Sustained-release microspheres containing donepezil and pamoic acid

Abstract

Provided are: a sustained-release microsphere comprising donepezil or a pharmaceutically acceptable salt thereof, pamoic acid, and a biocompatible polymer; a pharmaceutical composition for preventing, ameliorating, or treating Alzheimer's disease or cognitive impairment, comprising the sustained-release microsphere; and a method for producing the sustained-release microsphere.

Description

Technical Field

[0001] The present invention relates to a long-acting microsphere injection containing donepezil and pamoic acid and a preparation method thereof. Background Art

[0002] Acetylcholine is a neurotransmitter synthesized in cholinergic neurons from choline and acetyl-CoA. If the concentration of such acetylcholine decreases, it may cause impairment of cognitive and perceptual abilities, which is closely related to Alzheimer's disease.

[0003] Donepezil is widely used as a dementia therapeutic agent for suppressing the decrease in acetylcholine concentration. Donepezil, as a cholinesterase inhibitor, suppresses the decrease in acetylcholine that occurs in patients with dementia caused by Alzheimer's disease and increases the acetylcholine concentration to a normal range.

[0004] Currently, donepezil is mostly taken orally once a day in the form of tablets. However, it must be taken for more than one month to show clinical efficacy, and Alzheimer's disease is a disease that mainly occurs in the elderly, so there are limitations to taking it as an oral preparation. Therefore, the demand for sustained-release preparations of anti-dementia drugs is increasing.

[0005] In the past, in order to develop sustained-release preparations, microsphere preparations using biocompatible polymers have become an active research hotspot and clinical application field. However, in order to produce such microsphere preparations for long-term continuous administration, the content of the drug to be contained in the microspheres must be quite high in consideration of the administration time and dosage. For example, in the case of Aricept, an oral preparation of donepezil, For tablets, the daily dosage is 5mg, 10mg, and 23mg respectively. If it is used as a sustained-release therapeutic agent for 1 month, a single drug dosage of 140mg to 280mg or more may be required. On the other hand, if it is developed into a sustained-release microsphere injection, the human dosage of microspheres containing drugs and polymers is difficult to be administered in a single dose when it is more than 1g. Therefore, it is easy to administer microspheres when administered in an amount of less than 1g. In order to reduce the amount of microspheres administered, it is preferred to increase the content of the drug in the microspheres. In this way, when the drug is contained in a high content in the microspheres, even if a biocompatible polymer with a sufficiently long decomposition rate is applied, the release period will not be long enough due to the high content of the drug, so that the desired administration time cannot be met, or the problem of "initial burst" of excessively fast drug release in the early stage may be caused. In this case, serious side effects may also occur due to the rapid increase in the blood concentration of the drug. On the other hand, if the drug content in the microspheres is reduced to solve this problem, the drug content for treatment is insufficient, resulting in a relatively excessive increase in the amount of microspheres for a single dose, which reduces the patient's medication compliance and causes discomfort.

[0006] Therefore, it is necessary to develop a donepezil sustained-release microsphere injection encapsulating a high content of donepezil and having a long-term stable drug release characteristic. Summary of the invention

[0007] Technical issues

[0008] The present invention has been made to solve the above-mentioned conventional problems, and an object of the present invention is to provide a donepezil sustained-release microsphere preparation having a long-term stable drug release property despite a high content of donepezil encapsulated in the microspheres, and a method for producing the same.

[0009] Solution to the problem

[0010] One aspect of the present invention provides a sustained-release microsphere, characterized in that it is manufactured using donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid and a biocompatible polymer.

[0011] Based on the free base form of donepezil, the molar ratio of the above active ingredient: pamoic acid is greater than 1:0.05 and less than 1:0.25, and the 7-day cumulative release of the above microspheres is less than 30% based on the free base of donepezil.

[0012] One aspect of the present invention provides a sustained-release microsphere, characterized in that it contains donepezil or a pharmaceutically acceptable salt thereof, pamoic acid and a biocompatible polymer as an active ingredient,

[0013] Based on the free base form of donepezil, the molar ratio of the active ingredient to pamoic acid is greater than 1:0.05 and less than 1:0.25,

[0014] The 7-day cumulative release of donepezil from the microspheres was less than 30%.

[0015] According to one aspect of the present invention, the donepezil and the pamoate salt may be in an amorphous state.

[0016] According to one aspect of the present invention, based on the above-mentioned free base form, the content of donepezil in the microspheres may be 75% by weight or less relative to the total weight of the microspheres.

[0017] According to one aspect of the present invention, the content of the biocompatible polymer can be 20 to 50% by weight relative to the total weight of the microspheres.

[0018] According to one aspect of the present invention, the content of the pamoic acid may be 2.5 to 20% by weight relative to the total weight of the microspheres.

