Sustained release microsphere containing medicine and pamoic acid

Abstract

Provided are: a sustained release microsphere containing a drug, pamoic acid, and a biocompatible polymer; the pharmaceutical composition containing the sustained release microsphere is used for preventing, improving or treating hepatitis B, prostate cancer, breast cancer, endometriosis, hysteromyoma, precocious puberty, acra hypertrophy, gastrointestinal pancreatic endocrine tumor, Alzheimer's disease or cognitive impairment; and a method for preparing the sustained release microspheres.

Description

Technical Field

[0001] The present invention relates to a sustained-release microsphere containing a drug and pamoic acid, and more specifically, to a sustained-release microsphere preparation containing a drug and pamoic acid, which encapsulates a high content of the drug and exhibits long-term stable drug release characteristics; and a preparation method thereof. Background Art

[0002] The development of sustained-release formulations using microsphere formulations of biocompatible polymers has developed into an active field of research interest and clinical application. However, even if microspheres using only biocompatible polymers are not nanoparticles, microspheres exhibit an "initial burst" phenomenon in which rapid drug release occurs at the beginning of release. This "initial burst" phenomenon may cause side effects due to the rapid increase in drug concentration, and there is a problem that the drug released rapidly in the initial stage is metabolized and does not show a medical effect.

[0003] As a result of extensive research to solve the problem of rapid initial release of the drug in such microspheres, the inventors of the present disclosure have confirmed that pamoic acid can be used as a pharmaceutically acceptable salt or additive that can serve as a release control agent for the drug in the microspheres. In addition, through repeated research, the inventors of the present disclosure have confirmed an unexpected problem in which the extent of release depends on the amount of sodium contained in the pamoic acid.

[0004] Therefore, the inventors of the present disclosure have completed the development of a sustained-release microsphere injectable solution that has the characteristics of encapsulating a high content of drug and stably releasing the drug over a long period of time, while solving the problems of the related art. Summary of the invention

[0005] Technical issues

[0006] The present disclosure is designed to solve the problems of the related art as described above, and provides a sustained-release microsphere preparation and a preparation method thereof, which encapsulates a high content of drug and exhibits long-term stable drug release characteristics.

[0007] In addition, the present invention uses pamoic acid as a pharmaceutically acceptable salt or additive to solve the problem of excessive initial release of high-content drugs, and specifically provides a method for preparing a sustained-release injection with long-term therapeutic effect by quantitatively controlling the sodium or potassium contained in pamoic acid.

[0008] Technical Solution

[0009] In one aspect of the present disclosure, there may be provided a sustained-release microsphere containing a drug, pamoic acid and a biocompatible polymer, wherein the content of sodium contained in the microsphere is less than 1,600 ppm.

[0010] In one aspect of the present disclosure, there may be provided a sustained-release microsphere prepared using a drug, pamoic acid and a biocompatible polymer, wherein the molar ratio of the drug to the pamoic acid is 1:0.01-1:1, and the content of sodium contained in the microsphere is less than 1,600 ppm.

[0011] In one aspect of the present disclosure, there is provided a sustained-release microsphere prepared using a drug, pamoic acid and a biocompatible polymer, wherein the molar ratio of the drug to the pamoic acid is 1:0.01-1:1 based on the total weight of the pamoic acid, and the content of sodium contained in the pamoic acid is less than 10 weight %.

[0012] In one aspect of the present disclosure, the sustained-release microspheres may also contain the pamoate salt of the drug.

[0013] In one aspect of the present disclosure, the drug can be selected from one or more of the group consisting of donepezil, rivastigmine, entecavir, leuprolide, octreotide, memantine, lamivudine, rotigotine, ropinirole, bupivacaine, ropivacaine, meloxicam, buprenorphine, fentanyl, nimodipine, granisetron, triamcinolone, cytarabine, carmustine, tamsulosin, pamacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, triptorelin, buserelin, nafarelin, deslorelin, pasireotide, lanreotide, vapreotide, exenatide, liraglutide, lixisenatide, semaglutide or a pharmaceutically acceptable salt thereof.

[0014] In one aspect of the present disclosure, the initial release rate of the drug on the first day may be less than 15%.

[0015] In one aspect of the present disclosure, the content of the drug may be 10 wt % to 79 wt % based on the total weight of the sustained-release microspheres.

[0016] In one aspect of the present disclosure, the biocompatible polymer may be 20 wt % to 85 wt % based on the total weight of the sustained-release microspheres.

[0017] In one aspect of the present disclosure, the pamoic acid may be 1 wt % to 30 wt % based on the total weight of the sustained-release microspheres.

[0018] In one aspect of the present disclosure, the drug in the sustained-release microspheres can be released for 1 month to 6 months.

[0019] In one aspect of the present disclosure, the microspheres can be used for injection.

[0020] In one aspect of the present disclosure, a pharmaceutical composition comprising sustained-release microspheres may be provided for preventing, improving or treating hepatitis B, prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty, acromegaly, gastrointestinal pancreatic endocrine tumors, Alzheimer's disease or cognitive impairment.

[0021] In one aspect of the present disclosure, a method for preparing sustained-release microspheres may be provided.

[0022] Beneficial Effects

[0023] The sustained-release microsphere formulation of the present disclosure can increase patient compliance, thereby maximizing therapeutic efficacy by maintaining the therapeutic concentration range of the drug for a long period of time without excessive initial release of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a graph showing the in vitro drug release rate on day 1 depending on the sodium content in the delayed-release microspheres containing donepezil.

