Long-acting injectable composition comprising sustained-release microspheres containing brexpiprazo

Abstract

Sustained-release microspheres containing brexpiprazole as an active pharmaceutical ingredient, according to the present invention, additionally contain a specific drug loading enhancer as a part of microsphere elements, and thus, while containing a large amount of the active pharmaceutical ingredient, can maintain a low initial release amount on the first day and achieve long-term sustained-release.

Description

Long-acting injectable composition comprising sustained-release microspheres containing brexpiprazole

[0001] The present invention relates to a long-acting injection composition comprising sustained-release microspheres containing a high content of brexpiprazole as an active pharmaceutical ingredient (API).

[0002]

[0003] Brexpiprazole (7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]quinolin-2(1H)-one), sold under the brand name Rexulti, has partial agonist activity at dopamine D2 receptors (some D2 receptor agonist activity), and serotonin 5-HT 2A It has receptor antagonist activity and adrenergic α1 receptor antagonist activity, and in addition, it has simultaneous serotonin uptake inhibition (or serotonin reuptake inhibition) activity, and is known to have a wide therapeutic spectrum for central nervous system diseases, and has been approved as an agent for the treatment of schizophrenia and as an adjunctive treatment for major depressive disorder (MDD). In addition, in May 2023, the indication for brexpiprazole in the United States was expanded to include the treatment of agitation associated with dementia due to Alzheimer's disease.

[0004]

[0005] Brexpiprazole was first disclosed in PCT Publication No. WO2006112464 and has the following chemical structural formula.

[0006]

[0007]

[0008] Meanwhile, the demand for long-acting injectable medications is increasing because the medication compliance rate is very low in patients suffering from schizophrenia, major depressive disorder, persistent depressive disorder, and agitation associated with Alzheimer's disease.

[0009]

[0010] Microsphere formulations using biocompatible polymers, developed for sustained-release formulations, have become a field of active research interest and clinical application. However, to manufacture these microsphere formulations for long-term, continuous administration, the drug contained within the microspheres must be contained in a significantly high amount, considering the duration and dosage required.

[0011]

[0012] However, brexpiprazole is a poorly soluble drug, making it difficult to encapsulate a sufficient amount within biodegradable polymer microspheres. Furthermore, to successfully encapsulate a high drug content within the microspheres, a biocompatible polymer with a sufficiently long degradation rate must be used. However, microspheres containing high doses of brexpiprazole may not have a sufficiently long drug release period due to the high drug content, making it impossible to meet the desired administration period. Alternatively, an "initial burst" of drug release may occur, resulting in rapid drug release at the beginning of the release. This may lead to various side effects due to a rapid increase in drug concentration in the blood. Furthermore, reducing the drug content within the microspheres to address these issues may result in an excessive increase in the amount of microspheres administered per dose, which may result in poor patient compliance, discomfort, and / or adverse effects due to the large amount of biodegradable polymer.

[0013]

[0014] In general, the higher the drug substance content loaded into the microspheres, the lower the biodegradable polymer content that acts as a matrix to support the drug, resulting in an excessive initial drug release or difficulty in achieving long-term sustained release. Furthermore, biodegradable polymers are expensive, and the higher the polymer content administered in vivo, the more likely various side effects there are. In other words, controlling the drug release pattern while increasing the drug substance content loaded into the microspheres and reducing the biodegradable polymer content can be seen as a key indicator of technological advancement. Furthermore, some drugs tend to have lower bioavailability when formulated into sustained-release microspheres. Therefore, commercialization may be difficult if the drug substance content contained in sustained-release microspheres is low.

[0015]

[0016] Accordingly, the inventor of the present invention has discovered that when a specific drug loading extender is added as part of the microsphere component in the manufacture of sustained-release microspheres containing brexpiprazole, a high content of active substance can be contained while maintaining a low initial release amount on the first day and achieving sustained-release for a long period of time, and has completed the present invention.

[0017]

[0018] An object of the present invention is to provide a long-acting injection composition comprising sustained-release microparticles containing a high content of brexpiprazole or a pharmaceutically acceptable salt thereof and having a stable drug release profile.

[0019] Another object of the present invention is to provide sustained-release microspheres or sustained-release microsphere blends included in the above injectable composition.

[0020] Another object of the present invention is to provide a method for producing the above-mentioned western-style microspheres.

[0021]

[0022] The term "one or more" in the present invention means "number" corresponding to one or more. In the present invention, when a certain configuration is one or more, it may preferably be one, two or more, three or more, one to three, or one to two, but is not limited thereto. The term "one or more" may be used interchangeably with the term "one or more" in the present invention.

[0023] The term "polymer blend" of the present invention means that two or more types of polymers are used in one microparticle.

[0024] The term "microsphere blend" of the present invention means a combination of two or more types of microspheres having different compositions, and may be, for example, a microsphere blend containing the same drug but different types of biodegradable polymers and / or drug loading extenders, or a microsphere blend combining microspheres containing an additional usable steroidal anti-inflammatory agent.

[0025] The term "dispersed phase (DP)" of the present invention means an oily solution containing a biodegradable polymer and an organic solvent, or an oily solution further containing a drug.

[0026] The term "continuous phase (CP)" of the present invention refers to an aqueous solution that forms an emulsion with the dispersed phase and serves to disperse fine droplets of the dispersion, and includes a surfactant.

[0027] The term "continuous phase mixed with organic solvent" in the present invention means that the organic solvent is mixed into a fresh continuous phase by extracting the dispersed organic solvent in the emulsion toward the continuous phase. Here, since the continuous phase mixed with organic solvent is selectively heated to evaporate the organic solvent, the continuous phase mixed with organic solvent may have only a portion or a trace concentration of organic solvent remaining, or the organic solvent may be completely evaporated.

[0028]

[0029]

[0030] The sustained-release microspheres containing brexpiprazole as a pharmaceutical substance according to the present invention have the effect of containing a high content of the pharmaceutical substance while maintaining a low initial release amount on the first day and achieving sustained-release for a long period of time by adding a specific drug loading extender as part of the microsphere components.

[0031]

[0032] Figure 1 is an image of the surface shape of microspheres manufactured in Comparative Example 1-3 and Example 1-9 analyzed using a scanning electron microscope (SEM).

[0033] FIG. 2 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of a 4-6 week sustained-release microparticle according to one embodiment of the present invention.

[0034] FIG. 3 is a graph showing the in vivo cumulative release rate of brexpiprazole over time of 8-10 week sustained-release microspheres according to one embodiment of the present invention.

[0035] FIG. 4 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of 12-16 week sustained-release microspheres according to one embodiment of the present invention.

[0036] FIG. 5 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of 24-32 weeks of sustained-release microspheres according to one embodiment of the present invention.

[0037] FIG. 6 is a graph showing the cumulative release rate of brexpiprazole over time of a sustained-release microsphere blend comprising a combination of 32-week sustained-release microspheres and 4-6-week sustained-release microspheres in a weight ratio of 1:5 according to one embodiment of the present invention.

[0038]

[0039] Long-acting injectable composition

[0040] The present invention,

[0041] (i) sustained-release microspheres comprising brexpiprazole or a pharmaceutically acceptable salt thereof as a pharmaceutical substance, a biodegradable polymer, and a drug loading extender; or

[0042] (ii) a long-acting injection composition comprising a sustained-release microsphere blend, which is a combination of 2-3 types of sustained-release microspheres of (i) having different compositions;

[0043] Containing 5-70 wt% of the active substance based on the total weight of the sustained-release microspheres of the above (i) or the sustained-release microsphere blend of the above (ii),

[0044] The above drug loading extender is benzyl alcohol (BnOH) or acetic acid (AcOH),

[0045] The initial release amount of the active substance on the first day after in vivo administration of the above-mentioned western-release microspheres is 10% or less,

[0046] A long-acting injection composition is provided, wherein the active substance is released for 4 to 32 weeks after administration of the above-mentioned western-release microparticles in a living body.

