Sustained-release microspheres containing a drug and pamoic acid

Abstract

Sustained-release microspheres containing a drug, pamoic acid, and a biocompatible polymer, pharmaceutical compositions for the prevention, improvement, or treatment of hepatitis B, prostate cancer, breast cancer, endometriosis, uterine myoma, precocious puberty, acromegaly, gastroenteropancreatic endocrine tumors, Alzheimer's disease, or cognitive dysfunction, and methods for producing the sustained-release microspheres are provided.

Description

Technical Field

[0001] The present invention relates to sustained-release microspheres containing a drug and pamoic acid, and more particularly, to a sustained-release microsphere preparation containing a drug and pamoic acid having the characteristics of long-term stable drug release encapsulating a high content of the drug, and a method for producing the same.

Background Art

[0002] In order to develop sustained-release preparations, microsphere preparations using biocompatible polymers have developed as an active research interest field and clinical application field. However, microspheres using only biocompatible polymers exhibit an "initial burst" phenomenon in which rapid drug release occurs at the initial stage despite not being nanoparticles. Such an "initial burst" phenomenon may cause side effects due to a rapid increase in drug concentration, and there is a problem that the drug rapidly released initially is metabolized without exerting its medicinal effect.

[0003] As a result of intensive research to improve such problems of rapid initial release of drugs in microspheres, the present inventors have confirmed that pamoic acid can be used as a pharmaceutically usable salt or additive that can act as a drug release regulator in microspheres. Furthermore, the present inventors have confirmed through further research an unpredictable problem that the degree of release varies depending on the amount of sodium contained in pamoic acid.

[0004] Therefore, the present inventors have completed the development of a sustained-release microsphere injection having the characteristics of long-term stable drug release encapsulating a high content of the drug while solving the problems of the prior art.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention was devised to solve the problems of the prior art as described above, and an object thereof is to provide a sustained-release microsphere preparation having characteristics of stable drug release over a long period with a high content of drug encapsulated therein and a method for producing the same.

[0006] Furthermore, the present invention uses pamoic acid as a pharmaceutically usable salt or additive for improving excessive initial release of a high-content drug, and particularly provides a method for producing a sustained-release injection having a sustained drug effect over a long period by quantitatively adjusting sodium or potassium contained in pamoic acid.

Means for Solving the Problems

[0007] In one aspect of the present invention, there can be provided 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.

[0008] In one aspect of the present invention, there can be provided a sustained-release microsphere produced using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is 1:0.01 to 1:1, and the sodium content in the microsphere is less than 1,600 ppm.

[0009] In one aspect of the present invention, there can be provided a sustained-release microsphere produced using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is 1:0.01 to 1:1, and the sodium content contained in the pamoic acid is 10% by weight or less based on the total weight of the pamoic acid.

[0010] In one aspect of the present invention, the sustained-release microsphere may further contain a pamoate of the drug.

[0011] In one aspect of the present invention, the drug may be one or more selected from the group consisting of donepezil, rivastigmine, entecavir, leuprorelin, octreotide, memantine, lamivudine, rotigotine, ropinirole, bupivacaine, ropivacaine, meloxicam, buprenorphine, fentanyl, nimodipine, granisetron, triamcinolone, cytarabine, carmustine, tamsulosin, celecoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, tryptorelin, buserelin, nafarelin, deslorelin, pasireotide, lanreotide, vapreotide, exenatide, liraglutide, lixisenatide, semaglutide, and pharmaceutically acceptable salts thereof.

[0012] In one aspect of the present invention, the initial release rate of the drug per day may be less than 15%.

[0013] In one aspect of the present invention, the content of the drug may be 10 to 79% by weight based on the total weight of the sustained-release microspheres.

[0014] In one aspect of the present invention, the biocompatible polymer may be 20 to 85% by weight based on the total weight of the sustained-release microspheres.

[0015] In one aspect of the present invention, the pamoic acid may be 1 to 30% by weight based on the total weight of the sustained-release microspheres.

[0016] In one aspect of the present invention, the drug in the sustained-release microspheres may be released over a period of 1 month to 6 months.

[0017] In one aspect of the present invention, the microspheres may be for injection.

[0018] In one aspect of the present invention, a pharmaceutical composition for preventing, improving, or treating hepatitis B, prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty, acromegaly, gastroenteropancreatic endocrine tumors, Alzheimer's disease, or cognitive impairment, which contains sustained-release microspheres, can be provided.

[0019] In one aspect of the present invention, a method for manufacturing the sustained-release microspheres can be provided.