[0019] According to one aspect of the present invention, the one-day release amount of the above-mentioned active ingredient may be less than 10%.

[0020] According to one aspect of the present invention, the AUC of the microspheres when released in vivo for 1 day may be less than 4%.

[0021] According to one aspect of the present invention, the drug in the sustained-release microspheres can be released for 1 month to 6 months.

[0022] According to one aspect of the present invention, the average particle size (Dv50) of the sustained-release microspheres may be greater than 10 μm.

[0023] According to one aspect of the present invention, the above-mentioned microspheres can be used for injection.

[0024] According to one aspect of the present invention, a pharmaceutical composition for preventing, improving or treating Alzheimer's disease or cognitive dysfunction comprising sustained-release microspheres is provided.

[0025] According to one aspect of the present invention, a method for preparing the sustained-release microspheres is provided.

[0026] According to one aspect of the present invention, there are provided sustained-release microspheres containing donepezil at a molar ratio of pamoic acid to donepezil of 0.05 to 0.25 and a content of 75 wt % or less, an injection containing the microspheres, and a method for producing the same.

[0027] In addition, an injection containing sustained-release microspheres capable of sustained release for 1 to 6 months and a method for producing the same are provided, wherein the initial release of the microspheres in one day is less than 10% and the initial release in seven days is less than 30%.

[0028] Effects of the Invention

[0029] The donepezil sustained-release microsphere preparation of the present invention can maintain the concentration of the drug in the therapeutic range for a long time without excessive initial release of the drug, thereby improving the drug administration compliance of Alzheimer's patients and maximizing the therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a graph showing the 7-day cumulative release rate according to the amount of pamoic acid added to donepezil sustained-release microspheres.

[0031] Figure 2 is an X-ray diffraction pattern of microspheres containing donepezil and pamoic acid.

[0032] Figure 3 This is a graph confirming the blood drug concentration of the drug up to 91 days after the sustained-release donepezil microspheres of Comparative Example 3, Example 9 (intramuscular), Example 10 (intramuscular) and Example 10 (subcutaneous) were intramuscularly or subcutaneously administered to animals. DETAILED DESCRIPTION

[0033] Hereinafter, the present invention will be described in more detail.

[0034] In one embodiment, the present invention relates to a sustained-release microsphere, characterized in that it is produced using donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid, and a biocompatible polymer.

[0035] Based on the free base form of donepezil, the molar ratio of the active ingredient to pamoic acid is greater than 1:0.05 and less than 1:0.25,

[0036] The 7-day cumulative release of donepezil from the microspheres was less than 30%.

[0037] In another embodiment, the present invention relates to a sustained-release microsphere, characterized in that it contains donepezil or a pharmaceutically acceptable salt thereof, pamoic acid and a biocompatible polymer as an active ingredient.

[0038] Based on the free base form of donepezil, the molar ratio of donepezil to pamoic acid is greater than 1:0.05 and less than 1:0.25,

[0039] The 7-day cumulative release of donepezil from the microspheres was less than 30%.

[0040] In the past, in order to develop sustained-release preparations, microsphere preparations using biocompatible polymers have become an active research hotspot and clinical application field. However, in order to manufacture such microsphere preparations for long-term continuous administration, the content of the drug to be contained in the microspheres must be quite high, considering the administration time and dosage. In this way, when the drug is contained in the microspheres at a high content, even if a biocompatible polymer with a sufficiently long decomposition rate is used, the release period is not long enough due to the high content of the drug, so that the desired administration time cannot be met, or the problem of "initial burst release" of drug release that occurs too quickly at the initial stage of release may be caused. In this case, various side effects may occur due to the rapid increase in the blood concentration of the drug, especially for drugs with low therapeutic index. Serious problems may also occur. On the other hand, if the content of the drug contained in the microspheres is reduced in order to solve this problem, there is a problem that the content of the drug used for treatment is insufficient, resulting in a relatively excessive increase in the amount of microspheres for a single administration, thereby reducing the patient's compliance and causing discomfort.

[0041] Therefore, the present inventors have confirmed that if pamoic acid is added together with the drug when manufacturing microspheres, the problem of initial violent release and insufficient drug release time can be solved even if a large amount of drug is contained. However, when pamoic acid is used to manufacture microspheres, it is unexpectedly confirmed that if pamoic acid is used together with donepezil at the above content ratio, the problem of initial violent release and insufficient drug release time can be solved even if a large amount of drug is contained.