[0025] Figure 2 is a graph showing the in vitro drug release rate depending on the sodium content in pamoic acid in the delayed-release microspheres containing donepezil. DETAILED DESCRIPTION

[0026] Hereinafter, the present disclosure will be described in more detail.

[0027] In one embodiment, the present disclosure relates to a sustained-release microsphere containing a drug, pamoic acid, and a biocompatible polymer, wherein the sodium content in the microsphere is less than 1,600 ppm.

[0028] In another embodiment, the present disclosure relates to a sustained-release microsphere prepared using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to the pamoic acid is 1:0.01-1:1, and the sodium content in the microsphere is less than 1,600 ppm.

[0029] In another embodiment, the present disclosure relates to a sustained-release microsphere prepared using a drug, pamoic acid and a biocompatible polymer, wherein the molar ratio of the drug to the pamoic acid is 1:0.01-1:1 based on the weight of the pamoic acid, and the content of sodium contained in the pamoic acid is less than 10 weight %.

[0030] In another embodiment, the present disclosure relates to a sustained-release microsphere comprising a drug, pamoic acid and a biocompatible polymer, wherein the microsphere contains potassium.

[0031] In yet another embodiment, the present disclosure relates to a sustained-release microsphere prepared using a drug, pamoic acid and a biocompatible polymer, wherein the molar ratio of the drug to the pamoic acid is 1:0.01-1:1, and the pamoic acid contains potassium.

[0032] The development of conventional sustained-release preparations using microsphere preparations of biocompatible polymers has developed into an active field of research interest and clinical application. However, in order to prepare such microsphere preparations for long-term continuous administration, the drug contained in the microspheres should contain a relatively high amount by considering the administration period and dosage. In the case of such microspheres containing a high content of drug, even if a biocompatible polymer with a sufficiently long decomposition rate is used, the required administration period may not be met because the release period is not long enough due to the high drug content or the "initial burst" problem of excessive drug release may occur at the beginning of release. In this case, various side effects may occur due to the rapid increase in the blood concentration of the drug, and serious problems may occur especially in the case of a drug with a low therapeutic index. At the same time, if the content of the drug contained in the microspheres is reduced in order to solve these problems, there is a problem of excessive increase in the single dose of the microspheres due to insufficient drug content for treatment, resulting in non-compliance and discomfort of the patient.

[0033] Therefore, the inventors have found that adding pamoic acid to prepare microspheres together with drugs can solve the problem of rapid initial release and insufficient drug release period, even if containing a large amount of drugs. However, the inventors have also found that when pamoic acid is used to prepare microspheres, the sodium or potassium content contained in pamoic acid unexpectedly significantly affects the release of the drug in the microspheres.

[0034] Therefore, the present disclosure provides a microsphere containing a drug as an active ingredient, pamoic acid and a biocompatible polymer, wherein the content of sodium in the microsphere is less than 1,600ppm. Preferably, the content of sodium can be less than 1,550ppm, less than 1,500ppm, less than 1,450ppm, less than 1,400ppm, less than 1,350ppm, less than 1,300ppm, less than 1,250ppm, less than 1,200ppm, less than 1,150ppm, less than 1,100ppm, less than 1,050ppm or less than 1,000ppm. Alternatively, the content of sodium can be 0.01ppm-1,600ppm, 0.1ppm-1,400ppm, 1ppm-1,200ppm, 10ppm-1,000ppm or 100ppm-900ppm.

[0035] Specifically, any drug can be used as the drug as an active ingredient contained in the microspheres of the present disclosure, as long as it is intended for sustained or controlled release over a desired period of time. Examples of such drugs may contain at least one selected from the group consisting of donepezil, rivastigmine, entecavir, leuprolide, octreotide, and pharmaceutically acceptable salts thereof, but are not limited thereto.

[0036] The biocompatible polymer may be at least one selected from the group consisting of lactide-co-glycolide, lactide-co-glycolide glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and copolymers of polyglycolide and polylactide, but is not limited thereto. In a preferred embodiment, the molar ratio of lactide to glycolide in the copolymer may be 40:60-90:10, 45:55-85:15 or 50:50-75:25, for example, in the case of a copolymer of polyglycolide and polylactide, it may be 45:55, 50:50, 75:25 or 85:15.

[0037] The biocompatible polymer may have a weight average molecular weight of 4,000-240,000. For example, the weight average molecular weight of the biocompatible polymer includes all lower numerical ranges within the above ranges, such as a weight average molecular weight of 4,000-100,000, a weight average molecular weight of 7,000-50,000, a weight average molecular weight of 5,000-20,000, a weight average molecular weight of 10,000-18,000, and a weight average molecular weight of 18,000-28,000.

[0038] When two or more types of biocompatible polymers are included, the biocompatible polymers can be a composition or blend of polymers of different exemplary polymer types from each other, but can be a composition of polymers of the same type of polymer having different intrinsic viscosities and / or monomer ratios (e.g., a composition or blend of two or more lactide-glycolide copolymers having different intrinsic viscosities), or polymers having different end groups (e.g., ester end groups or acid end groups). Examples of commercially available biocompatible polymers that can be used in the present disclosure may include RG 502H, RG 503H, RG 504H, RG 502, RG 503, RG 504, RG 653H, RG 752H, RG 753H, RG 752S, RG 755S, RG 756S, RG 858S, R 202H, R 203H, R 205H, R 202S, R 202S, R 205S, which are the Resomer series from EvonikRohm GmbH, and PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG7502, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG 5010, PL 10, PL 18, PL 24, PL 32, PL 38, PDL 20, PDL 45, PC 02, PC 04, PC 12, PC 17 and PC 24 (which are manufactured by Corbion alone or in combination or blend), but not limited thereto. In a preferred embodiment, the intrinsic viscosity of the biocompatible polymer may be 0.16 dL / g-1.9 dL / g. The intrinsic viscosity of the biocompatible polymer used in the present disclosure is measured at a concentration of 0.1% (w / v) in chloroform using an Ubbelohde viscometer at 25°C.