[0047]

[0048] The long-acting injection composition according to the present invention may comprise (i) sustained-release microspheres or (ii) a sustained-release microsphere blend comprising two or three types of sustained-release microspheres of (i) having different compositions. Here, different compositions refer to different compositions of biodegradable polymers, drug loading extenders, etc.

[0049]

[0050] As the above-mentioned active substance, brexpiprazole may be in the form of a free base or a pharmaceutically acceptable salt form.

[0051] Pharmaceutically acceptable salts include, without limitation, salts commonly used in the art. The term "pharmaceutically acceptable salt" in the present invention refers to any organic or inorganic addition salt of the compound described above, which is relatively non-toxic and harmless to the patient and exhibits an effective effect, and whose side effects do not diminish the beneficial effects of the active ingredient.

[0052]

[0053] The content of brexpiprazole or a pharmaceutically acceptable salt thereof as an active substance relative to the total weight of the sustained-release microspheres of the above (i) or the sustained-release microsphere blend of the above (ii) may be selected as a lower limit of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or 65 wt% or more, and may be selected as an upper limit of 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 55, 50, 45 or 40 wt% or less. The content of the active substance in the microspheres may be included in a range formed by a combination of the lower limits and the upper limits relative to the total weight of the microspheres. For example, it may be 5-70 wt%, 10-70 wt%, 15-70 wt%, 20-70 wt%, 25-70 wt%, 30-70 wt%, 35-70 wt%, 40-70 wt%, 45-70 wt%, 50-70 wt%, 55-70 wt% or 60-70 wt%, but is not limited thereto.

[0054] If brexpiprazole is included in excess of 70 wt%, there may be problems such as rapid release of the active ingredient (API) at the initial stage of administration or difficulty in achieving long-term sustained release. In general, sustained-release microspheres containing a low content of active ingredient may have problems such as increased manufacturing costs and side effects (such as inflammatory reactions) due to increased polymer usage, increased patient discomfort due to increased total number of microspheres included in a single-dose injection, and low bioavailability.

[0055]

[0056] In the present invention, the role of the drug loading extender is to enable sustained-release microparticles to contain a high content of active substance while maintaining a low initial release amount on the first day and achieving sustained release over a long period of time. Examples of the drug loading extender include benzyl alcohol, acetic acid, and the like, which may be used alone or in combination.

[0057] The content of the above drug loading extender can be selected as 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 58 ppm or more in the microspheres, with a lower limit of 50000, 45000, 40000, 35000, 30000, 25000, 24000, 23000, 22000, 21147, 21000, 20000, 15000, 10000, 5000, 4000, 3000, 2000, 1000, 750, 500, 400, 300, 200, An upper limit of 100 ppm or less can be selected. The content of the drug loading extender can be included in a range consisting of a combination of the lower and upper limits with respect to the total weight of the microparticles. For example, 0.01-50000 ppm, 0.01-45000 ppm, 0.01-40000 ppm, 0.01-35000 ppm, 0.01-30000 ppm, 0.01-25000 ppm, 0.1-25000 ppm, 0.5-25000 ppm, 1-25000 ppm, 5-25000 ppm, 10-25000 ppm, 20-25000 ppm, 30-25000 ppm, 40-25000 ppm, 45-25000 ppm, 50-25000 ppm, 50-24000 ppm, 50-23000 ppm, 50-22000 ppm or It may be 58-21147 ppm, but is not limited thereto.

[0058]

[0059] The above biodegradable polymers include polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), polyhydroxybutyric acid (PLA), polyhydroxybutyric acid (PLGA ... Polyhydroxybutyrate-co-hydroxyvalerate (PHB), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, poly(butylene succinate-co-lactic acid) (PBSLA), etc. can be used alone or in combination of two or more. For example, the biodegradable polymers can be used in combination of one to three or one to two.Additionally, a copolymer of the above-mentioned selected polymer and polyethylene glycol (Polyethylenglycol, PEG), or a polymer-sugar complex in which the above-mentioned selected polymer or copolymer is combined with sugar may be used.

[0060] Specifically, the biodegradable polymer may be one type of polylactide (PLA) or one type of poly(lactide-co-glycolide) (PLGA), or a combination of two types of PLA, two types of PLGA, or one type of PLA and one type of PLGA may be used as a polymer blend.

[0061] The lower limit of the intrinsic viscosity of the above biodegradable polymer may be 0.14, 0.15, 0.16, 0.20, 0.25, 0.26, 0.32, 0.33, 0.39, 0.40, 0.45, 0.50, 0.55, 0.61, 0.70, 0.71, 0.76, 0.80, 0.83, 0.90, 0.95, 1.00 or 1.30 dL / g or more, and the upper limit may be 0.16, 0.20, 0.22, 0.24, 0.25, 0.35, 0.40, 0.42, 0.44, 0.49, 0.50, 0.54, 0.60, The intrinsic viscosity of the biodegradable polymer may be 0.68, 0.70, 0.74, 0.75, 0.85, 0.90, 0.93, 0.94, 1.00, 1.20, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90 or 2.00 dL / g or less. The intrinsic viscosity of the biodegradable polymer may be used in a range by combining the lower and upper limits. Specifically, the intrinsic viscosity of the biodegradable polymer may be 0.14-2.00 dL / g. Specifically, as a biodegradable polymer, PLA may be used having an intrinsic viscosity of 0.14-1.2, 0.14-1.0, 0.14-0.8, 0.14-0.7, 0.14-0.66, 0.16-1.2, 0.16-1.0, 0.16-0.8, 0.16-0.7 or 0.16-0.66 dL / g, and as a biodegradable polymer, PLGA may be used having an intrinsic viscosity of 0.08-2.00, 0.10-2.00, 0.12-2.00 or 0.14-2.00 dL / g. In the present invention, the intrinsic viscosity refers to that measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer.

[0062] The intrinsic viscosity of the biodegradable polymer can be used in a wide range, and from this point of view, if it exceeds the upper limit, there may be a problem that the release of the drug is too delayed (occurrence of a lag phase) or the reproducibility of microsphere manufacturing is reduced, and there may be a problem that an excessive amount of organic solvent must be used due to the high viscosity, and if it is below the lower limit, the molecular weight of the polymer may be insufficient, which may cause a burst release of the drug or a problem that it is difficult to exhibit a long-term sustained-release pattern. In one embodiment, in the case of a polymer blend in which two or more types of polymers are mixed and used, a polymer having a low intrinsic viscosity and a polymer having a high intrinsic viscosity may be mixed and used so that the mixed intrinsic viscosity is included within the desirable range of the intrinsic viscosity. In another embodiment, in the case of a microsphere blend in which two or three types of sustained-release microspheres are mixed and used, sustained-release microspheres including a polymer having a low intrinsic viscosity and sustained-release microspheres including a polymer having a high intrinsic viscosity may be mixed and used. For example, if there are microspheres including a polymer blend of PLA and PLGA, and a microsphere blend which is a combination of PLA microspheres and PLGA microspheres, and PLA and PLGA having the same polymer properties (intrinsic viscosity, terminal groups, repeat unit molar ratio, etc.) are used, the microspheres including the polymer blend may exhibit a drug release profile similar to that of the microsphere blend.

[0063] The biodegradable polymer may be one having a carboxylic acid or ester terminal group. Here, the biodegradable polymer having an ester terminal group has a slower decomposition rate than the biodegradable polymer having a carboxylic acid terminal group, so that the terminal group can be selected and used according to the target duration of efficacy.

[0064] When PLGA is used as the biodegradable polymer, the molar ratio of lactide:glycolide repeating units in the PLGA may be 40:60 to 90:10, or 50:50 to 85:15, and specifically 50:50, 65:35, 75:25, 82:18, or 85:15.