[0042] Specifically, in the present invention, based on the free base form of donepezil, the molar ratio of donepezil as an active ingredient: pamoic acid (i.e., the molar ratio of donepezil free base: pamoic acid) can be greater than 1:0.05 and less than 1:0.25, preferably greater than 1:0.05 and less than 1:0.2, greater than 1:0.05 and less than 1:0.19, 1:0.07 to 1:0.22, 1:0.08 to 1:0.20, 1:0.09 to 1:0.19, 1:0.1 to 1:0.25, 1:0.125 to 1:0.25.

[0043] In another embodiment, the content of pamoic acid in the sustained-release microspheres of the present invention may be 2.5 to 20 wt %, 2.5 to 17 wt %, 2.5 to 15 wt % or 2.5 to 13 wt % relative to the weight of the entire microspheres, but is not limited thereto.

[0044] The content of the biocompatible polymer can be 20 to 50 wt % or 24 to 50 wt % relative to the weight of the entire microsphere, but is not limited thereto.

[0045] The above-mentioned biocompatible polymer can be at least one selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide) glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and a copolymer of polyglycolide and polylactide, but is not limited thereto.

[0046] As the above-mentioned biocompatible polymer, polylactide can be preferably used. In addition, two or more polymers can be blended and used. As an example, polylactide and poly (lactide-co-glycolide) can be blended to produce. In this case, the content of polylactide is preferably 50% by weight or more relative to the overall polymer weight.

[0047] In a preferred embodiment, in the case of a copolymer of polyglycolide and polylactide, the molar ratio of lactide to glycolide in the copolymer may be 40:60 to 90:10, 45:55 to 85:15 or 50:50 to 75:25, for example, 45:55, 50:50, 75:25 or 85:15.

[0048] Such a biocompatible polymer may have a weight average molecular weight of 4,000 to 240,000. For example, the weight average molecular weight of the above biocompatible polymer includes all lower numerical ranges within the above ranges such as a weight average molecular weight of 4,000 to 100,000, a weight average molecular weight of 7,000 to 50,000, a weight average molecular weight of 5,000 to 20,000, a weight average molecular weight of 10,000 to 18,000, and a weight average molecular weight of 18,000 to 28,000.

[0049] When two or more of the above-mentioned biocompatible polymers are included, the polymers may be a combination or blend of polymers of different types as exemplified above, but may also be a combination of polymers of the same polymer type but having different intrinsic viscosities and / or monomer ratios (for example, a combination or blend of two or more poly(lactide-co-glycolide)s having different intrinsic viscosities), or may be polymers of the same type having different end groups (for example, an ester end group or an acid end group). Examples of commercially available biocompatible polymers that can be used in the present invention include RG 502H, RG 503H, RG 504H, RG 502, RG 503, RG504, RG 653H, RG 752H, RG 753H, RG 752S, RG 755S, RG 756S, RG 858S, R202H, R 203H, R205H, R 202S, R 203S, and R 205S from Evonik Rohm GmbH; and PDL 02, PDL 04, PDL 05, PDL 06, PDLG7502A, PDLG 7502, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG One of PD5004, PDLG5010, PL 10, PL 18, PL 24, PL 32, PL 38, PDL 20, PDL 45, PC 02, PC 04, PC 12, PC 17, PC24, or a combination or blend thereof, but not limited thereto.

[0050] As the above-mentioned biocompatible polymer, polylactide can be preferably used. Preferably, the intrinsic viscosity of the above-mentioned polylactide can be 0.25dL / g to 2.0dL / g, 0.25dL / g to 1.7dL / g or 0.25dL / g to 1.5dL / g. When the intrinsic viscosity of the polylactide is less than 0.25dL / g and the viscosity is low, there is a problem that the active ingredient cannot be well encapsulated in the microspheres, and when the viscosity is greater than 1.5dL / g, there is a problem that the manufacturing yield of the microspheres becomes low and the economic efficiency is reduced.

[0051] The intrinsic viscosity of the polylactide used in the present invention refers to the viscosity measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer.

[0052] Furthermore, two or more polymers may be blended and used. For example, polylactide and poly(lactide-co-glycolide) may be blended and produced. In this case, the content of polylactide is preferably 50% or more.

[0053] The sustained-release microspheres may further contain donepezil pamoate.

[0054] In one embodiment, donepezil and the pamoate form of donepezil and / or pamoic acid may coexist in the sustained-release microspheres of the present invention.

[0055] In one embodiment, the donepezil pamoate may be amorphous.

[0056] In one embodiment, the above-mentioned donepezil can be donepezil free base.

[0057] In one embodiment, based on the above-mentioned free base form, the content of donepezil can be less than 75% by weight, 40 to 75% by weight, 40 to 70% by weight, 40 to 65% by weight, 45 to 75% by weight, 45 to 70% by weight, 45 to 65% by weight, 45 to 60% by weight, 50 to 75% by weight, 50 to 70% by weight, 50 to 65% by weight or 50 to 60% by weight relative to the total weight of the microspheres, but is not limited thereto.