Effects of the Invention

[0020] The sustained-release microsphere preparation according to the present invention can maintain the therapeutic range concentration of the drug for a long time without excessive initial release of the drug, improve the patient's medication compliance, and maximize the therapeutic effect.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0022] Hereinafter, the present invention will be described in more detail.

[0023] In one aspect, the present invention is sustained-release microspheres containing a drug, pamoic acid, and a biocompatible polymer, wherein the sodium content in the microspheres is less than 1,600 ppm.

[0024] In another aspect, the present invention is sustained-release microspheres manufactured using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is 1:0.01 to 1:1, and the sodium content in the microspheres is less than 1,600 ppm.

[0025] In yet another aspect, the present invention relates to a sustained-release microsphere prepared using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is 1:0.01 to 1:1, and the sodium content contained in the pamoic acid is 10% by weight or less based on the weight of the pamoic acid.

[0026] In yet another aspect, the present invention relates to a sustained-release microsphere containing a drug, pamoic acid, and a biocompatible polymer, and containing potassium in the microsphere.

[0027] In yet another aspect, the present invention relates to a sustained-release microsphere prepared using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is 1:0.01 to 1:1, and the pamoic acid contains potassium.

[0028] Conventionally, in order to develop a sustained-release formulation, microsphere formulations using biocompatible polymers have evolved into active research and clinical application fields. However, for such long-term continuous administration, the drug to be contained in the microspheres must be contained in a very high amount considering the administration period and dosage. When the drug is contained in the microspheres in such a high content, even if a biocompatible polymer with a sufficiently long degradation rate is applied, due to the high drug content, the release period cannot be made sufficiently long to match the desired administration period, or an 'initial burst' problem occurs where the drug release is too fast at the initial stage. In this case, various side effects may occur due to a rapid increase in the blood concentration of the drug, and particularly serious problems may occur in the case of drugs with a low therapeutic index. On the other hand, in order to solve such problems, when the content of the drug contained in the microspheres is lowered, since the content of the drug for treatment is not sufficient, the amount of microspheres administered relatively once excessively increases, resulting in problems such as a decrease in the patient's medication compliance and inconvenience.

[0029] Therefore, the inventors of the present invention confirmed that when pamoic acid is added together with a drug during the production of microspheres, even if a large amount of the drug is contained, the problems of initial rapid release and insufficient release of the drug over a sufficient period can be solved. By the way, it was also confirmed that when pamoic acid is used for the production of microspheres in this way, the drug release in the microspheres is significantly affected by the unexpected sodium or potassium content in pamoic acid.

[0030] Accordingly, the present invention relates to microspheres containing a drug, pamoic acid, and a biocompatible polymer as active ingredients, characterized in that the sodium content in the microspheres is less than 1,600 ppm. Preferably, the sodium content may be less than 1,550 ppm, less than 1,500 ppm, less than 1,450 ppm, less than 1,400 ppm, less than 1,350 ppm, less than 1,300 ppm, less than 1,250 ppm, less than 1,200 ppm, less than 1,150 ppm, less than 1,100 ppm, less than 1,050 ppm, or less than 1,000 ppm. Alternatively, the sodium content may be 0.01 to 1,600 ppm, 0.1 to 1,400 ppm, 1 to 1,200 ppm, 10 to 1,000 ppm, or 100 to 900 ppm.

[0031] Specifically, any drug can be used as long as it is intended to achieve sustained release or controlled release over a desired period as an active ingredient contained in the microspheres according to the present invention. Examples of such drugs include, but are not limited to, donepezil, rivastigmine, entecavir, leuprorelin, octreotide, and one or more selected from the group consisting of pharmaceutically acceptable salts thereof.

[0032] 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 copolymers of polyglycolide and polylactide, but is not limited thereto. 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, such as 45:55, 50:50, 75:25, or 85:15.

[0033] 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 biocompatible polymer may be 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, a weight average molecular weight of 18,000 to 28,000, etc., including all lower numerical ranges within the above range.

[0034] When two or more types of the biocompatible polymers are included, the combination or blend of the exemplified polymer types may be different from each other, but the combination of polymers having different intrinsic viscosities and / or monomer ratios of the same type of polymer (for example, a combination or blend of two or more poly(lactide-co-glycolide) having different intrinsic viscosities), or the same type of polymer having different end groups (for example, the end group is an ester or the end group is an acid) may be used. Examples of commercially available biocompatible polymers that can be used in the present invention include Resomer-based 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 203S, R 205S of Evonik Rohm GmbH, PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, 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, PC 24 of Corbion, alone or in combination or blend, etc., but not limited thereto. In a preferred embodiment, the biocompatible polymer may have an intrinsic viscosity of 0.16 to 1.9 dL / g. The intrinsic viscosity of the biocompatible polymer used in the present invention refers to that measured at 25 °C in chloroform at a concentration of 0.1% (w / v) using an Ubbelohde viscometer.