[0039] The sustained-release microspheres may also contain the pamoate salt of the drug.

[0040] In an embodiment, the pamoate form of the drug and / or pamoic acid may be present together with the drug in the sustained-release microspheres of the present disclosure.

[0041] In embodiments, the sodium may be in the form of monosodium or disodium.

[0042] In addition, with respect to the molar ratio of the drug free base to pamoic acid in the microspheres of the present disclosure, the content ratio of the drug to pamoic acid is 1:0.01-1:1.

[0043] When the above range is satisfied, it has an advantage of being able to maintain an appropriate release rate during the release period without making the release rate of the drug too fast or too slow.

[0044] The microspheres disclosed herein preferably have a uniform particle size distribution. Compared with microspheres with uneven particle size distribution, microspheres with uniform particle size distribution can be more accurately dosed during injection and have less variation. Preferably, the span value of the microspheres disclosed herein is 1.2 or less. The term "span value" used herein is an indicator of the uniformity of the microsphere particle size, and refers to the value obtained by the particle size distribution formula (span value) = (Dv0.9-Dv0.1) / Dv0.5. Herein, Dv0.1 represents the particle size corresponding to 10% of the volume % in the microsphere particle size distribution curve, Dv0.5 represents the particle size corresponding to 50% of the volume % in the microsphere particle size distribution curve, and Dv0.9 represents the particle size corresponding to 90% of the volume % in the microsphere particle size distribution curve.

[0045] According to the present disclosure, the initial release rate of the drug in the microspheres on the first day can be less than 15%. Preferably, the initial release rate can be less than 14%, less than 13%, less than 12%, less than 11% or less than 10%, but not limited thereto.

[0046] In a specific embodiment, the content of the drug may be 10 wt %-79 wt %, 10 wt %-75 wt % or 10 wt %-70 wt % based on the total weight of the sustained-release microspheres, but is not limited thereto.

[0047] In a specific embodiment, the microspheres disclosed herein may be sustained-release microspheres containing donepezil, wherein the molar ratio of donepezil to pamoic acid is 1:0.05-1:1, and the content thereof is 40%-70% (w / w).

[0048] In another specific embodiment, the donepezil microspheres (microspheres containing donepezil) disclosed in the present invention may be sustained-release microspheres capable of sustained-release donepezil for 1 month to 6 months, wherein the initial release of the microspheres on the first day is less than 15%, 0.01%-15% or 0.1%-15%, and the sodium content contained in the microspheres is less than 1,600 ppm or 10 ppm-1,300 ppm.

[0049] In another specific embodiment, the microspheres disclosed herein may be sustained-release microspheres capable of sustained release, wherein the molar ratio of rivastigmine to pamoic acid is 1:0.3-1:1 or 1:0.4-1:0.6, the content of rivastigmine as an active ingredient is at most 30 wt %, preferably 10 wt %-30 wt % or 15 wt %-26 wt %, based on the total weight of the microspheres, the initial release on the first day is less than 15%, 0.01%-2.5%, 0.02%-2.3% or 0.03%-2%, and the content of sodium contained in the microspheres is less than 50 ppm, less than 40 ppm, less than 30 ppm or 5 ppm-30 ppm.

[0050] In another specific embodiment, the microspheres disclosed herein may be sustained-release microspheres capable of sustained release, wherein the molar ratio of entecavir to pamoic acid is 1:0.0-1:0.25, the content of entecavir as an active ingredient is greater than 22 wt% and 22 wt%-40 wt% based on the total weight of the microspheres, the initial release position on the first day is less than 10%, 0.1%-5% or 0.1%-3%, and the sodium content in the microspheres is 100 ppm-300 ppm or less than 150 ppm-200 ppm.

[0051] In another specific embodiment, the microspheres disclosed herein may be sustained-release microspheres capable of sustained release, wherein the molar ratio of leuprolide to pamoic acid is 1:0.05-1:0.1, the content of leuprolide as an active ingredient is greater than 10 wt % and greater than 10 wt %-20 wt % based on the total weight of the microspheres, the initial release on the first day is less than 15%, and the sodium content in the microspheres is less than 100 ppm, or 1 ppm-50 ppm.

[0052] In another specific embodiment, the microspheres disclosed herein may be sustained-release microspheres capable of sustained release, wherein the molar ratio of octreotide to pamoic acid is 1:0.1-1:1.2 or 1:0.15-1:1.13, the content of octreotide as an active ingredient is greater than 10 wt%, 10 wt%-40 wt% or 10 wt%-30 wt% based on the total weight of the microspheres, the initial release on the first day is less than 15%, 1%-12% or 1%-10%, and the sodium content in the microspheres is less than 1,600 ppm.

[0053] In a specific embodiment, the drug in the sustained-release microspheres of the present disclosure can be released for 1 month to 6 months, 1 month to 5 months, 1 month to 3 months, or 1 month to 2 months.