[0058] When the above range is met, there is an advantage that an appropriate release rate can be maintained during the release period without causing a sharp or excessive delay in drug release.

[0059] The microspheres of the present invention preferably have a uniform particle distribution. Microspheres having a uniform particle distribution can be administered with less deviation and more accurate amount during injection compared to non-uniform microspheres.

[0060] The span value of the microspheres of the present invention is preferably 1.2 or less.

[0061] The term "span value" used in the present invention is an index representing the uniformity of the particle size of microspheres, and the span value refers to a value obtained by the following mathematical formula 1.

[0062] [Mathematical formula 1]

[0063] Span Value = (Dv0.9-Dv0.1) / Dv0.5

[0064] Among them, Dv0.1 refers to the particle size corresponding to 10% of the volume % in the particle size distribution curve of the microspheres, Dv0.5 refers to the particle size corresponding to 50% of the volume % in the particle size distribution curve of the microspheres, and Dv0.9 refers to the particle size corresponding to 90% of the volume % in the particle size distribution curve of the microspheres.

[0065] In a specific embodiment, the average particle size (Dv50) of the microspheres of the present invention can be greater than 10um, preferably greater than 15um, greater than 20um, greater than 30um, less than 150um, less than 120um, less than 100um, less than 90um, less than 80um, less than 70um, 10 to 150um, 10 to 120um, 10 to 100um, 10 to 90um, 15 to 90um, 15 to 80um, 20 to 90um, 20 to 80um, 30 to 80um or 30 to 70um.

[0066] According to the present invention, the one-day initial release rate of the drug in the microspheres may be less than 10%. Preferably, the initial release rate may be less than 9%, less than 8% or less than 7%, but not limited thereto.

[0067] According to the present invention, the AUC of the microspheres released in vivo for 1 day can be less than 4% of the overall AUC. Preferably, the AUC of the microspheres released for 1 day can be less than 4% or less than 3%, and can be more than 0.01%, more than 0.3% or more than 0.5%, but is not limited thereto.

[0068] In a specific embodiment, donepezil or a pharmaceutically acceptable salt thereof in the sustained-release microspheres of the present invention can be released for 1 month to 6 months.

[0069] In a specific embodiment, the sustained-release microspheres of the present invention can be used for injection.

[0070] In another embodiment, the present invention relates to a pharmaceutical composition for preventing, improving or treating Alzheimer's disease or cognitive dysfunction comprising the sustained-release microspheres. More specifically, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition may be an injectable preparation.

[0071] Hereinafter, the method for producing the sustained-release microspheres of the present invention will be described in detail.

[0072] The sustained-release microspheres of the present invention can be produced, for example, by using a "solvent extraction and evaporation method", but the production method is not limited thereto.

[0073] As a specific example of the method for producing sustained-release microspheres of the present invention, a method for producing sustained-release microspheres comprising the following steps is provided:

[0074] (a) a step of dissolving donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid and a biocompatible polymer in a dispersed phase solvent to prepare a dispersed phase;

[0075] (b) a step of adding the dispersed phase produced in the above step (a) to an aqueous solution containing a surfactant as a continuous phase to produce an emulsion;

[0076] (c) extracting the dispersed phase in the dispersed phase of the emulsion produced in the above step (b) with a solvent to a continuous phase, and evaporating the above extracted solvent to form microspheres to produce a suspension containing microspheres; and

[0077] (d) a step of recovering microspheres from the suspension of step (c) to produce microspheres,

[0078] Furthermore, it is characterized in that, based on the free base form of donepezil, the molar ratio of the above-mentioned active ingredient: pamoic acid is greater than 1:0.05 and is less than 1:0.25.

[0079] In the above production method, unless otherwise mentioned, matters concerning donepezil or a pharmaceutically acceptable salt thereof, pamoic acid, and a biocompatible polymer can be directly applied to matters described in the above microspheres.

[0080] In a specific embodiment, the content of the above-mentioned active ingredient can be less than 75% by weight relative to the total weight of the microspheres.

[0081] In a specific embodiment, the content of the biocompatible polymer can be 20 to 50% by weight relative to the total weight of the microspheres.

[0082] In a specific embodiment, the content of the pamoic acid can be 2.5 to 20 weight % relative to the total weight of the microspheres.

[0083] In a specific embodiment, in step (a), the active ingredient may be in the form of a free base, and pamoic acid may be contained in the form of a powder or a solution.

[0084] In a specific embodiment, in step (a), pamoic acid may be added to a solution of the active ingredient dissolved in a dispersed phase solvent.