[0035] The sustained-release microparticles may additionally contain a pamoate salt of the drug.

[0036] In one embodiment, in the sustained-release microparticles according to the present invention, a pamoate form and / or pamoic acid of the drug can be present together with the drug.

[0037] In one embodiment, the sodium may be in the monosodium or disodium form.

[0038] Also, in the microspheres according to the present invention, the content ratio of the drug to pamoic acid is 1:0.01 to 1:1 in terms of the molar ratio of the free base of the drug to pamoic acid.

[0039] When the above range is satisfied, it has the advantage that an appropriate release rate can be maintained during the release period without the release of the drug being too rapid or overly delayed.

[0040] The microspheres of the present invention preferably have a uniform particle size distribution. Microspheres with a uniform particle size distribution have a smaller deviation during injection compared to non-uniform microspheres and can be administered in a more accurate amount. Preferably, the Span value of the microspheres of the present invention is 1.2 or less. The term "Span value" used in the present invention is an index indicating the uniformity of the particle size of the microspheres and means a value obtained by the formula size distribution (Span value) = (Dv0.9 - Dv0.1) / Dv0.5. Here, Dv0.1 means the particle size corresponding to 10% by volume in the particle size distribution curve of the microspheres, Dv0.5 means the particle size corresponding to 50% by volume in the particle size distribution curve of the microspheres, and Dv0.9 means the particle size corresponding to 90% by volume in the particle size distribution curve of the microspheres.

[0041] According to the present invention, the initial release rate of the drug in the microspheres may be less than 15% per day. Preferably, the initial release rate is less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, but not limited thereto.

[0042] In a specific embodiment, the content of the drug is 10 to 79% by weight, 10 to 75% by weight, or 10 to 70% by weight, but not limited thereto, based on the total weight of the sustained-release microspheres.

[0043] In a specific embodiment, the microspheres according to the present invention may be sustained-release microspheres containing donepezil with a molar ratio of pamoic acid to donepezil of 1:0.05 to 1:1 and a content of 40 to 70% (w / w).

[0044] In another specific embodiment, the donepezil microspheres according to the present invention have an initial release of 15% or less, 0.01 to 15%, or 0.1 to 15% per day, and the sodium content in the microspheres is less than 1,600 ppm, or 10 to 1,300 ppm, and may be sustained-release microspheres capable of sustained release of donepezil for 1 to 6 months.

[0045] In another specific embodiment, the microspheres according to the present invention have a molar ratio of rivastigmine to pamoic acid of 1:0.3 to 1:1, or 1:0.4 to 1:0.6, and contain up to 30% by weight, preferably 10 to 30% by weight, or 15 to 26% by weight of rivastigmine as the active ingredient based on the total weight of the microspheres. The initial release per day is less than 15%, 0.01 to 2.5%, 0.02 to 2.3%, or 0.03 to 2%, and the sodium content in the microspheres is less than 50 ppm, less than 40 ppm, less than 30 ppm, or 5 to 30 ppm, and may be sustained-release microspheres capable of sustained release.

[0046] In another specific embodiment, the microspheres according to the present invention have a molar ratio of entecavir to pamoic acid of 1:0.0 to 1:0.25, and contain 22% by weight or more, 22 to 40% by weight of entecavir as the active ingredient based on the total microspheres. The initial release per day is less than 10%, 0.1 to 5%, or 0.1 to 3%, and the sodium content in the microspheres is 100 to 300 ppm or less than 150 to 200 ppm, and may be sustained-release microspheres capable of sustained release.

[0047] In another specific embodiment, the microspheres according to the present invention have a molar ratio of leuprorelin to pamoic acid of 1:0.05 to 1:0.1, contain 10% by weight or more and 10 to 20% by weight of leuprorelin as the active ingredient with respect to the total microspheres, have an initial release of 15% or less in one day, and may be sustained-release microspheres capable of sustained release with a sodium content in the microspheres of less than 100 ppm or 1 to 50 ppm.

[0048] In another specific embodiment, the microspheres according to the present invention have a molar ratio of octreotide to pamoic acid of 1:0.1 to 1:1.2 or 1:0.15 to 1:1.13, contain 10% by weight or more, 10 to 40% by weight, or 10 to 30% by weight of octreotide as the active ingredient with respect to the total microspheres, have an initial release of less than 15%, 1 to 12%, or 1 to 10% in one day, and may be sustained-release microspheres capable of sustained release with a sodium content in the microspheres of less than 1,600 ppm.