[0054] In a specific embodiment, the sustained-release microspheres of the present disclosure can be used for injection.

[0055] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising sustained-release microspheres for preventing, improving or treating hepatitis B, prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty, acromegaly, gastrointestinal pancreatic endocrine tumors, Alzheimer's disease or cognitive impairment. More specifically, the pharmaceutical composition may also contain a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition may be an injectable preparation.

[0056] Hereinafter, the preparation method of the sustained-release microsphere injection of the present disclosure will be described in detail.

[0057] The sustained-release microspheres of the present disclosure can be prepared, for example, using the “solvent extraction and evaporation method”, but are not limited thereto.

[0058] As a specific example of the method for preparing sustained-release microspheres disclosed in the present invention, a method for preparing sustained-release microspheres is provided, which comprises the following steps:

[0059] (a) preparing a dispersed phase by dissolving a drug, pamoic acid and a biocompatible polymer in a solvent for a dispersed phase;

[0060] (b) preparing an emulsion by adding the dispersed phase prepared in step (a) to an aqueous solution containing a surfactant as a continuous phase;

[0061] (c) preparing a suspension containing microspheres by extracting a solvent for a dispersed phase in the emulsion prepared in step (b) into a continuous phase, and evaporating the extracted solvent to form microspheres; and

[0062] (d) preparing microspheres by recovering the microspheres from the suspension of step (c),

[0063] Wherein, based on the total weight of the pamoic acid, the content of sodium in the pamoic acid is 10 weight %.

[0064] Unless otherwise indicated, in the method of preparation, materials related to the drug, pamoic acid, sodium or potassium, and biocompatible polymers, etc., can be administered as described for the microspheres.

[0065] Specifically, the molar ratio of the drug to pamoic acid may be 1:0.01-1:1 based on the free base form of the active ingredient.

[0066] Furthermore, in specific embodiments, the drug may be in the free base form in step (a), and the pamoic acid may be included in the form of a powder or a solution.

[0067] In a specific embodiment, step (a) is performed by adding pamoic acid to a solution of the drug dissolved in a solvent for the dispersed phase.

[0068] The solvent used for the dispersed phase is not limited but may include dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycofurol, methyl isopropyl ketone, dimethyl carbonate or a mixed solvent thereof.

[0069] In a specific embodiment, the solvent for the dispersed phase can be a mixed solvent, in which case the amount of the solvent having a water-immiscible property in the mixed solvent is preferably at least 30% (w / w), 30%-90% (w / w), 30%-85% (w / w), 40%-90% (w / w), 40%-85% (w / w), based on the total weight of the mixed solvent. When preparing the microspheres disclosed herein, the lower the content of sodium pamoic acid, the less the amount of solvent used for the dispersed phase can be.

[0070] In addition, the solvent for the dispersed phase is used as the first solvent, and in addition, it can also contain one or more selected from the group consisting of chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, methyl ethyl ketone, acetic acid, methanol, ethanol, propanol, benzyl alcohol and mixed solvents thereof as the second solvent.

[0071] The method for uniformly mixing the dispersed phase and the continuous phase containing the surfactant in step (b) is not particularly limited, but can be performed using a high-speed stirrer, an inline mixer, a membrane emulsification method, a microfluidic emulsification method, or the like.

[0072] The type of surfactant used in step (b) is not particularly limited, and any type that can help the dispersed phase to form a stable droplet-shaped dispersed phase in the continuous phase can be used. The surfactant can be preferably selected from the group consisting of methylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives and mixtures thereof, and most preferably polyvinyl alcohol can be used as the surfactant.

[0073] In step (b), the content of the surfactant in the continuous phase containing the surfactant may be 0.01 w / v%-20 w / v%, preferably 0.1 w / v%-5 w / v%, based on the total volume of the continuous phase containing the surfactant. When the content of the surfactant is less than 0.01 w / v%, a droplet-shaped dispersed phase or emulsion may not be formed in the continuous phase, and when the content of the surfactant exceeds 20 w / v%, it may be difficult to remove the surfactant after fine particles are formed in the continuous phase due to the excess surfactant.

[0074] Water can be used as the solvent of the continuous phase used in step (b), and water partially 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, tetrahydrofuran polyglycol ether, methyl isopropyl ketone, dimethyl carbonate and ethyl acetate can be used to control the speed of extracting the organic solvent from the dispersed phase in the emulsion state.

[0075] In step (c), when the emulsion containing the droplet-shaped dispersed phase and the continuous phase containing the surfactant are maintained or stirred at a temperature below the boiling point of the organic solvent for a period of time, such as 2 hours to 48 hours, the organic solvent can be extracted from the droplet-shaped dispersed phase to the continuous phase. Part of the organic solvent extracted to the continuous phase can evaporate from the surface. When the organic solvent is extracted from the droplet-shaped dispersed phase, the droplet-shaped dispersed phase can solidify to form microspheres.

[0076] In order to additionally and effectively remove the organic solvent in step (c), heat may be applied to the temperature of the continuous phase for a certain period of time.

[0077] In step (d), the method of recovering the microspheres of the present disclosure may be performed using various known techniques, for example, methods such as filtration or centrifugation may be used.

[0078] Between steps (c) and (d), residual surfactant may be removed by filtration and washing, and the microspheres may be recovered by filtration again.