[0085] The dispersed phase solvent is preferably a solvent that is immiscible with water and accounts for at least 50% (w / w) of the entire mixed solvent, but is not limited thereto.

[0086] Such a dispersed phase solvent is not limited and may include dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, tetraethylene glycol, methyl isopropyl ketone, dimethyl carbonate or a mixed solvent thereof.

[0087] The dispersed phase solvent may further contain one or more selected from the group consisting of chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methanol, ethanol, propanol, benzyl alcohol, and mixed solvents thereof.

[0088] The method for homogeneously mixing the dispersed phase and the continuous phase containing the surfactant in the above step (b) is not particularly limited, and can be implemented using a high-speed stirrer, a liquid continuous mixer, a membrane emulsion method, a microfluidic emulsion method, etc. When a high-speed stirrer or a liquid continuous mixer is used to form an emulsion, it is difficult to obtain a uniform emulsion, so it is preferred to add a screening process between the steps (c) and (d) described later. When a membrane emulsion method and a microfluidic emulsion method are used, an emulsion of uniform size can be obtained without adding a screening process between the steps (c) and (d) described later, so it is more preferred.

[0089] The type of surfactant used in the above step (b) is not particularly limited, and any surfactant can be used as long as it can help the dispersed phase to form a stable droplet dispersed phase in the continuous phase. The above surfactant can preferably be selected from the group consisting of methylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives and mixtures thereof, and most preferably polyvinyl alcohol can be used.

[0090] In the above step (b), the content of the surfactant in the continuous phase containing the surfactant may be 0.01 w / v% to 20 w / v%, preferably 0.1 w / v% to 5 w / v%, based on the total volume of the continuous phase containing the surfactant. If the content of the surfactant is less than 0.01 w / v%, a dispersed phase or emulsion in the form of droplets may not be formed in the continuous phase, and if the content of the surfactant is greater than 20 w / v%, it may be difficult to remove the surfactant after forming microparticles in the continuous phase due to excessive surfactant.

[0091] The continuous phase used in the above step (b) can be water. In order to adjust the rate of extracting the organic solvent from the dispersed phase in the emulsion state, water containing one or more selected from the group consisting of methanol, ethanol, propanol, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, tetraethylene glycol, methyl isopropyl ketone, dimethyl carbonate and ethyl acetate can be used.

[0092] The continuous phase may be used in an amount of 5,000 (v / w) % to 100,000 (v / v) % relative to the dispersed phase solvent, but is not limited thereto.

[0093] In the above step (c), if the emulsion containing the dispersed phase in the form of droplets and the continuous phase containing the surfactant is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain period of time, for example, 2 hours to 48 hours, the organic solvent can be extracted from the dispersed phase in the form of droplets to the continuous phase. A portion of the organic solvent extracted to the continuous phase may evaporate from the surface. While the organic solvent is extracted from the dispersed phase in the form of droplets, the dispersed phase in the form of droplets can be solidified to form microspheres.

[0094] In order to further effectively remove the organic solvent in the above step (c), heat may be applied to the temperature of the continuous phase for a certain period of time.

[0095] In the above step (d), the method for recovering the microspheres of the present invention can be implemented using various known techniques, for example, by filtration or centrifugal separation.

[0096] Between the above steps (c) and (d), the residual surfactant can be removed by filtering and washing, and then filtered again to recover the microspheres.

[0097] The washing step for removing the residual surfactant can usually be performed using water, and the above washing step can be repeated multiple times.

[0098] In addition, as described above, in the case where a high-speed stirrer or a liquid continuous mixer is used to form an emulsion in the above step (b), a screening process can be further used between the above steps (c) and (d) to obtain uniform microspheres. The screening process can be performed using known techniques, and microspheres of uniform size can be obtained by filtering out microspheres of small particles and large particles using sieve membranes of different sizes.

[0099] In the production method of the present invention, after the above step (d) or after the above filtering and washing steps, the obtained microspheres can be dried by a common drying method to finally obtain dried microspheres.

[0100] Below, preferred embodiments are provided to help understand the present invention, but it is obvious to those skilled in the art that the following embodiments are merely illustrative of the present invention, and various changes and modifications can be made within the scope of the scope and technical idea of ​​the present invention. Of course, such changes and modifications also fall within the scope of the appended claims.

[0101] Implementation

[0102] [Example]

[0103] The present invention will be described in further detail below by way of examples. These examples are only used to illustrate the present invention, and therefore the scope of the present invention should not be construed as being limited by these examples.