[0049] In a specific embodiment, the drug in the sustained-release microspheres according to the present invention may be released over 1 month to 6 months, 1 month to 5 months, 1 month to 3 months, or 1 month to 2 months.

[0050] In a specific embodiment, the sustained-release microspheres according to the present invention may be for injection.

[0051] In yet another aspect, the present invention relates to a pharmaceutical composition for preventing, improving or treating hepatitis B, prostate cancer, breast cancer, endometriosis, uterine myoma, precocious puberty, acromegaly, gastroenteropancreatic endocrine tumors, Alzheimer's disease or cognitive impairment, comprising the above-mentioned sustained-release microspheres. More specifically, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition may be an injection preparation.

[0052] Hereinafter, the manufacturing method of the sustained-release microsphere injection of the present invention will be specifically described.

[0053] The sustained-release microspheres according to the present invention are produced, for example, using the "solvent extraction and evaporation method", but the production method is not limited thereto.

[0054] As a specific example of the method for producing sustained-release microspheres according to the present invention, there is provided a method for producing sustained-release microspheres including the following steps: (a) A step of dissolving a drug, pamoic acid, and a biocompatible polymer in a solvent for the dispersed phase to produce 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 solvent for the dispersed phase from the dispersed phase of the emulsion produced in step (b) with the continuous phase, evaporating the extracted solvent to form microspheres, and producing a suspension containing the microspheres; and (d) A step of recovering the microspheres from the suspension in step (c) to produce the microspheres, At this time, the sodium content in the pamoic acid is 10% by weight based on the total weight of the pamoic acid.

[0055] In the above production method, unless otherwise specified, matters regarding the drug, pamoic acid, sodium or potassium, and the biocompatible polymer can be directly applied as described for the microspheres.

[0056] Specifically, the molar ratio of the drug:pamoic acid may be 1:0.01 to 1:1 based on the free base form of the active ingredient.

[0057] Also, in a specific embodiment, in step (a), the drug is in the free base form, and the pamoic acid is included in the form of a powder or a solution.

[0058] As a specific embodiment, in step (a), pamoic acid may be added to a solution of the drug dissolved in the solvent for the dispersed phase.

[0059] There is no restriction on the solvent for the dispersed phase, but it may include dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycol formal, methyl isopropyl ketone, dimethyl carbonate, or a mixed solvent thereof.

[0060] In a specific embodiment, the solvent for the dispersed phase may be a mixed solvent. At this time, the solvent having a property of being immiscible with water in the mixed solvent is preferably used in an amount of at least 30% (w / w) or more, 30 - 90% (w / w), 30 - 85% (w / w), 40 - 90% (w / w), or 40 - 85% (w / w) based on the total weight of the mixed solvent. When producing the microspheres according to the present invention, the lower the sodium content of pamitic acid, the more the amount of the solvent for the dispersed phase can be reduced.

[0061] Alternatively, using the solvent for the dispersed phase as the first solvent, one or more selected from the group consisting of chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, and a mixed solvent thereof may be additionally included as the second solvent.

[0062] In step (b), the method for uniformly mixing the dispersed phase and the continuous phase containing the surfactant is not particularly limited, but it can be carried out using a high-speed stirrer, an in-line mixer, a membrane emulsion method, a microfluidics emulsion method, etc.

[0063] The type of surfactant used in step (b) is not particularly limited, and any surfactant can be used as long as it can help the dispersed phase form stable droplets in the continuous phase. The surfactant is preferably selected from the group consisting of methyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivative, and mixtures thereof. Most preferably, polyvinyl alcohol can be used.

[0064] In 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. When the content of the surfactant is less than 0.01 w / v%, a dispersed phase or emulsion in droplet form may not be formed in the continuous phase. When the content of the surfactant exceeds 20 w / v%, after fine particles are formed in the continuous phase by the excess surfactant, it becomes difficult to remove the surfactant.

[0065] Water can be used as the solvent of the continuous phase used in step (b). To adjust the extraction rate of the organic solvent from the dispersed phase in the emulsion state, water containing one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycol formal, methyl isopropyl ketone, dimethyl carbonate, and ethyl acetate can be used.

[0066] In step (c), if an emulsion containing a dispersed phase in the form of droplets and a continuous phase containing a 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 to 48 hours, the organic solvent is extracted from the dispersed phase in the form of droplets into the continuous phase. A part of the organic solvent extracted into the continuous phase can evaporate from the surface. While the organic solvent is being extracted from the dispersed phase in the form of droplets, the dispersed phase in the form of droplets can be solidified to form microspheres.