[0065] The content of the biodegradable polymer may be the remaining content after deducting the content of the active pharmaceutical ingredient (API) and the drug loading extender from the total weight of the microparticles. Here, the content of trace impurities is excluded. Specifically, the content of the biodegradable polymer in the microparticles may be selected as a lower limit of 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 wt% or more with respect to the total weight of the microparticles, and may be selected as an upper limit of 94.999999, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35 or 30 wt% or less with respect to the total weight of the microparticles. The content of the biodegradable polymer in the above microparticles may be included in a range consisting of a combination of the lower and upper limits above with respect to the total weight of the microparticles. For example, it may be 25-94.999999 wt%, 25-90 wt%, 25-80 wt%, 25-70 wt%, 25-65 wt%, 25-60 wt%, 25-55 wt%, 25-50 wt%, 25-45 wt%, 25-40 wt%, 25-35 wt%, or 25-30 wt%, but is not limited thereto. Other examples include, but are not limited to, 26-94.999999 wt%, 26-90 wt%, 26-80 wt%, 26-70 wt%, 26-65 wt%, 26-60 wt%, 26-55 wt%, 26-50 wt%, 26-45 wt%, 26-40 wt%, 26-35 wt% or 26-30 wt%. For example, the weight percent may be, but is not limited to, 27-94.999999 wt%, 27-90 wt%, 27-80 wt%, 27-70 wt%, 27-65 wt%, 27-60 wt%, 27-55 wt%, 27-50 wt%, 27-45 wt%, 27-40 wt%, 27-35 wt% or 27-30 wt%. For example, the weight percent may be, but is not limited to, 27.8-94.999999 wt%, 27.8-90 wt%, 27.8-80 wt%, 27.8-70 wt%, 27.8-65 wt%, 27.8-60 wt%, 27.It may be, but is not limited to, 8-55 wt%, 27.8-50 wt%, 27.8-45 wt%, 27.8-40 wt%, 27.8-35 wt% or 27.8-30 wt%.

[0066]

[0067] For example, in the case of a 'polymer blend' using two types of the biodegradable polymers, it may include two types of polymers of different types, such as PLA and PLGA, or it may include two types of biodegradable polymers of the same type, such as PLGA 1 and PLGA 2. If the same type of polymers are used, a combination of polymers having different intrinsic viscosity, repeat unit molar ratio, and terminal groups may be used.

[0068] In addition, when using two types of the biodegradable polymers, they can be mixed and used in various content ratios. For example, the content ratio may be 1:1 to 1:10, 1:1 to 1:8, 1:1 to 1:6, 1:1 to 1:5, or 1:1 to 1:4 by weight, but is not limited thereto.

[0069] For example, the drug release profile of sustained-release microspheres comprising a blend of two polymers (e.g., polymer a and polymer b) may be similar to the drug release profile of a microsphere blend that is a combination of microspheres comprising polymer a and microspheres comprising polymer b.

[0070] Examples of commercially available biodegradable polymers that can be used in the present invention include the Resomer® series from Evonik and the PURASORB® series from Corbion. For example, the biodegradable polymers of the Resomer series of Evonik include RG501H, RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, RG858S, R202H, R203H, R202S, R203S, R205H, R205S, etc., and the biodegradable polymers of the PURASORB series of Corbion include PDL 02A, PDL 02, PDL 04A, PDL 04, PDL 05A, PDL 05, PDL 06A, PDL 06, PDLG 7502A, PDLG 7502, PDLG 7504A, PDLG 7504, PDLG 7507, PDLG 7510, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG 5010, PDLG 5505G, PL 10, PL 18, PL 24, PL 32, PL 38, PL 65, PLDL 7024, PLDL, 7028, PLDL, 7038, PLDL 7060, PLDL 8038, PLDL 8058, PG 20, PLG 1017, PLG 8218, PLG 8523, PLG 8531, PC 02, PC 04, PC 08, PC 12, PC 17, PLC 7015, etc. alone, in combination or blend, etc., but are not limited thereto. Suitable intrinsic viscosity, repeat unit molar ratio, terminal groups, etc. of the biocompatible polymer applicable to the present invention can be appropriately selected by those skilled in the art in consideration of the degradation rate of the biocompatible polymer and the resulting drug release rate.

[0071]

[0072] The sustained-release microspheres according to the present invention may have an initial release amount of the active pharmaceutical ingredient (API) on day 1 after in vivo administration of 10% or less, 9% or less, 8% or less, or 7% or less. The initial release amount on day 1 refers to the cumulative release amount up to day 1 of the total amount of drug loaded into the microspheres. If the initial release amount on day 1 exceeds 10%, problems may arise due to a rapid increase in the initial blood drug concentration in the body.

[0073]

[0074] The sustained-release microspheres of the present invention can release the active substance for 4-32 weeks after in vivo administration. For example, the active substance can be released for 4-6 weeks, 8-10 weeks, 12-16 weeks, or 24-32 weeks, and the sustained-release microspheres can be manufactured according to the target release period.

[0075]

[0076] The sustained-release microspheres according to the present invention may further include a steroidal anti-inflammatory agent, and may be in the form of co-encapsulated microspheres containing both brexpiprazole as an active substance and the steroidal anti-inflammatory agent in one microsphere.

[0077] In addition, the sustained-release microsphere blend according to the present invention may further include a steroidal anti-inflammatory agent in at least one of the 2-3 types of sustained-release microspheres, and this may be in the form of co-encapsulated microspheres containing both brexpiprazole as an active substance and a steroidal anti-inflammatory agent in at least one of the 2-3 types of sustained-release microspheres.

[0078] Furthermore, the long-acting injection composition according to the present invention may further include sustained-release microspheres containing a steroidal anti-inflammatory agent, which may be in the form of a microsphere blend in which sustained-release microspheres containing brexpiprazole as a pharmaceutical agent and sustained-release microspheres containing a steroidal anti-inflammatory agent are combined.

[0079] The above steroidal anti-inflammatory agent can play a role in alleviating the inflammatory response caused by the biodegradable polymer included in the sustained-release microspheres. The upper limit may be 0.1 part by weight or less, 0.05 part by weight or less, 0.01 part by weight or less, 0.005 part by weight or less, or 0.001 part by weight or less of the steroidal anti-inflammatory agent relative to 1 part by weight of brexpiprazole, which is the active substance of the present invention, and the lower limit may be 0.0001 part by weight or more, 0.0002 part by weight or more, 0.0003 part by weight or more, 0.0004 part by weight or more, or 0.0005 part by weight or more. The content of the steroidal anti-inflammatory agent relative to 1 part by weight of brexpiprazole may be included in a range consisting of a combination of the above lower limits and upper limits. For example, when using dexamethasone acetate as a steroidal anti-inflammatory agent, 0.0001-0.0020 parts by weight, 0.0002-0.0018 parts by weight, 0.0003-0.0016 parts by weight, 0.0004-0.0013 parts by weight, or 0.0005-0.0010 parts by weight of the steroidal anti-inflammatory agent can be used per 1 part by weight of brexpiprazole.

[0080] Specific examples of the above steroidal anti-inflammatory agents include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximethasone, dexamethasone, dexamethasone acetate, dexamethasone phosphate, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone Acetonide, fluocinonide, flucortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, Prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide,Beclomethasone dipropionate, betamethasone, budesonide, deflazacort, dexamethasone, dexamethasone acetate, dexamethasone phosphate, difluprednate, epinephrine, fludrocortisone, fluocinolone acetonide, fluocortin, fluorometholone, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, Triamcinolone, etc. can be used alone or in combination of two or more. As an example of the present invention, the steroidal anti-inflammatory agent can be dexamethasone acetate.

[0081]

[0082] Brexpiprazole, the active pharmaceutical ingredient (API) of the present invention, is a dopamine D2 receptor partial agonist activity (D2 receptor partial agonist activity) and serotonin 5-HT sold under the trade name Rexulti. 2A It has receptor antagonist activity and adrenergic α1 receptor antagonist activity, and in addition, it has simultaneous serotonin uptake inhibition (or serotonin reuptake inhibition) activity, and is known to have a wide therapeutic spectrum for central nervous system diseases, and has been approved as an agent for the treatment of schizophrenia and as an adjunctive treatment for major depressive disorder (MDD). In addition, in May 2023, the indication for brexpiprazole in the United States was expanded to include the treatment of agitation associated with dementia due to Alzheimer's disease.