[0104] Comparative Example 1. Preparation of Donepezil Microspheres without Addition of Pamoic Acid

[0105] The dispersed phase was prepared by mixing 3.0 g of the biocompatible polymer Purasorb PDL02A (manufacturer: Corbion, the Netherlands) and 2.0 g of donepezil base (manufacturer: Neuland Laboratories, India) with 9.0 g of dichloromethane (manufacturer: JT Baker, the United States) and dissolving them fully until they became transparent to the naked eye. The continuous phase was a 0.1% polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution, and the prepared dispersed phase was injected while connecting 3,000 mL of the continuous phase to an emulsifier equipped with a porous membrane with a diameter of 40 μm to produce microspheres. The microsphere suspension was placed in a mixing container and stirred at a speed of 200 rpm.

[0106] The temperature of the membrane emulsification device and the preparation container is maintained at 25°C. If the injection of the dispersed phase is completed, the suspension in the preparation container is stirred at a speed of 200 rpm and maintained at a temperature of 25°C for 60 minutes. Then, the temperature is maintained at 45°C for 3 hours to remove the organic solvent. If the removal of the organic solvent is completed, the temperature of the microsphere suspension is reduced to 25°C. The microsphere suspension is repeatedly washed several times with ultrapure water to remove the residual polyvinyl alcohol, and then the microspheres are freeze-dried.

[0107] Comparative Example 2-6. Preparation of Donepezil Microspheres with Different Pamoic Acid Ratios

[0108] The dispersed phase was prepared by mixing a biocompatible polymer and donepezil base (manufacturer: Neuland Laboratories, India) with dichloromethane (manufacturer: JT Baker, USA) and dissolving them sufficiently until they became transparent to the naked eye. The continuous phase was a 0.1% polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution, and the prepared dispersed phase was injected while the continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm to produce microspheres. The microsphere suspension was placed in a mixing container and stirred at a speed of 200 rpm.

[0109] The temperature of the membrane emulsification device and the preparation container is maintained at 25°C. If the injection of the dispersed phase is completed, the suspension in the preparation container is stirred at a speed of 200 rpm and maintained at a temperature of 25°C for 60 minutes. Then, the temperature is maintained at 45°C for 3 hours to remove the organic solvent. If the removal of the organic solvent is completed, the temperature of the microsphere suspension is reduced to 25°C. The microsphere suspension is repeatedly washed several times with ultrapure water to remove the residual polyvinyl alcohol, and then the microspheres are freeze-dried.

[0110] The types and amounts of polymers used in this comparative example, the amounts of drugs, the amounts of pamoic acid, the solvents used, the amounts of dispersed phase solvents used, and the amounts of continuous phase used are shown in the following Table 1. In the following Table 1, the molar ratio of drug: pamoic acid is expressed based on the free base form of the drug.

[0111] Example 1-10. Preparation of Donepezil Microspheres Added with Pamoic Acid

[0112] The dispersed phase was prepared by mixing a biocompatible polymer and donepezil base (manufacturer: Neuland Laboratories, India), pamoic acid and dichloromethane (manufacturer: JT Baker, USA) and dissolving them fully until they became transparent to the naked eye. The continuous phase was a 0.1% polyvinyl alcohol aqueous solution (viscosity: 4.8-5.8 mPa·s) aqueous solution, and the prepared dispersed phase was injected while the continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm to produce microspheres. The microsphere suspension was placed in a mixing container and stirred at a speed of 200 rpm.

[0113] The temperature of the membrane emulsification device and the preparation container is maintained at 25°C. If the injection of the dispersed phase is completed, the suspension in the preparation container is stirred at a speed of 200 rpm and maintained at a temperature of 25°C for 60 minutes. Then, the temperature is maintained at 45°C for 3 hours to remove the organic solvent. If the removal of the organic solvent is completed, the temperature of the microsphere suspension is reduced to 25°C. The microsphere suspension is repeatedly washed several times with ultrapure water to remove the residual polyvinyl alcohol, and then the microspheres are freeze-dried.

[0114] The types and amounts of polymers used in this example, the amount of drugs used, the amount of pamoic acid used, the amount of solvents used, the amount of dispersed phase solvents used, and the amount of continuous phase used are shown in the following Table 1. In the following Table 1, the molar ratio of drug: pamoic acid is expressed based on the free base form of the drug.

[0115] [Table 1]

[0116]

[0117]

[0118] (Viscosities of the polymers used: PDL04A (0.35-0.45 dL / g), PDL06 (0.54-0.66 dL / g), R205S (0.55-0.75 dL / g), PDL02A (0.16-0.24 dL / g), PDL45 (3.5-5.5 dL / g))

[0119] Experimental Example 1. Determination of drug content in sustained-release microspheres

[0120] In order to determine the drug content of the microspheres manufactured in the above embodiment, 10 mg of microspheres were completely dissolved in dimethyl sulfoxide and then diluted with mobile phase. 20 uL of the diluted solution was injected into HPLC and measured at a detection wavelength of 271 nm. The chromatographic column used in this determination was Inertsil ODS-3, 5um, 4.6x150mm, and the mobile phase was phosphate buffer (pH 5.0) and acetonitrile mixed in a ratio of 60:40 (v / v). The encapsulation amount measured is shown in Table 2.