[0079] The washing step for removing residual surfactant may generally be carried out using water, and the washing step may be repeated multiple times.

[0080] The preparation method of the present disclosure can be performed by drying the obtained microspheres using a conventional drying method after step (d) or after the filtering and washing steps to obtain final dried microspheres.

[0081] Hereinafter, preferred embodiments of the present disclosure will be described to facilitate understanding of the present disclosure. However, it is obvious to those skilled in the art that the following embodiments are illustrative of the present disclosure and that various changes and modifications may be made within the scope and spirit of the present disclosure.

[0082] Embodiments of the present invention

[0083] [Example]

[0084] Hereinafter, the present disclosure will be described in more detail by way of examples. These examples are for illustrative purposes only, and the present disclosure is not intended to be limited to these examples.

[0085] Preparation Example 1. Preparation of sustained-release microspheres containing donepezil

[0086] To verify the effect of the sodium content in the donepezil-containing sustained-release microspheres of the present disclosure, donepezil microspheres were prepared.

[0087] After the biocompatible polymer, donepezil base (manufacturer: Neuland Laboratories, India) and pamoic acid (manufacturer: Kyungbo Pharmaceutical, TCI) were mixed with dichloromethane (manufacturer: JT Baker, USA) or a mixed solvent of dichloromethane and DMSO, and fully dissolved until the solution became transparent to the naked eye, it was used as a dispersed phase. A 0.1% polyvinyl alcohol (viscosity: 4.8-5.8 mPa s) aqueous solution was used as a continuous phase, and the continuous phase was connected to an emulsifying device equipped with a porous membrane with a diameter of 40 μm, and the prepared dispersed phase was injected at the same time to prepare microspheres, and the microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0088] The temperature of the membrane emulsification device and the preparation container was maintained at 25°C, and after the injection of the dispersed phase was completed, the suspension in the preparation container was stirred at a speed of 200 rpm while being maintained at a temperature of 25°C for 60 minutes. Then, it was maintained at a temperature of 45°C for 3 hours while removing the organic solvent. When the organic solvent was removed, the temperature of the microsphere suspension was reduced to 25°C. The microsphere suspension was repeatedly washed with ultrapure water to remove the residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0089] The biocompatible polymers used as dispersed phases are PLA polymers, and Purasorb PDL04A ((IV = 0.35-0.45 dL / g; manufacturer: Corbion, Germany), Purasorb PDL02A ((IV = 0.16-0.24 dL / g; manufacturer: Corbion, Germany), Resomer R 205S (IV = 0.55-0.75 dL / g; manufacturer: Evonik, Germany), Resomer R 23H (IV = 0.25-0.35 dL / g; manufacturer: Evonik, Germany), Resomer R202H (IV = 0.16-0.24 dL / g; manufacturer: Evonik, Germany) and Resomer R 205S (IV = 0.55-0.75 dL / g; manufacturer: Evonik, Germany) are used alone or in a mixture.

[0090] The type and amount of the polymer used in this preparation example, the amount of the drug used, the amount of pamoic acid used, the solvent used, the amount of the solvent for the dispersed phase and the amount of the continuous phase used are shown in Table 1 below.

[0091] [Table 1]

[0092]

[0093] Preparation Example 2: Preparation of sustained-release microspheres containing rivastigmine

[0094] The dispersed phase was prepared by mixing a biocompatible polymer, rivastigmine (rivastigmine base), pamoic acid, and DCM alone or a co-solvent of DCM and DMSO. A 0.5% (w / v) polyvinyl alcohol aqueous solution was used as the continuous phase, and the dispersed phase was injected and stirred into the continuous phase using a homogenizer to prepare microspheres.

[0095] The temperature of the preparation container was maintained at 25° C., and after the injection of the dispersed phase was completed, the temperature of the microsphere suspension was heated to 45° C. and maintained for 3 hours to remove the organic solvent. When the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25° C. The microsphere suspension was repeatedly washed with distilled water several times, and then the microspheres were recovered and dried.

[0096] The biocompatible polymers used as dispersed phase were PLGA polymers, as well as Resomer RG 503H (IV = 0.32-0.44 dL / g; manufacturer: Evonik, Germany), Resomer RG 653H (IV = 0.32-0.44 dL / g; manufacturer: Evonik, Germany), Resomer RG 753H (IV = 0.32-0.44 dL / g; manufacturer: Evonik, Germany), Resomer RG 753S (IV = 0.32-0.44 dL / g; manufacturer: Evonik, Germany), Resomer RG 858S (IV = 1.3-1.7 dL / g; manufacturer: Evonik, Germany), Resomer R 203H (IV = 0.25-0.35 dL / g; manufacturer: Evonik, Germany), and Resomer R 753S (IV = 0.32-0.44 dL / g; manufacturer: Evonik, Germany). 203S (IV=0.25-0.35 dL / g; manufacturer: Evonik, Germany) was used as the PLA polymer alone or in a mixture.

[0097] The type and amount of the polymer used in this preparation example, the amount of the drug used, the amount of pamoic acid used, the solvent used, the amount of the solvent for the dispersed phase and the amount of the continuous phase used are shown in Table 2 below.