[0083] That is, the long-acting injection composition according to the present invention can include all indications known as the medical use of brexpiprazole, and specifically can be used for the prevention, improvement, or treatment of mental health diseases such as schizophrenia, major depressive disorder, persistent depressive disorder, and agitation associated with Alzheimer's dementia.

[0084]

[0085] In the long-acting injection composition according to the present invention, sustained-release microparticles or sustained-release microparticle blends can be formulated as injections by suspending them in a pharmaceutically acceptable vehicle.

[0086] The microspheres can be formulated as aqueous or oily suspensions by adding appropriate excipients. For example, if the microspheres are formulated as a suspension, those skilled in the art can select and formulate a dispersion medium that allows the microspheres to exhibit excellent dispersibility. Furthermore, the injectable composition according to the present invention may further include thickeners, stabilizers, isotonic agents, pH regulators, surfactants, buffers, excipients, carriers, and the like.

[0087] The isotonic agent can be a water-soluble excipient or sugar such as mannitol, sucrose, sorbitol, trehalose, lactose, sodium chloride, etc., and the thickening agent can be carmellose sodium, carboxymethyl cellulose sodium, povidone, etc. The surfactant can be a polyoxyethylene sorbitan type, such as polysorbate 80, polysorbate 20, etc., and a sorbitan ester type, such as Span 80, Span 20, etc. In addition, the buffering agent can be sodium monohydrogen phosphate, anhydrous citric acid, sodium hydroxide, sodium chloride, etc.

[0088]

[0089] The sustained-release microspheres of (i) above or the sustained-release microsphere blend of (ii) above

[0090] The present invention provides (i) sustained-release microparticles or (ii) sustained-release microparticle blends included in the long-acting injectable composition.

[0091] In one embodiment, the sustained-release microspheres of (i) or the sustained-release microsphere blend of (ii) may be present in a separate vial from the dispersion medium, and may be suspended in a pharmaceutically acceptable vehicle immediately prior to administration to a patient. In another embodiment, a kit comprising the sustained-release microspheres of (i) or the sustained-release microsphere blend of (ii), a pharmaceutically acceptable vehicle, and a syringe is provided. In yet another embodiment, the sustained-release microspheres of (i) or the sustained-release microsphere blend of (ii) and the pharmaceutically acceptable vehicle are filled in a syringe, but may also be present independently of each other in separate compartments within the syringe.

[0092]

[0093] Manufacturing method

[0094] The present invention provides a method for producing sustained-release microspheres containing brexpiprazole or a pharmaceutically acceptable salt thereof, which may include the following steps.

[0095] (a) A step of preparing an oil phase (O phase) in which brexpiprazole or a pharmaceutically acceptable salt thereof, a biodegradable polymer, and a drug loading extender are dissolved in an organic solvent as a pharmaceutical substance;

[0096] (b) a step of preparing a water phase (W phase) in which a surfactant is dissolved in water as a continuous phase;

[0097] (c) a step of forming an emulsion (O / W) solution by mixing the dispersed phase and the continuous phase; and

[0098] (d) a step of extracting the dispersed organic solvent in the emulsion solution toward the continuous phase to generate microspheres;

[0099] The above drug loading increasing agent is benzyl alcohol or acetic acid.

[0100]

[0101] In the manufacturing method according to the present invention, the description of the active substance, brexpiprazole or a pharmaceutically acceptable salt thereof, a biodegradable polymer, a drug loading extender, etc. is replaced with the description of the long-acting injection described above.

[0102]

[0103] Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.

[0104]

[0105] In the manufacturing method according to the present invention, step (a) is a step of preparing an oil phase (O phase) in which brexpiprazole or a pharmaceutically acceptable salt thereof, a biodegradable polymer, and a drug loading extender are dissolved in an organic solvent as a pharmaceutical substance, as a dispersion phase.

[0106] The above organic solvent may be dichloromethane, dimethyl carbonate, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, n-methyl pyrrolidone, methyl alcohol, ethyl alcohol, propyl alcohol, etc., which may be used alone or in combination of two or more.

[0107] The above organic solvent is used to dissolve pharmaceutical substances and biodegradable polymers, and when a drug loading extender is used, the amount of organic solvent required for dissolution can be significantly reduced.

[0108] The drug loading extender may be used in an amount of 0.01-5.00 parts by weight, 0.02-4.50 parts by weight, 0.03-4.00 parts by weight, 0.04-3.50 parts by weight, 0.05-3.00 parts by weight, 0.06-2.60 parts by weight, 0.07-2.20 parts by weight, 0.08-2.10 parts by weight, or 0.083-2.013 parts by weight, relative to 1 part by weight of the combined weight of the above-mentioned pharmaceutical substance and biodegradable polymer.

[0109] When using BnOH as a drug loading extender, the drug loading extender may be used in an amount of 0.10-5.00 parts by weight, 0.30-4.00 parts by weight, 0.40-3.00 parts by weight, 0.45-2.50 parts by weight, 0.48-2.20 parts by weight, 0.50-2.10 parts by weight, or 0.567-2.013 parts by weight per 1 part by weight of the combined weight of the pharmaceutical substance and the biodegradable polymer.

[0110] When using AcOH as a drug loading extender, the drug loading extender may be used in an amount of 0.020-1.000 parts by weight, 0.040-0.500 parts by weight, 0.060-0.400 parts by weight, 0.070-0.350 parts by weight, or 0.08-0.260 parts by weight per 1 part by weight of the combined weight of the pharmaceutical substance and the biodegradable polymer.

[0111] The drug loading extender may be used in an amount of 0.005-2.500 parts by weight, 0.008-2.100 parts by weight, 0.011-1.700 parts by weight, 0.015-1.400 parts by weight, 0.017-1.200 parts by weight, 0.018-1.100 parts by weight, or 0.019-1.007 parts by weight, relative to 1 part by weight of the organic solvent.

[0112] When using BnOH as a drug loading extender, 0.030-2.500 parts by weight, 0.060-2.000 parts by weight, 0.090-1.500 parts by weight, 0.100-1.200 parts by weight, 0.120-1.100 parts by weight, or 0.126-1.007 parts by weight of the drug loading extender can be used per 1 part by weight of the organic solvent.

[0113] When using AcOH as a drug loading extender, the drug loading extender may be used in an amount of 0.005-0.350 parts by weight, 0.007-0.250 parts by weight, 0.009-0.150 parts by weight, 0.012-0.120 parts by weight, 0.017-0.090 parts by weight, or 0.019-0.084 parts by weight per 1 part by weight of the organic solvent.

[0114]

[0115] In the manufacturing method according to the present invention, step (b) is a step of preparing a water phase (W phase) in which a surfactant is dissolved in water as a continuous phase.

[0116] The water used above may be purified water, distilled water, or water for injection.

[0117] The type of the above surfactant is not particularly limited, and any surfactant that can help the dispersed phase form a stable droplet emulsion within the continuous phase can be used. Specifically, the surfactant may be polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, etc., used alone or in combination of two or more. More specifically, the surfactant may be polyvinyl alcohol.

[0118] The content of the surfactant in the continuous phase may be 0.01 w / v% to 20 w / v%, specifically 0.03 w / v% to 18 w / v%, 0.05 w / v% to 15 w / v%, 0.07 w / v% to 10 w / v%, or 0.1 w / v% to 5 w / v%, based on the total volume of the continuous phase including the surfactant, and may be a combination of the lower and upper limits of the above-described ranges. When the content of the surfactant is less than 0.01 w / v%, a dispersed phase emulsion in the form of droplets may not be formed in the continuous phase, and when the content of the surfactant exceeds 20 w / v%, after microspheres are formed in the continuous phase due to an excess of surfactant, it may be difficult to remove the surfactant.

[0119] The above continuous phase may further include methyl alcohol, ethyl alcohol, propyl alcohol, ethyl acetate, etc., either singly or in combination of two or more, for the purpose of controlling the extraction rate of the organic solvent from the dispersed phase in the emulsion state. In addition, the above continuous phase may further include sodium chloride for the purpose of controlling the osmotic pressure.

