from caliprazine microparticles 25.8 mg of microparticles from sample 1 were added to 25 mL of PBS buffer, 23.6 mg of microparticles from sample 2 were added to 25 mL of PBS buffer, and 28.1 mg of microparticles from sample 3 were added to 25 mL of PBS buffer. The suspension of microparticles was stirred in a water bath maintained at 45°C for 10 days. On each day, 5 mL of the drug-releasing solution was taken and filtered through a 0.45 μm membrane filter. 5 mL of PBS buffer was added to compensate for the loss of the dissolution. Then, 1 mL of the solution was accurately measured and diluted to 50 mL with methanol. The absorbance was measured at 254 nm and substituted into a regression equation to calculate the amount of drug released. The absorbance of each sample at different time points is shown in Table 4.

[0066] [Table 4]

[0067] The amount of drug released was calculated and is shown in Table 5.

[0068] [Table 5]

[0069] Example 5. Drug release profile and kinetics of caliprazine microparticles The absorbance values ​​are substituted into the regression equation Y = 0.0154X - 0.0055 to calculate the concentration. Next, the concentration is multiplied by the dilution factor of 50 and then by the PBS volume of 25 mL to determine the amount of drug released in the dissolution. According to the drug load, sample 1 microsphere contains 5.87 mg of drug, sample 2 microsphere contains 4.56 mg, and sample 3 microsphere contains 6.58 mg. Therefore, the final drug release rates are 87.7% for sample 1, 84.2% for sample 2, and 87.1% for sample 3. The drug release profiles are shown in Figure 2. Surprisingly, the drug release was found to follow zero-order release kinetics, which means that the drug release rate is constant over the long term, resulting in stable drug blood concentrations over the long term after microparticle accumulation infusion, which is very advantageous for accumulation infusion to patients. Caliprazine is a basic drug, and the anionic and cationic groups at the acid terminus of PLGA complex. Thus, this complexation suppresses undesirable initial release, resulting in desirable zero-order drug release rate kinetics from the caliprazine microparticles. The zero-order release kinetics of caliprazine microparticles in this invention are shown in Figure 3.

[0070] The zero-order emission equation for sample 1 is Qt = 7.6289t + 21.601(R 2 =0.9382), for sample 2, Qt = 7.278t + 20.365(R 2 =0.9518), for sample 3, Qt = 8.1302t + 12.837(R 2 = 0.9823). Qt is the ratio to the total amount released, and t is time.

[0071] Example 6. Preparation of calipladine microparticles by solvent extraction method Dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize the mixture to obtain an emulsion. Add this emulsion to a 10% ethanol solution and stir with a magnetic stirrer for 3 hours to extract the DCM solvent. Sieve the hardened microspheres through a 20 μm sieve and dry in a vacuum oven to remove residual solvent and water.

[0072] Example 7. Preparation of calipladine microparticles by solvent extraction method Dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of ethyl acetate. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize the mixture to obtain an emulsion. Add this emulsion to a 10% ethanol solution and stir with a magnetic stirrer for 3 hours to extract the ethyl acetate solvent. Sieve the hardened microspheres through a 20 μm sieve, dry them in a vacuum oven to remove residual solvent and water.

[0073] Example 8. Preparation of calipladine microparticles with two particle size distributions by solvent extraction method. Dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize this mixture at low speed to obtain an emulsion with larger particle sizes. Add this emulsion to a 10% ethanol solution and stir with a magnetic stirrer for 3 hours to extract the DCM solvent. Sieve the cured microspheres through a 50 μm sieve and dry in a vacuum oven to remove residual solvent and water vapor. Next, dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize this mixture at high speed to obtain an emulsion with smaller particle sizes. Add this emulsion to a 10% ethanol solution and stir with a magnetic stirrer for 3 hours to extract the DCM solvent. The hardened microspheres are sieved through a 10 μm sieve and dried in a vacuum oven to remove residual solvent and moisture. The particles of two size distributions are aseptically mixed to obtain a mixture of microparticles to provide the desired drug release profile.