[0098] [Table 2]

[0099]

[0100] Preparation Example 3: Preparation of sustained-release microspheres containing leuprorelin acetate

[0101] The dispersed phase was prepared by mixing a biocompatible polymer, Leuprorelin acetate, Pamoic acid and a co-solvent of DCM and methanol. A 1.0% (w / v) polyvinyl alcohol aqueous solution was used as the continuous phase, and microspheres were prepared by connecting the continuous phase to an emulsifying device equipped with a 20 μm diameter porous membrane while injecting the prepared dispersed phase. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0102] The temperature of the preparation container was maintained at 15°C for 24 hours, and 2,500 mL of 40.0% (w / v) ethanol was added to the dispersed phase to remove the organic solvent. The dispersed phase exchange process was performed twice with 5,000 mL of 0.5% (w / v) polyvinyl alcohol and 20.0% (w / v) ethanol aqueous solution. After removing the organic solvent, the microsphere suspension was repeatedly washed several times with distilled water, and then the microspheres were recovered and dried.

[0103] The biocompatible polymer used as the dispersed phase was a PLA polymer, and Resomer R202H (IV = 0.16-0.24 dL / g; manufacturer: Evonik, Germany) was used alone.

[0104] The type and amount of the polymer used, the amount of the drug used, the amount of pamoic acid used, the solvent used, the amount of the solvent for the dispersed phase and the amount of the continuous phase used in this preparation example are shown in Table 3 below.

[0105] [Table 3]

[0106]

[0107] Preparation Example 4: Preparation of sustained-release microspheres containing entecavir

[0108] The dispersed phase was prepared by mixing the biocompatible polymers Resomer RG 858S (manufacturer: Evonik, Germany) and Resomer R203H (manufacturer: Evonik, Germany) in a ratio of 7:3 or 5:5, adding dichloromethane (manufacturer: JT Baker, USA) to the polymer mixture, and then stirring until fully dissolved. Subsequently, dimethyl sulfoxide was added to entecavir (manufacturer: Kyungbo Pharmaceutical, South Korea) and pamoic acid (manufacturer: JT Baker, USA), stirred until dissolved, and the two solutions were mixed for use. A 0.5% polyvinyl alcohol aqueous solution with 5% (w / w) NaCl was added as the continuous phase. After installing a high-speed stirrer in the continuous phase, stirring was performed at 3,000 rpm while injecting the dispersed phase to prepare an emulsion in which a biodegradable polymer containing entecavir was dispersed, and the microspheres were recovered using a sieve immediately after preparation and washed thoroughly. Thereafter, the suspension was transferred back to the preparation container for stirring, and the remaining organic solvent was removed while being kept at 45°C for 3 hours. Then, the temperature of the microsphere suspension was lowered to room temperature, and the microspheres were filtered, treated with triple distilled water to remove residual polyvinyl alcohol, and then freeze-dried.

[0109] The type and amount of the polymer used in this preparation example, the amount of the drug used, the amount of pamoic acid used, the solvent used, the amount of the solvent for the dispersed phase and the amount of the continuous phase used are shown in Table 4 below.

[0110] [Table 4]

[0111]

[0112] Preparation Example 5: Preparation of sustained-release microspheres containing octreotide

[0113] The dispersed phase was prepared by adding dichloromethane (manufacturer: JT Baker, USA) to the biocompatible polymer and stirring until fully dissolved. Thereafter, dimethyl sulfoxide (manufacturer: JT Baker, USA) was added to octreotide (manufacturer: Hemmo, India) and pamoic acid, stirred until dissolved, and then the two solutions were mixed for use. A 0.1% polyvinyl alcohol aqueous solution with 5% (w / w) NaCl was added as the continuous phase. Microspheres were prepared by connecting 2,000 mL of the continuous phase to an emulsifying device equipped with a porous membrane with a diameter of 30 μm and injecting the prepared dispersed phase at the same time, and stirring the suspension at 200 rpm. Then, the remaining organic solvent was removed while being kept at 40 ° C for 3 hours. When the removal was completed, the temperature of the microsphere suspension was reduced to room temperature, the microspheres were filtered, treated with triple distilled water to remove residual polyvinyl alcohol, and then freeze-dried.

[0114] The biocompatible polymers used as dispersed phase were RG 753H (manufacturer: Evonik, Germany, viscosity: 0.32-0.44 dL / g), PDLG 7504A (manufacturer: Corbion, Netherlands, viscosity: 0.39-0.48 dL / g) and RG 853H (manufacturer: Evonik, Germany, viscosity: 0.44 dL / g), used alone or in mixture.

[0115] The type and amount of the polymer used in this preparation example, the amount of the drug used, the amount of pamoic acid used, the solvent used, the amount of the solvent for the dispersed phase and the amount of the continuous phase used are shown in Table 5 below.

[0116] [Table 5]

[0117]

[0118] Experimental Example 1. Measurement of drug content in sustained-release microspheres containing donepezil

[0119] In order to measure the drug content of the microspheres prepared in Preparation Example 1, 10 mg of microspheres were completely dissolved in dimethyl sulfoxide and then diluted with mobile phase. 20 μL of the diluted solution was injected into HPLC and measured at a detection wavelength of 271 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6×150 mm, and the mobile phase was a mixture of phosphate buffer (pH 5.0) and acetonitrile in a ratio of 60:40 (v / v). The amount of encapsulated drug measured is shown in Table 6.

[0120] Experimental Example 2. Measurement of drug content of rivastigmine sustained-release microspheres

[0121] In order to measure the drug content of the microspheres prepared in Preparation Example 2, 45 mg of microspheres were completely dissolved in 25 mL of dimethyl sulfoxide and then diluted with mobile phase. 20 μL of the diluted solution was injected into HPLC and measured at a detection wavelength of 214 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6 × 250 mm, and the mobile phase was a mixture of phosphate buffer (pH 7.0) and acetonitrile in a ratio of 77: 23 (v / v). The amount of encapsulated drug measured is shown in Table 6.