[0121] Experimental Example 2. Particle size analysis of sustained-release microspheres

[0122] In order to quantitatively measure the average particle size, distribution and uniformity of microspheres, laser diffraction was used to test. The microspheres manufactured in the embodiment were mixed with ultrapure water containing a surfactant, mixed for 20 seconds using a vortex mixer, and then placed in an ultrasonic generator for dispersion. The solution was placed in a particle size analyzer (Paar, PSA 900L, Austria) and the particle size was measured.

[0123] The particle size measurement results of the sustained-release microspheres containing donepezil produced in the above comparative example are shown in Table 2 below.

[0124] [Table 2]

[0125]

[0126]

[0127] Experimental Example 3: Crystallization of donepezil, pamoic acid and mixtures thereof by X-ray diffraction analysis analyze

[0128] In order to confirm whether the crystalline forms of donepezil and pamoic acid substances themselves and the crystalline forms of the mixture of donepezil and pamoic acid contained in the microspheres are the same, the crystalline forms of the mixture of donepezil and pamoic acid in the microspheres prepared in the above examples and the crystalline forms of donepezil and pamoic acid substances themselves were confirmed using an X-ray diffraction analyzer. The results are shown in Tables 3 and 4, respectively. Figure 2 shown.

[0129] Table 3 shows the 2θ (±0.2) values ​​of the peaks shown by the X-ray diffraction analysis results of donepezil and pamoic acid substances themselves.

[0130] [Table 3]

[0131]

[0132] From Table 3 and Figure 2It was confirmed that donepezil, pamoic acid, and a mixture of donepezil and pamoic acid showed a specific 2θ (2-Theta) peak in XRD as shown in Table 3. Figure 2 It was confirmed that these peaks did not appear in the microspheres containing donepezil and pamoic acid.

[0133] According to this result, donepezil and pamoic acid in the microspheres of the present invention are present in an amorphous state.

[0134] Experimental Example 4: In vitro (in vitro) testing of microspheres based on the content ratio of donepezil to pamoic acid In vitro initial drug release assay

[0135] In order to confirm the drug release of the microspheres based on the content ratio of donepezil or a pharmaceutically acceptable salt thereof to pamoic acid used in the microspheres produced in the above Examples, the following experiment was performed.

[0136] 10 mg of microspheres were placed in a HDPE wide-mouth bottle, and 50 mL of release test solution (pH 7.4 aqueous solution containing phosphate and sodium azide) was added, and then stored in an incubator at 37° C. 1 mL of this solution was taken as the test solution, and 1 mL of new release test solution was added to the wide-mouth bottle.

[0137] The sample was collected at a specified time, and the content and release rate were analyzed by HPLC under the same analysis conditions as in Experimental Example 1. The results are shown in Table 4.

[0138] [Table 4]

[0139] distinguish Drug release on the first day (%) Cumulative release of drug on the 7th day (%) Example 2 0.6 21.2 Example 3 1.2 22.1 Example 4 2.04 24.8 Example 5 0.38 3.57 Example 6 5.09 29.9 Example 7 0.3 2.3 Example 8 0.3 2.1 Example 9 1.1 11.7 Example 10 1.5 26.6 Comparative Example 1 5.2 55.2 Comparative Example 2 5.0 51.5 Comparative Example 3 4.5 - Comparative Example 4 90.1 - Comparative Example 5 80.7 -

[0140] It can be confirmed from the above Table 4 that, in the case of the microspheres of the present invention, the microspheres having a molar ratio of donepezil to pamoic acid greater than 1:0.05 and less than 1:0.25 will slowly release the drug for a long time when the microspheres are administered without the problem of excessive initial release of the drug, and thus are preferred in terms of drug release. In addition, in the case of the microspheres of the present invention, the cumulative release of the drug of the microspheres having a molar ratio of donepezil to pamoic acid greater than 1:0.05 and less than 1:0.25 will decrease as the ratio of pamoic acid increases, so even if the drug content in the microspheres is increased, excessive initial release of the drug can be prevented.

[0141] In addition, in the case of the microspheres of Examples 2, 4 and 5 in which the encapsulation rate of donepezil in the microspheres of the present invention was 89% or more and the molar ratio of donepezil to pamoic acid used was 1:0.05 or less, it was confirmed that the cumulative release amount on the 7th day was 50% or more, indicating excessive release.