[0120]

[0121] In the manufacturing method according to the present invention, step (c) is a step of forming an emulsion (O / W) solution by mixing the dispersed phase and the continuous phase.

[0122] The volume ratio of the dispersed phase and the continuous phase in the above emulsion solution may be 1:1 to 1:20 at the time of forming the emulsion, and may be 1:1 to 1:1000 at the time of organic solvent extraction from the dispersed phase of the emulsion solution to the continuous phase. The above emulsion solution may be prepared using a device such as a membrane emulsification method using a porous filter, an inline mixer, a static mixer, or a microfluidic system.

[0123]

[0124] In the manufacturing method according to the present invention, step (d) is a step of extracting the dispersed organic solvent in the emulsion solution toward the continuous phase to generate microspheres.

[0125] The above step (d) may further include a heating treatment for evaporation of the organic solvent.

[0126] After the above step (d), a step (e) of discharging part or all of the continuous phase mixed with the organic solvent and replacing it with a fresh continuous phase may be further included.

[0127] In the above step (d), a one-time process of extracting the organic solvent in the dispersed phase toward the initially supplied continuous phase, i.e. a 'static process' without a replacement process of a fresh continuous phase, can be performed.

[0128] As another example, a "substitution process" can be implemented, which discharges the continuous phase mixed with the organic solvent and supplies a fresh continuous phase. This substitution process is a discontinuous process and can be performed in multiple stages.

[0129] As another example, it can be carried out as a 'continuous process' that simultaneously supplies a fresh continuous phase while discharging a continuous phase mixed with organic solvent.

[0130] When the above-mentioned 'substitution process' or 'continuous process' is used, the efficiency of removing the organic solvent dispersed in the emulsion can be further increased.

[0131]

[0132] The present invention will be described in more detail with reference to the following examples, but the scope of protection of the present invention is not limited to the following exemplary examples.

[0133]

[0134] polymer raw materials

[0135] The manufacturer, product name, model name, and characteristics of the polymers used in the examples are summarized in Table 1 below. In Table 1 below, the intrinsic viscosity of each product model of the manufacturer Corbion is disclosed as a single numerical value on the manufacturer's website, but is described as a range in the COA (Certificate of Analysis) provided by the manufacturer, so the intrinsic viscosity according to the COA is described.

[0136] ManufacturerProduct NameModel NameIntrinsic Viscosity (dL / g)Lactide:Glycolide Molar Ratio in Terminal GroupPLGAPLACorbionPURASORBPDL060.54-0.66Ester-CorbionPURASORBPDL04A0.35-0.45Acid-CorbionPURASORBPDL02A0.16-0.24Acid-EvonikRESORMERR202H0.16-0.24Acid-EvonikRESORMERR203H0.25-0.35Acid-PLGACorbionPURASORBPDLG7504A0.38-0.48Acid75:25CorbionPURASORBPDLG7502A0.16-0.24Acid75:25CorbionPURASORBPDL G5004A0.32-0.48Acid50:50CorbionPURASORBPDLG5002A0.16-0.24Acid50:50CorbionPURASORBPLG82181.5-2.0Ester82:18EvonikRESORMERRG653H0.32-0.44Acid65:35Evon ikRESORMERRG753H0.32-0.44Acid75:25EvonikRESORMERRG503H0.32-0.44Acid50:50EvonikRESORMERRG752H0.14-0.22Acid75:25EvonikRESORMERRG757S0.9-1.3Ester75:25

[0137] <Comparative Examples 1-1 to 1-3> Preparation of microspheres containing brexpiprazole without using a drug loading extender

[0138] The dispersed phase (DP) was prepared by mixing a biocompatible polymer and the active pharmaceutical ingredient (API), brexpiprazole free base (manufacturer: Cambrex, Italy), in dichloromethane (DCM) as a solvent. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0139] A 0.1 to 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8 to 5.8 mPa·s) aqueous solution was prepared as a continuous phase (CP).

[0140] An emulsion solution was prepared by injecting the continuous phase and the dispersed phase simultaneously into an emulsifying device equipped with a porous membrane with a diameter of 40 μm.

[0141] The emulsion solution was placed in a preparation vessel and stirred at 200 rpm, and the temperature of the preparation vessel was maintained at 25°C. After the dispersion phase injection was completed, the temperature of the emulsion solution was maintained at 40-45°C for 3 hours, while the organic solvent was extracted from the emulsion into the continuous phase to prepare a microsphere suspension. Here, the organic solvent mixed in the continuous phase was evaporated by heating. Optionally, during the process of extracting the organic solvent from the emulsion into the continuous phase, a continuous phase exchange process was added to supply a fresh continuous phase (CP) and discharge the continuous phase mixed with the organic solvent to ensure smooth removal of the organic solvent.

[0142] After the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25°C, filtered, and washed three times with distilled water to remove any residual polyvinyl alcohol, and the microspheres were obtained. The microspheres obtained at this stage were lyophilized to recover the final brexpiprazole-containing microspheres.

[0143] The types of polymers, amounts of drugs, etc. used in Comparative Examples 1-1 to 1-3 are shown in Table 2.

[0144]

[0145] * API (Active Pharmaceutical Ingredient): Brexpiprazole free base

[0146] * T / L: API Target Loading (API content percentage out of the total amount of polymer and API)

[0147]

[0148] <Comparative Examples 2-1 to 2-2> Preparation of microspheres containing more than 70 wt% of brexpiprazole using benzyl alcohol (BnOH) as a drug loading increasing agent

[0149] The dispersed phase (DP) was prepared by mixing a biocompatible polymer, brexpiprazole free base (manufacturer: Cambrex, Italy) as the active ingredient (API), and benzyl alcohol (BnOH) as a drug loading extender in dichloromethane (DCM) as the solvent. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0150] A 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8–5.8 mPa·s) aqueous solution was prepared as a continuous phase (CP).

[0151] An emulsion solution was prepared by injecting the continuous phase and the dispersed phase simultaneously into an emulsifying device equipped with a porous membrane with a diameter of 40 μm.

[0152] The emulsion solution was placed in a preparation vessel and stirred at 200 rpm, and the temperature of the preparation vessel was maintained at 25°C. After the injection of the dispersed phase, the temperature of the emulsion solution was maintained at 45°C for 3 hours, while the organic solvent was extracted from the emulsion into the continuous phase to prepare a microsphere suspension. Here, the organic solvent mixed in the continuous phase was evaporated by heating. In addition, during the process of extracting the organic solvent from the emulsion into the continuous phase, a continuous phase exchange process was added to supply a fresh continuous phase (CP) and discharge the continuous phase mixed with the organic solvent to ensure smooth removal of the organic solvent.

[0153] After the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25°C, filtered, and washed three times with distilled water to remove any residual polyvinyl alcohol, and the microspheres were obtained. The microspheres obtained at this stage were lyophilized to recover the final brexpiprazole-containing microspheres.

[0154] The types of polymers, amounts of drugs, etc. used in Comparative Examples 2-1 to 2-2 are shown in Table 3.

[0155]

[0156] * API (Active Pharmaceutical Ingredient): Brexpiprazole free base

[0157] * T / L: API Target Loading (API content percentage out of the total amount of polymer and API)

[0158]

[0159] <Comparative Examples 3-1 to 3-2> Preparation of microspheres containing brexpiprazole using formic acid as a drug loading extender

[0160] The dispersed phase (DP) was prepared by mixing a biocompatible polymer, brexpiprazole free base (manufacturer: MSN Life Sciences private Limited, India) as an active pharmaceutical ingredient (API), and formic acid as a drug loading extender in dichloromethane (DCM) as a solvent. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0161] A 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8–5.8 mPa·s) aqueous solution was prepared as a continuous phase (CP).

[0162] An emulsion solution was prepared by injecting the continuous phase and the dispersed phase simultaneously into an emulsifying device equipped with a porous membrane with a diameter of 20 μm.