[0122] Experimental Example 3. Measurement of drug content in acetate sustained-release microspheres containing leuprolide

[0123] In order to measure the drug content of the microspheres prepared in Preparation Example 3, 10 mg of microspheres were completely dissolved in 2.5 mL of acetonitrile, and then 7.5 mL of 0.1% (w / w) trifluoroacetic acid aqueous solution was added to extract the microspheres. The filtrate using a 0.45 μm filter was used as the test solution. 20 μL of the test solution was injected into the HPLC and measured at a detection wavelength of 280 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6×150 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 in a ratio of 25:75 (v / v). The amount of encapsulated drug measured is shown in Table 6.

[0124] Experimental Example 4. Measurement of drug content in sustained-release microspheres containing entecavir

[0125] In order to measure the drug content of the microspheres prepared in Preparation Example 4, 10 mg of microspheres were completely dissolved in dimethyl sulfoxide and then diluted with dimethyl sulfoxide again. 5 μL of the diluted solution was injected into the HPLC and measured at a detection wavelength of 214 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6×150 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 in a ratio of 91.5:8.5 (v / v). The amount of encapsulated drug measured is shown in Table 6.

[0126] Experimental Example 5. Measurement of drug content in sustained-release microspheres containing octreotide

[0127] In order to measure the drug content of the microspheres in Preparation Example 5, 10 mg of microspheres were completely dissolved in dimethyl sulfoxide and then diluted with dimethyl sulfoxide again. 10 μL of the diluted solution was injected into the HPLC and measured at a detection wavelength of 254 nm. The column used in this measurement was Inertsil ODS-3, 5 μm, 4.6×150 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 in a ratio of 80:20 (v / v). The amount of encapsulated drug measured is shown in Table 6.

[0128] Experimental Example 6. Particle size analysis of sustained-release microspheres

[0129] In order to quantitatively measure the average particle size, distribution and uniformity of the microspheres, laser diffraction was used for testing.

[0130] The particle size measurement results of the sustained-release microspheres prepared in Examples and Comparative Examples are shown in Table 6 below.

[0131] [Table 6]

[0132]

[0133] Experimental Example 7: Measuring the sodium content in the pamoic acid raw material

[0134] In order to measure the sodium content in the pamoic acid used in the embodiment and the comparative example, 300mg pamoic acid was mixed with 6mL nitric acid aqueous solution (the nitric acid aqueous solution was mixed with ultrapure water in a ratio of 1:1) and 3mL hydrogen peroxide, heated at 100°C or higher, and then acid was added until the gas produced during the dissolution process changed from yellow to white. The sample obtained was weighed, dissolved in ultrapure water, and injected into an inductively coupled plasma emission spectrometer (ICP-O ES) (ThermoScientific Co., iCAP6300 Duo, UK) to measure at a detection wavelength of 598.5nm.

[0135] The amount of sodium measured is shown in Table 7.

[0136] Experimental Example 8: Measurement of Sodium Content in Sustained-Release Microspheres

[0137] In order to measure the sodium content in the microspheres prepared in Examples and Comparative Examples, the sodium content was measured in the same manner as in Experimental Example 7 using 300 mg of pamoic acid.

[0138] [Table 7]

[0139] category Sodium content in pamoate (ppm) Sodium content in microspheres (ppm) Example 1 38 14.2 Example 2 1,530 34.7 Example 3 2,600 67.4 Example 4 33,919 601 Example 5 456 32 Example 6 27 21 Example 7 2,600 76 Embodiment 11 285 26 Embodiment 15 2,600 29.0 Comparative Example 1 101,681 1,640 Comparative Example 2 101,681 1970

[0140] Experimental Example 9: In vitro initial drug release measurement of donepezil microspheres depending on sodium content

[0141] In order to verify that the initial drug release of the microspheres depends on the sodium content in the pamoic acid used in the microspheres prepared in Preparation Example 1 and the sodium content in the microspheres, the following experiment was performed. 10 mg of microspheres were placed in a HDPE wide-mouth bottle, 50 mL of the release test solution was added, and stored in a 37 ° C incubator. After 24 hours, 1 mL of the test solution was taken and centrifuged. Under the same analytical conditions as in Experimental Example 1, the donepezil content and release rate of the obtained supernatant were analyzed using HPLC. The release test solution used for this measurement is a pH 7.4 aqueous solution containing phosphate and sodium azide.

[0142] The results are shown in Table 8 and Figure 1 middle.

[0143] Experimental Example 10: In vivo drug release measurement depending on the sodium content of pamoic acid

[0144] In order to evaluate the drug release from the microspheres depending on the sodium content of pamoic acid used in the microspheres prepared in the examples, after a single administration of donepezil to SD rats, the blood concentration of donepezil was measured to confirm the pharmacokinetics of the drug.

[0145] The dose of donepezil in the microspheres was measured to be 26.04 mg / head, dispersed in 0.3 mL of suspension, and then injected intramuscularly into SD rats. 0.25-0.5 mL of blood was collected at each predetermined time, and the blood concentration of donepezil was measured using HPLC. The drug concentration (ng / mL) of Examples 5, 6 and 7 over time is shown in Figure 2 middle.