[0142] Furthermore, when the content of donepezil used in the microspheres of the present invention was 80% by weight, it was found that a high release rate of 80% or more was exhibited from the first day of release, indicating a strong initial release.

[0143] Experimental Example 5: Confirmation of the pharmacokinetics of a single subcutaneous administration of the microspheres of the present invention using animals

[0144] In order to confirm the pharmacokinetics of donepezil after a single administration to animals and to confirm the drug release of the microspheres based on the content ratio of donepezil or a pharmaceutically acceptable salt thereof to pamoic acid used in the microspheres prepared in the above Examples, the donepezil concentration in blood was measured.

[0145] The donepezil dosage was 26.04 mg / head, and the microspheres were dispersed in 0.3 mL of suspension and injected intramuscularly or subcutaneously into SD rats. 0.25-0.5 mL of blood was collected at a pre-planned time, and the donepezil concentration in the blood was measured by HPLC. The AUC (%) on the first day is shown in Table 5.

[0146] [Table 5]

[0147]

[0148]

Claims

1. A sustained-release microsphere, characterized in that: The invention is produced by using donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid and a biocompatible polymer. Based on the free base form of donepezil, the molar ratio of the active ingredient to pamoic acid is greater than 1:0.05 and less than 1:0.25, The 7-day cumulative release of donepezil from the microspheres was less than 30%.

2. A sustained-release microsphere, characterized in that: Containing donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid and a biocompatible polymer, Based on the free base form of donepezil, the molar ratio of the active ingredient to pamoic acid is greater than 1:0.05 and less than 1:0.25, The 7-day cumulative release of donepezil from the microspheres was less than 30%. 3 . The sustained-release microspheres according to claim 1 , wherein the donepezil or a pharmaceutically acceptable salt thereof and the pamoate are amorphous.

4. The sustained-release microspheres according to claim 1 or 2, wherein the content of donepezil is less than 75% by weight relative to the total weight of the microspheres, based on the free base form. The sustained-release microspheres according to claim 1 or 2, wherein the donepezil is donepezil free base. The sustained-release microspheres according to claim 1 or 2, wherein the daily release amount of the active ingredient is less than 10%.

7. The sustained-release microspheres according to claim 1 or 2, wherein the AUC of the microspheres when released in vivo for 1 day is less than 4%. The sustained-release microspheres according to claim 1 or 2, wherein the drug in the sustained-release microspheres is released for 1 month to 6 months.

9. The sustained-release microspheres according to claim 1 or 2, wherein the average particle size Dv50 is greater than 10 μm.

10. The sustained-release microspheres according to claim 1 or 2, wherein the biocompatible polymer is at least one selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide) glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and a copolymer of polyglycolide and polylactide. The sustained-release microspheres according to claim 1 or 2, which are used in injection preparations.

12. A pharmaceutical composition for preventing, improving or treating Alzheimer's disease or cognitive dysfunction, comprising the sustained-release microspheres according to claim 1 or 2.

13. The pharmaceutical composition according to claim 12, further comprising a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 12 , which is an injection preparation.

15. The method for producing sustained-release microspheres according to claim 1 or 2, characterized in that: include: (a) a step of dissolving donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pamoic acid and a biocompatible polymer in a dispersed phase solvent to prepare a dispersed phase; (b) a step of adding the dispersed phase produced in step (a) to an aqueous solution containing a surfactant as a continuous phase to produce an emulsion; (c) extracting the dispersed phase in the dispersed phase of the emulsion produced in step (b) with a solvent to obtain a continuous phase, and evaporating the extracted solvent to form microspheres to produce a suspension containing microspheres; and (d) a step of recovering microspheres from the suspension of step (c) to produce microspheres, The molar ratio of the active ingredient to pamoic acid is greater than 1:0.05 and less than 1:0.25 based on the free base form of the active ingredient. 16 . The production method according to claim 15 , wherein the content of the active ingredient is 40 to 70% by weight relative to the total weight of the microspheres.

17. The production method according to claim 15, wherein in step (a), the donepezil is in the form of a free base.

18. The production method according to claim 15, wherein in step (a), pamoic acid is added to a solution of the drug dissolved in a dispersed phase solvent.

19. The production method according to claim 15, wherein the dispersed phase solvent comprises dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, tetraethylene glycol, methyl isopropyl ketone, dimethyl carbonate or a mixed solvent thereof.

20. The production method according to claim 15, wherein the dispersed phase solvent further comprises one or more selected from the group consisting of chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methanol, ethanol, propanol, benzyl alcohol, and mixed solvents thereof.

21. The manufacturing method according to claim 15, wherein the biocompatible polymer is at least one selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide) glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and a copolymer of polyglycolide and polylactide.

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