[0074] Example 9. Preparation of calipladine microparticles with three particle size distributions by solvent extraction method. Dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize this mixture at a low speed to obtain an emulsion with larger particle sizes. Dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize this mixture at a medium speed to obtain an emulsion with medium particle sizes. Next, dissolve 70 mg of PLGA(50:50) polymer and 30 mg of caliprazine in 2 mL of DCM. Add the resulting solution to 20 mL of 1% PVA solution. Homogenize this mixture at a high speed to obtain an emulsion with smaller particle sizes. All three emulsions are mixed together, and the mixed emulsion is added to a 10% ethanol solution. The mixture is stirred with a magnetic stirrer for 3 hours to extract the DCM solvent. The hardened microspheres are sieved through a 60 μm sieve and dried in a vacuum oven to remove residual solvent and water.

[0075] Example 10. Preparation of calipladine nanoparticles by solvent evaporation method Dissolve 10 mg of PLGA(50:50) polymer and 5 mg of caliprazine in 1 mL of DCM. Add the resulting solution to 20 mL of 1.0% PVA solution under magnetic stirring. Sonicate the crude emulsion with a probe sonicator for 2 minutes. Stir the emulsion using a magnetic stirrer and evaporate the DCM solvent over 12 hours. The nanoparticles are obtained after filtration or centrifugation and stored for further use.

[0076] Example 11. Production of microspheres and nanoparticles by freeze-drying The obtained microspheres and nanoparticles are filtered and transferred to a freeze-drying vial. The moist microspheres and nanoparticles in the vial are rapidly frozen in a freezer at minus 80 degrees Celsius or under liquid nitrogen conditions. The frozen cake in the vial is quickly transferred to a freeze-dryer. Primary and secondary drying are performed for 3 days using a temperature increase program set from minus 40 degrees Celsius to 15 degrees Celsius to remove moisture from the microspheres and nanoparticles. The final moisture content can be measured using a Karl Fischer titrator. The vial is sealed to contain the dried microspheres and nanoparticles and stored in a refrigerator for further use.

[0077] Those skilled in the art will understand the further features and advantages of the methods, systems, and apparatus disclosed in the present invention based on the embodiments described above. Accordingly, the methods, systems, and apparatus disclosed in the present invention are not limited to those specifically shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference, in whole and / or for the specific reasons for their citation herein.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of an activator selected from caliprazine or a salt thereof, a biodegradable and biocompatible polymer containing a polymer matrix material, and a nonionic water-soluble colloid, The activator is ionically complexed with the biodegradable and biocompatible polymer, or the activator is dispersed in the polymer matrix material. The composition is in the form of microparticles, microspheres, nanoparticles, or a combination thereof. The polymer matrix material comprises a biodegradable and biocompatible polymer selected from the group consisting of polylactic acid, polyglycolic acid, the copolymer, poly(lactic acid-caprolactone), and poly(glycolic acid-caprolactone). The nonionic water-soluble colloid comprises a compound selected from the group consisting of one or more of poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween 80, Tween 20, or Span. The aforementioned pharmaceutical composition is prepared as an injectable preparation. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the caliprazine or a salt thereof is present in the composition at a concentration between approximately 0.1% and approximately 90% wt / wt.

3. The pharmaceutical composition according to claim 1, wherein the composition comprises microparticles, microspheres, nanoparticles, or aggregates of combinations thereof.

4. The pharmaceutical composition according to claim 3, wherein the aggregate comprises a collection of microparticles, microspheres, or nanoparticles that define the average diameter size.