[0146] Experimental Example 11: In vitro initial drug release measurement of rivastigmine microspheres depending on sodium content

[0147] In order to evaluate the initial drug release of microspheres depending on the sodium content in the pamoic acid used in the microspheres prepared in Preparation Example 2 and the sodium content in the microspheres, the following experiment was performed.

[0148] 22 mg of microspheres were placed in a HDPE wide-mouth bottle, 50 mL of release test solution was added, and stored in a 37 ° C incubator. After 24 hours, 1 mL of the test solution was taken and centrifuged. Under the same analytical conditions as in Experimental Example 2, the rivastigmine content and release rate of the obtained supernatant were analyzed using HPLC. The release test solution used for this measurement was a pH 7.4 aqueous solution containing phosphate and sodium azide.

[0149] The results are shown in Table 8.

[0150] [Table 8]

[0151]

[0152] As shown in Table 8 above, when the content of sodium contained in the pamoic acid used to prepare the microspheres was 10% by weight or more based on the weight of pamoic acid, and the content of sodium contained in the microspheres was 1,600 ppm or more, excessive initial release of the drug was observed on day 1. Therefore, the sodium content in the pamoic acid salt used in the microspheres should be lower than a certain level in the microspheres to ensure that the initial release rate on day 1 when the microspheres are administered remains below 15%, thereby allowing the drug to be gradually released over a long period of time without excessive initial release of the drug, which is ideal in terms of drug release.

Claims

1. A sustained-release microsphere prepared by using a drug, pamoic acid and a biocompatible polymer, in, The molar ratio of the drug to the pamoic acid is 1:0.01-1:1, and the content of sodium contained in the microspheres is less than 1,600 ppm.

2. A sustained-release microsphere prepared using a drug, pamoic acid and a biocompatible polymer, in, The molar ratio of the drug to the pamoic acid is 1:0.01-1:1, and the content of sodium contained in the pamoic acid is less than 10 weight % based on the total weight of the pamoic acid.

3. A sustained-release microsphere comprising a drug; pamoic acid; and a biocompatible polymer, wherein: The content of sodium contained in the microspheres is less than 1,600 ppm.

4. The sustained-release microspheres according to claim 3, wherein: The sustained-release microspheres also contain the drug pamoxate.

5. The sustained-release microspheres according to any one of claims 1 to 3, wherein The sodium is in the form of monosodium or disodium.

6. The sustained-release microspheres according to any one of claims 1 to 3, wherein The drug is at least one selected from the group consisting of donepezil, rivastigmine, entecavir, leuprorelin, octreotide and pharmaceutically acceptable salts thereof.

7. The sustained-release microspheres according to any one of claims 1 to 3, wherein The initial release rate of the drug on day 1 was less than 15%.

8. The sustained-release microspheres according to any one of claims 1 to 3, wherein Based on the total weight of the sustained-release microspheres, the content of the active ingredient is 10 wt % to 79 wt %.

9. The sustained-release microspheres according to any one of claims 1 to 3, wherein The drug release in the sustained-release microspheres lasts for 1 month to 6 months.

10. The sustained-release microspheres according to any one of claims 1 to 3, wherein The biocompatible polymer is at least one selected from the group consisting of lactide-co-glycolide, lactide-co-glycolide glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and copolymers of polyglycolide and polylactide.

11. The sustained-release microspheres according to any one of claims 1 to 3, wherein The sustained-release microspheres are used for injection.

12. A pharmaceutical composition comprising the sustained-release microspheres according to any one of claims 1 to 3, wherein: The pharmaceutical composition is used for preventing, improving or treating hepatitis B, prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty, acromegaly, gastrointestinal pancreatic endocrine tumors, Alzheimer's disease or cognitive impairment.

13. The pharmaceutical composition according to claim 12, further comprising a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 12, wherein The pharmaceutical composition is an injectable preparation.

15. The method for preparing sustained-release microspheres according to any one of claims 1 to 3, comprising: (a) preparing a dispersed phase by dissolving a drug, pamoic acid and a biocompatible polymer in a solvent for a dispersed phase; (b) preparing an emulsion by adding the dispersed phase prepared in step (a) to an aqueous solution containing a surfactant as a continuous phase; (c) preparing a suspension containing microspheres by extracting a solvent for the dispersed phase in the emulsion prepared in step (b) into the continuous phase, and evaporating the extracted solvent to form microspheres; as well as (d) preparing microspheres by recovering the microspheres from the suspension of step (c), Wherein, based on the weight of the pamoic acid, the content of sodium contained in the pamoic acid is less than 10 weight %.

16. The preparation method according to claim 15, wherein: The molar ratio of the drug to the pamoic acid is 1:0.01-1:1 based on the free base form of the active ingredient.

17. The preparation method according to claim 15, wherein: The drug is in the free base form in step (a).

18. The preparation method according to claim 15, wherein: The step (a) is performed by adding the pamoic acid to a solution of the drug dissolved in a solvent for the dispersed phase.

19. The preparation method according to claim 15, wherein: The solvent used for the dispersed phase includes dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, tetramethylene glycol ether, methyl isopropyl ketone, dimethyl carbonate or a mixed solvent thereof.

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

21. The preparation method according to claim 15, wherein: The biocompatible polymer is at least one selected from the group consisting of lactide-co-glycolide, lactide-co-glycolide glucose, polylactide, polyglycolide, polycaprolactone and mixtures thereof; and polyglycolide, polylactide and copolymers of polyglycolide and polylactide.

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