[0163] The emulsion solution was placed in a preparation vessel and stirred at 200 rpm, while the temperature of the preparation vessel was maintained at 15°C. After the dispersion phase was injected, the temperature of the emulsion solution was maintained at 15°C for 1 hour, and then at 40°C for 2 hours, while extracting the organic solvent from the emulsion as a continuous phase to prepare a microsphere suspension. Here, the organic solvent mixed in the continuous phase was evaporated by heating.

[0164] After the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25°C, filtered, and washed three times with distilled water to remove any residual polyvinyl alcohol, and the microspheres were obtained. The microspheres obtained at this stage were lyophilized to recover the final brexpiprazole-containing microspheres.

[0165] The types of polymers, amounts of drugs, etc. used in Comparative Examples 3-1 and 3-2 are shown in Table 4.

[0166]

[0167] * API (Active Pharmaceutical Ingredient): Brexpiprazole free base

[0168] * T / L: API Target Loading (API content percentage out of the total amount of polymer and API)

[0169]

[0170] <Examples 1-1 to 1-56> Preparation of microspheres containing brexpiprazole using benzyl alcohol (BnOH) as a drug loading increasing agent

[0171] The dispersed phase (DP) was prepared by mixing a biocompatible polymer, brexpiprazole free base (manufacturer: Cambrex, Italy) as an active ingredient (API), and benzyl alcohol (BnOH) as a drug loading extender in dichloromethane (DCM) as a solvent. The dispersed phase was stirred for more than 30 minutes to ensure sufficient dissolution before use. Here, Examples 1-34 to 1-35 additionally used 0.00067 g of dexamethasone acetate together with brexpiprazole free base as an active ingredient (API).

[0172] A 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8–5.8 mPa·s) aqueous solution was prepared as a continuous phase (CP).

[0173] An emulsion solution was prepared by injecting the continuous phase and the dispersed phase simultaneously into an emulsifying device equipped with a porous membrane with a diameter of 40 μm.

[0174] The emulsion solution was placed in a preparation vessel and stirred at 200 rpm, and the temperature of the preparation vessel was maintained at 25℃. After the injection of the dispersed phase, the temperature of the emulsion solution was maintained at 45-55℃ for 3 hours, and the organic solvent was extracted from the emulsion into the continuous phase to prepare a microsphere suspension. Here, the organic solvent mixed in the continuous phase was evaporated by heating. In addition, during the process of extracting the organic solvent from the emulsion into the continuous phase, a continuous phase exchange process was added to supply a fresh continuous phase (CP) and discharge the continuous phase mixed with the organic solvent to ensure smooth removal of the organic solvent.

[0175] After the organic solvent was removed, the temperature of the microparticle suspension was lowered to 25°C, and then filtered and washed 1 to 3 times with a washing solution (3-distilled water for Examples 1-1 to 1-35, 1% (w / v) Tween 20 for Examples 1-36 to 1-38, and 0.01% (w / v) acetic acid for Examples 1-39 to 1-56) to remove residual polyvinyl alcohol and obtain microparticles. The microparticles obtained at this stage were freeze-dried to recover the final brexpiprazole-containing microparticles.

[0176] The types of polymers, amounts of drugs, etc. used in Examples 1-1 to 1-56 are shown in Table 5.

[0177]

[0178] * API (Active Pharmaceutical Ingredient): Brexpiprazole free base

[0179] * T / L: API Target Loading (API content percentage out of the total amount of polymer and API)

[0180] * Examples 1-34 and 1-35 are co-encapsulated microspheres containing brexpiprazole and dexamethasone acetate as APIs.

[0181]

[0182] <Examples 2-1 to 2-13> Preparation of microspheres containing brexpiprazole using acetic acid (AcOH) as a drug loading increasing agent

[0183] The dispersed phase (DP) was prepared by mixing a biocompatible polymer, brexpiprazole free base (manufacturer: Cambrex, Italy) as an active pharmaceutical ingredient (API), and acetic acid (AcOH) as a drug loading extender in dichloromethane (DCM) as a solvent. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0184] A 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8–5.8 mPa·s) aqueous solution was prepared as a continuous phase (CP).

[0185] An emulsion solution was prepared by injecting the continuous phase and the dispersed phase simultaneously into an emulsifying device equipped with a porous membrane having a diameter of 20 or 40 μm. Specifically, Examples 2-1 to 2-12 used a porous membrane having a diameter of 20 μm, and the remaining Examples 2-13 used a porous membrane having a diameter of 40 μm.

[0186] In the case of Examples 2-1 to 2-13, the microparticle suspension was placed in a preparation vessel and stirred at a speed of 200 rpm, and the temperature of the preparation vessel was maintained at 15°C. Here, in the case of Examples 2-1 to 2-12, after the injection of the dispersed phase was completed, the temperature of the microparticle suspension was maintained at 15°C for 1 hour, and then maintained at 40°C for 2 hours, while extracting the organic solvent from the emulsion as a continuous phase, thereby preparing a microparticle suspension. In the case of Example 2-13, after the injection of the dispersed phase was completed, the temperature of the microparticle suspension was maintained at 45°C for 3 hours, while extracting the organic solvent from the emulsion as a continuous phase, thereby preparing a microparticle suspension. Here, the organic solvent mixed in the continuous phase was evaporated by heating.

[0187] After the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25°C, and the suspension was filtered and washed three times with a washing solution (tertiary distilled water) to remove any residual polyvinyl alcohol, and the microspheres were obtained. The microspheres obtained at this stage were freeze-dried to recover the final brexpiprazole-containing microspheres.

[0188] The types of polymers, amounts of drugs, etc. used in Examples 2-1 to 2-13 are shown in Table 6.

[0189]

[0190] * API (Active Pharmaceutical Ingredient): Brexpiprazole free base

[0191] * T / L: API Target Loading (API content percentage out of the total amount of polymer and API)

[0192]

[0193] <Examples 3-1 to 3-4> Preparation of sustained-release microparticle blend

[0194] Example 1-36, an example of a sustained-release microsphere with a 32-week release period, exhibits a delayed drug release phase for the initial 4 weeks (see FIGS. 5 and 6 ). Accordingly, a sustained-release microsphere blend was prepared by combining Example 1-36 with Example 1-11, 1-8, 1-12, or 1-37, which are examples of sustained-release microspheres with a 4-6 week release period that can compensate for the initial 4-week delayed drug release phase.

[0195]

[0196]

[0197] <Experimental Example 1> Evaluation of the effect of adding a drug loading extender on the maximum drug content that can be loaded into microspheres and the initial drug release amount on the first day in vitro.

[0198] (1) Measurement of drug (API) content and encapsulation rate in microparticles

[0199] In order to measure the drug (API) content of the microspheres manufactured in the above examples and comparative examples, 40 mg of microspheres were completely dissolved in 10 mL of dimethyl sulfoxide, and then a 10-fold diluted solution was used as a test solution. 10 μl of the diluted solution was injected into HPC and measured at a detection wavelength of 324 nm. The column used in this measurement was ZORBAX Eclipse XDB-C18, 5 μm, 4.6 x 150 mm, and the mobile phase was a mixture of acetonitrile containing 0.1% (w / w) trifluoroacetic acid and 0.1% (w / w) trifluoroacetic acid aqueous solution.

[0200]

[0201] Meanwhile, Examples 1-34 and 1-35 are microspheres co-encapsulated with brexpiprazole and dexamethasone acetate as APIs. In the case of dexamethasone acetate, the amount used was extremely small, so the content in the microspheres was minimal, at approximately 0.028-0.029%.

[0202] 'Drug (API) content' means the weight % of the encapsulated drug based on 100 weight % of the manufactured microspheres.

[0203] "Encapsulation rate" is the weight percent of encapsulated drug, expressed as a percentage, based on 100% of the total weight of the microspheres, divided by the weight percent of the drug used as raw material. Meanwhile, an encapsulation rate exceeding 100% can be interpreted as occurring due to loss of the polymer used during the manufacturing process.