5. The aforementioned calipladine, or a salt thereof, is present in the composition at a concentration of about 0.1% to about 90% wt / wt. The biodegradable and biocompatible polymer is selected from the group consisting of polylactic acid, polyglycolic acid, the copolymer, poly(lactic acid-caprolactone), and poly(glycolic acid-caprolactone). The nonionic water-soluble colloid is selected from the group consisting of one or more of poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween 80, Tween 20, or Span. The composition comprises microparticles, microspheres, nanoparticles, or aggregates of combinations thereof. The pharmaceutical composition according to claim 1, wherein the aggregate comprises one or more discrete groups of microparticles, microspheres, or nanoparticles, and each discrete group of microparticles, microspheres, or nanoparticles defines an average diameter size different from that of the other two or more discrete groups of microparticles, microspheres, or nanoparticles.

6. The pharmaceutical composition according to claim 1, wherein the microparticles, microspheres, nanoparticles, or combinations thereof exhibit a desirable drug release profile.

7. The pharmaceutical composition according to claim 1, wherein the microparticles, microspheres, nanoparticles, or combinations thereof exhibit zero-order emission characteristics.

8. The pharmaceutical composition according to claim 1, wherein the biodegradable and biocompatible polymer comprises poly(d,l-lactic acid-co-glycolic acid) and poly(d,l-lactic acid)(d,l-PLA) copolymer, poly(d,l-lactic acid-co-glycolide) copolymer, polylactic acid, polyglycolic acid, or a combination thereof.

9. The pharmaceutical composition according to claim 8, wherein the copolymer is poly(d,l-lactide-co-glycolide) and the molar ratio of lactide to glycolide in the copolymer is about 95:5 to about 5:

95.

10. A method for producing injectable sustained-release microparticles and nanoparticles, The process involves dissolving one activator and one or more biodegradable / biocompatible polymers in a solvent that does not have high solubility in water and has a boiling point below 100°C, or in a blend of different solvents, to form an organic phase. The steps include: quenching the aforementioned organic phase with a nonionic water-soluble colloidal aqueous solution to form a quenched composition; The steps include homogenizing the quenched composition to form an emulsion, The step of removing the solvent or the blend of different solvents from the emulsion to form microparticles, microspheres, or nanoparticles, The activator is selected from the group consisting of caliprazine or its salts. The biodegradable and biocompatible polymer is selected from the group consisting of polylactic acid, polyglycolic acid, the copolymer, poly(lactic acid-caprolactone), and poly(glycolic acid-caprolactone). A method comprising a compound selected from the group consisting of one or more of the following: poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween 80, Tween 20, or Span, wherein the nonionic water-soluble colloid is a compound selected from the group consisting of poly(vinyl alcohol), polysorbate, lecithin, carboxymethylcellulose, gelatin, poly(vinylpyrrolidone), Tween 80, Tween 20, or Span.

11. The method according to claim 10, wherein the solvent comprises one solvent for both the biodegradable and biocompatible polymer and the active ingredient, or comprises a blend of different solvents, one of which is a solvent for the biodegradable and biocompatible polymer and the other is a solvent for the activator.

12. The method according to claim 11, wherein the solvent for the biodegradable and biocompatible polymer is a poorly water-soluble solvent.

13. The method according to claim 11, wherein the solvent for the biodegradable and biocompatible polymer has a solubility of 10% to 100% with respect to the biodegradable and biocompatible polymer.

14. The method according to claim 10, further comprising the step of bringing the microparticles, microspheres, or nanoparticles into contact with a second quench solution.

15. The method according to claim 10, further comprising the step of washing the microparticles, microspheres, or nanoparticles with a washing solution containing a C1-C4 aliphatic alcohol.

16. The method according to claim 15, further comprising the step of drying the microparticles, microspheres, or nanoparticles at a temperature of about 10°C to about 50°C.

17. The method according to claim 15, further comprising the step of freeze-drying the microparticles, microspheres, or nanoparticles in a freeze-dryer or freeze-dryer.

18. The method according to claim 10, wherein the organic phase is bonded with the aqueous phase before the solvent is removed by evaporation, filtration, extraction, or freeze-drying.

19. The method according to claim 10, wherein the emulsion is prepared by a homogenizer, mixer, or microfluidizer.

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