[0204]

[0205] (2) Measurement of the initial drug release amount on the first day in vitro

[0206] This experiment confirmed whether an 'initial burst' occurred by measuring the initial release amount on the first day of the microspheres manufactured in the examples and comparative examples.

[0207] Specifically, 10 mg of microparticles and 50 mL of release test solution (phosphate-buffered saline, pH 7.4) were added and stored in a 37°C incubator. After 24 hours, 1 mL of the solution was taken, filtered through a 0.45 μm syringe filter, and 10 μL was injected into HPLC. At this time, the HPLC column and operating conditions are the same as the drug content HPLC analysis conditions.

[0208]

[0209] (3) Measurement of the content of benzyl alcohol (BnOH) as a drug loading increasing agent in microparticles

[0210] In order to measure the residual amount of benzyl alcohol in microparticles, the dried microparticles of Comparative Example 2 and Example 1 were used as samples, and the benzyl alcohol content was measured using high-performance liquid chromatography (HPLC). At this time, the column used was Inertsil ODS-3, (4.6 mm × 250 mm, 5 um) or an equivalent column, and a UV-Vis detector was used. As mobile phase A, 2.57 g of sodium phosphate dibasic dihydrate and 1.46 g of sodium phosphate monobasic monohydrate were dissolved in 1 L of purified water, and then phosphoric acid was added to adjust the pH to 7.0. As mobile phase B, acetonitrile was used, and the composition of mobile phase A / mobile phase B was changed from 70 / 30 (v / v) to 30 / 70 (v / v).

[0211] 1) Preparation of standard solution

[0212] Weigh accurately 25 mg of benzyl alcohol standard and place in a 100 mL volumetric flask, add mobile phase A and pre-discharge. Take 1.0 mL of this solution and place in a 10 mL volumetric flask, add 2 mL of N,N-dimethylformamide, then add mobile phase A and pre-discharge to prepare a standard solution.

[0213] 2) Preparation of test solution

[0214] In Comparative Example 2 and Example 1, 50 mg of dried microspheres were precisely weighed and placed in a 10 mL volumetric flask, dissolved in 2 mL of N,N-dimethylformamide, and then mobile phase A was added to mark the solution, centrifuged, and the supernatant was used as a test solution.

[0215]

[0216] (4) Measurement of the content of acetic acid (AcOH) as a drug loading increasing agent in microparticles

[0217] To measure the residual acetic acid in the microparticles, approximately 100 mg of the dried microparticles from Example 2 were weighed and placed in a 10 mL volumetric flask, 0.07% (v / v) phosphoric acid was added, and the mixture was mixed in a constant temperature water bath. The residual acetic acid content was measured using high performance liquid chromatography (HPLC). At this time, the column used was Inertsil C18 (manufacturer: GL Sciences) (4.6 mm x 250 mm, 5 um), and a Waters Alliance HPLC consisting of a 2489 UV / Vis detector and an e2695 Separations Module was used. 0.07% (v / v) phosphoric acid adjusted to pH 3.0 with 10 N sodium hydroxide solution was used as the mobile phase A, and methanol was used as the mobile phase B, and the composition of the mobile phase A / mobile phase B was changed from 95 / 5 (v / v) to 50 / 50 (v / v).

[0218] 1) Preparation of standard solution

[0219] Weigh accurately 500 mg of acetic acid standard and place in a 100 mL volumetric flask, add approximately 80 mL of 0.07% (v / v) phosphoric acid, mix, and then add 0.07% (v / v) phosphoric acid to make exactly 100 mL. Take exactly 1 mL of this solution and place in a 100 mL volumetric flask, add 0.07% (v / v) phosphoric acid to make exactly 100 mL. The solution filtered through a 0.45 um filter was used as the standard solution.

[0220] 2) Preparation of test solution

[0221] Weigh approximately 100 mg of the sample, add approximately 5 mL of 0.07% (v / v) phosphoric acid to a 10 mL volumetric flask, mix at 100 rpm in a 55°C constant temperature water bath for 2 hours, cool to room temperature, and add 0.07% (v / v) phosphoric acid to make exactly 10 mL. The solution filtered through a 0.45 um filter was used as the test solution.

[0222]

[0223]

[0224] * EE(%): Encapsulation Efficiency

[0225] * API(%): Percentage of API content in total weight of microparticles

[0226] * Day 1 (%): Initial in vitro drug release on day 1

[0227] * BnOH (ppm): Residual benzyl alcohol content in microparticles

[0228] * AcOH (ppm): Residual acetic acid content in microspheres

[0229] * NA: Measurement not performed

[0230]

[0231] As shown in Table 8,

[0232] In Comparative Examples 1-1 to 1-3, which did not use a drug loading extender, the API content was 17.1-45.9 wt%, and among these, in the case of Comparative Example 1-1, the API content was low at 17.1 wt%, so the initial release amount on the first day was good at the level of 1.8%, but in the case of Comparative Examples 1-2 to 1-3, the API content was high at 30.3-45.9 wt%, so the initial release amount on the first day was shown to increase rapidly to 8.7-17.2%, and in the case of Comparative Examples 2-1 to 2-2, despite using BnOH as a drug loading extender, the API content was very high at 73.2-73.8 wt%, so the initial release amount on the first day was high at 19.2-21.4%. In addition, in the case of Comparative Examples 3-1 to 3-2, the encapsulation rate of the microspheres using formic acid as a drug loading extender was found to be very low, making commercialization impossible.

[0233] On the other hand, in Examples 1-1 to 1-56 using benzyl alcohol (BnOH) as a drug loading extender, the initial release amount on the first day was low at 0.1-5.2% despite the high API content of 41.9-67.6 wt%, and in Examples 2-1 to 2-13 using acetic acid (AcOH) as a drug loading extender, the initial release amount on the first day was low at 0.3-6.3% despite the high API content of 31.3-66.2 wt%.

[0234] Therefore, it was confirmed that when benzyl alcohol (BnOH) or acetic acid (AcOH) is used as a drug loading extender, brexpiprazole can be loaded into microspheres at a high content of up to about 70 wt%, while the initial release amount on the first day can be controlled to a low level.

[0235]

[0236] <Experimental Example 2> SEM analysis of the surface properties of microspheres

[0237] The experiment was conducted to analyze the morphological characteristics of the manufactured microspheres using scanning electron microscopy (SEM).

[0238] 5 mg of microspheres were placed on an aluminum stub with carbon tape attached and coated with platinum using an ION-COATER (COXEM, Korea). The aluminum stub was mounted on a scanning electron microscope (COXEM EM-30, Korea), and the morphological characteristics of the microspheres were observed at an acceleration voltage of 10 kV.

[0239] Figure 1 is an image of the surface shape of microspheres manufactured in Comparative Example 1-3 and Example 1-9 analyzed using a scanning electron microscope (SEM).

[0240]

[0241] As shown in Fig. 1, the microspheres of Comparative Example 1-3, which did not use a drug loading extender, had a large number of large pores on the surface, whereas the microspheres of Example 1-9, which used benzyl alcohol (BnOH) as a drug loading extender, were confirmed to have a smooth surface with almost no pores, confirming that this is advantageous for a stable drug release pattern.

[0242]

[0243] <Experimental Example 3> Evaluation of the cumulative release rate of brexpiprazole in vivo over time

[0244] In order to evaluate the pharmacokinetics of microspheres containing brexpiprazole manufactured in the examples and comparative examples, the blood brexpiprazole concentration was measured over time after administration to rats, and the cumulative release rate was derived from this.

[0245] Specifically, for the brexpiprazole microsphere formulation, the microspheres were measured to be administered at a dosage of 3.4 mg / head as API, suspended in 0.2 mL of a dispersing solvent, and then intramuscularly injected into SD rats at a dosage of 0.2 mL / head. Blood was collected at pre-scheduled times, and the blood brexpiprazole concentration was measured using LC-MS / MS, and the cumulative release rate was derived based on the results. The cumulative release rates of the Examples and Comparative Examples are shown in Table 9 below, and some of the Examples suitable for the target duration of efficacy from Table 9 are summarized and shown in FIGS. 2 to 5.

[0246]

[0247] * d: day

[0248] * w: week

[0249]

[0250] FIG. 2 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of a 4-6 week sustained-release microparticle according to one embodiment of the present invention.

[0251] FIG. 3 is a graph showing the in vivo cumulative release rate of brexpiprazole over time of 8-10 week sustained-release microspheres according to one embodiment of the present invention.

[0252] FIG. 4 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of 12-16 week sustained-release microspheres according to one embodiment of the present invention.

[0253] FIG. 5 is a graph showing the cumulative release rate of brexpiprazole in vivo over time of 24-32 weeks of sustained-release microspheres according to one embodiment of the present invention.

[0254]

[0255] As shown in Table 9 and Figures 2 to 5, the microspheres according to one embodiment of the present invention were confirmed to stably release the drug over the target duration. Meanwhile, in the case of the 24-32 week sustained-release microspheres of Figure 5, a delayed drug release phase (lag phase) was observed until approximately day 28, indicating the need for improvement.

[0256]

[0257] As an example of a countermeasure to this, it is expected that the problem of the lag phase can be solved by using a microsphere blend that combines 24-32 week sustained release microspheres and 4-6 week sustained release microspheres, and a cumulative release rate simulation related to this was performed. For reference, in the field of sustained release microspheres, the cumulative release value can be predicted using the following mathematical equation 1 when blending microspheres based on the cumulative release value measured from each microsphere, and it is well known in the industry that such predicted values ​​are reliable because they are very similar to the actually measured values.

[0258] Specifically, the microsphere blends were prepared by mixing them in a weight ratio of 1 (32 weeks):5 (4-6 weeks) as in Examples 3-1 to 3-4. The cumulative release values ​​of blood brexpiprazole concentration measured from each microsphere used in Examples 3-1 to 3-4 were applied to the following mathematical formula 1 to derive the cumulative release rate of the microsphere blends according to Examples 3-1 to 3-4.

[0259] [Mathematical Formula 1]

[0260] {[(Total cumulative release value up to each time point of 4-6 weeks continuous microspheres*(5 / (1+5))) + (Total cumulative release value up to each time point of 32 weeks continuous microspheres*(1 / (1+5)))] / [(Total cumulative release value of 4-6 weeks continuous microspheres*(5 / (1+5))) + (Total cumulative release value of 32 weeks continuous microspheres*(1 / (1+5)))]} * 100

[0261]

[0262] The results of the cumulative release rate of brexpiprazole over time for the sustained-release microsphere blends according to Examples 3-1 to 3-4 are shown in Table 10 and Figure 6 below. Here, Example 1-36 is a sustained-release microsphere blend for 32 weeks.

[0263] FIG. 6 is a graph showing the cumulative release rate of brexpiprazole over time of a sustained-release microsphere blend comprising a combination of 32-week sustained-release microspheres and 4-6-week sustained-release microspheres in a weight ratio of 1:5 according to one embodiment of the present invention.

[0264]

[0265] * d: day

[0266] * w: week

[0267]

[0268] As shown in Table 10 and Fig. 6, Example 1-36, an example of a 32-week sustained-release microsphere, exhibits a drug release lag phase for the initial 4 weeks. Examples 3-1 to 3-4, sustained-release microsphere blends comprising Example 1-36 and Examples 1-11, 1-8, 1-12, or 1-37, an example of a 4-6 week sustained-release microsphere, exhibit stable drug release for 32 weeks without the occurrence of a drug release lag phase for the initial 4 weeks.

[0269]

[0270] The present invention has been described above, focusing on preferred embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. (i) sustained-release microspheres comprising brexpiprazole or a pharmaceutically acceptable salt thereof as a pharmaceutical substance, a biodegradable polymer, and a drug loading extender; or (ii) a long-acting injection composition comprising a sustained-release microsphere blend, which is a combination of 2-3 types of sustained-release microspheres of (i) having different compositions; Containing 5-70 wt% of the active substance based on the total weight of the sustained-release microspheres of the above (i) or the sustained-release microsphere blend of the above (ii), The above drug loading increasing agent is benzyl alcohol or acetic acid, The initial release amount of the active substance on the first day after in vivo administration of the above-mentioned western-release microspheres is 10% or less, A long-acting injection composition in which the active substance is released for 4-32 weeks after administration of the above-mentioned western-release microparticles in a living body.

2. In paragraph 1, A long-acting injection composition comprising 0.01 to 50000 ppm of a drug loading extender relative to the total weight of the sustained-release microspheres of the above (i) or the sustained-release microsphere blend of the above (ii).

3. In paragraph 1, The above biodegradable polymers include polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), polyhydroxybutyric acid (PLA), polyhydroxybutyric acid (PLGA ... A polymer selected from the group consisting of polyhydroxybutyrate-co-hydroxyvalerate (PHB), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide and poly(butylene succinate-co-lactic acid) (PBSLA); a simple mixture of two or three of the above-mentioned selected polymers; a copolymer of the above-mentioned selected polymer and polyethylenglycol (PEG);And a long-acting injection composition comprising at least one selected from the group consisting of a polymer-sugar complex in which the selected polymer or copolymer and sugar are combined.

4. In paragraph 3, A long-acting injection composition, wherein the intrinsic viscosity of the biodegradable polymer is 0.14-2.00 dL / g.

5. In paragraph 3, A long-acting injection composition, wherein the biodegradable polymer has a carboxylic acid or ester terminal group.

6. In paragraph 3, The above PLGA is a long-acting injection composition having a molar ratio of lactide:glycolide repeating units of 40:60 to 90:

10.

7. In paragraph 1, A long-acting injection composition, wherein the initial drug release amount on the first day after in vivo administration of the above-mentioned sustained-release microparticles is 7% or less.

8. In paragraph 1, A long-acting injection composition, wherein the above (i) western-release microparticles further comprise a steroidal anti-inflammatory agent.

9. In paragraph 1, A long-acting injection composition further comprising a steroidal anti-inflammatory agent in at least one of two or three sustained-release microspheres of the sustained-release microsphere blend of the above (ii).

10. In paragraph 1, A long-acting injection composition further comprising sustained-release microspheres containing a steroidal anti-inflammatory agent.

11. In paragraph 1, A long-acting injectable composition used for the prevention, improvement or treatment of one or more mental health disorders selected from the group consisting of schizophrenia, major depressive disorder, persistent depressive disorder and agitation associated with Alzheimer's dementia.

12. Western-release microspheres according to (i) of paragraph 1.

13. Blend of long-acting microspheres according to paragraph 1 (ii). 14.(a) A step of preparing an oil phase (O phase) in which brexpiprazole or a pharmaceutically acceptable salt thereof, a biodegradable polymer, and a drug loading extender are dissolved in an organic solvent as a pharmaceutical substance; (b) a step of preparing a water phase (W phase) in which a surfactant is dissolved in water as a continuous phase; (c) a step of forming an emulsion (O / W) solution by mixing the dispersed phase and the continuous phase; and (d) a step of extracting the dispersed organic solvent in the emulsion solution toward the continuous phase to generate microspheres; The above drug loading increasing agent is benzyl alcohol or acetic acid, A method for manufacturing a western-release microsphere according to Article 1.

15. In paragraph 14, A manufacturing method, wherein the above step (d) further includes a heating treatment for evaporating an organic solvent.

16. In paragraph 14, A manufacturing method, which further comprises, after the above step (d), a step (e) of discharging part or all of the continuous phase mixed with the organic solvent and replacing it with a fresh continuous phase.

17. In paragraph 14, A manufacturing method, wherein the organic solvent of the above step (a) is at least one selected from the group consisting of dichloromethane, dimethyl carbonate, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, n-methylpyrrolidone, methyl alcohol, ethyl alcohol, and propyl alcohol.

18. In paragraph 14, A manufacturing method, wherein the surfactant of the above step (b) is at least one selected from the group consisting of polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil.

19. In paragraph 14, A manufacturing method, wherein the continuous phase of the above step (b) further includes at least one selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.

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