[0067] In order to more efficiently remove the organic solvent in step (c), heat can be applied to the temperature of the continuous phase for a certain period of time.

[0068] In step (d), the method for recovering the microspheres according to the present invention can be carried out using various known techniques. For example, methods such as filtration or centrifugation can be utilized.

[0069] Between step (c) and step (d), the residual surfactant can be removed by filtration and washing, and then filtered again to recover the microspheres.

[0070] The washing step for removing the remaining surfactant can usually be carried out using water, and the washing step can be repeated several times.

[0071] In the production method of the present invention, after step (d) or after the filtration and washing steps, the obtained microspheres can be dried using a normal drying method to finally obtain dried microspheres.

[0072] Hereinafter, for the understanding of the present invention, preferred embodiments are presented. The following embodiments are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and technical idea of the present invention. It is natural that such deformations and modifications belong to the scope of the appended claims.

Examples

[0073] [Examples] Hereinafter, the present invention will be described in more detail through examples. These examples are merely for illustrative purposes of the present invention and are not to be construed as limiting the scope of the present invention.

[0074] Production Example 1. Production of Sustained-Release Microspheres Containing Donepezil In order to confirm the effect according to the sodium content of the sustained-release microspheres containing donepezil according to the present invention, donepezil microspheres were produced.

[0075] The dispersed phase was prepared by mixing a biocompatible polymer and donepezil base (manufacturer: Neuland Laboratories, India), pamoic acid (manufacturer: KB Pharm, TCI) with dichloromethane (manufacturer: J.T Baker, USA) or a mixed solvent of dichloromethane and DMSO until it became visually transparent and then used. The continuous phase was an aqueous solution of 0.1% polyvinyl alcohol (viscosity: 4.8 - 5.8 mPa·s). The continuous phase was connected to an emulsifying device equipped with a porous membrane with a diameter of 40 μm, and at the same time, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0076] The temperature of the membrane emulsifying device and the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the suspension in the preparation container was maintained at 25°C for 60 minutes while stirring at a speed of 200 rpm. Then, the organic solvent was removed while maintaining the temperature at 45°C for 3 hours. After the removal of the organic solvent was completed, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed several times with ultrapure water to remove the residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0077] The biocompatible polymer used as the dispersed phase was a PLA polymer, 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 203H (IV = 0.25 - 0.35 dL / g; manufacturer: Evonik, Germany), Resomer R 202H (IV = 0.16 - 0.24 dL / g; manufacturer: Evonik, Germany), and Resomer R 205S (IV = 0.55 - 0.75 dL / g; manufacturer: Evonik, Germany) were used alone or in combination.

[0078] The types and amounts of polymers used in this production example, the amounts of drugs used, the amounts of pamoic acid used, the solvents used, the amounts of dispersed phase solvents used, and the amounts of continuous phases used are as shown in Table 1 below.

[0079]

Table 1

[0080] Production Example 2: Production of Sustained Release Microspheres Containing Rivastigmine The dispersed phase was prepared by mixing a biocompatible polymer, Rivastigmine base, pamoic acid, DCM alone, or a co-solvent of DCM and DMSO. The continuous phase used was a 0.5% (w / v) aqueous polyvinyl alcohol solution, and the dispersed phase was injected and stirred through a homogenizer into the continuous phase to produce microspheres.

[0081] The temperature of the preparation container was maintained at 25°C. 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 while removing the organic solvent. After the removal of the organic solvent was completed, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed several times with distilled water, then recovered and dried.

[0082] The biocompatible polymer used as the dispersed phase was a PLGA polymer, 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) and Resomer RG 858S (IV = 1.3 - 1.7 dL / g; manufacturer: Evonik, Germany), and as PLA polymers, Resomer R203H (IV = 0.25 - 0.35 dL / g; manufacturer: Evonik, Germany) and Resomer R203S (IV = 0.25 - 0.35 dL / g; manufacturer: Evonik, Germany) were used alone or in combination.

[0083] The types and amounts of polymers used in this production example, the amount of drug used, the amount of pamoic acid used, the solvents used, the amount of dispersed phase solvent used, and the amount of continuous phase are as shown in Table 2 below.

[0084]

Table 2

[0085] Production Example 3: Production of Sustained Release Microspheres Containing Leuprorelin Acetate The dispersed phase was prepared by mixing a biocompatible polymer, leuprorelin acetate, pamoic acid, DCM and a methyl alcohol co-solvent. The continuous phase used was a 1.0% (w / v) aqueous polyvinyl alcohol solution, and while connecting the continuous phase to an emulsifying device equipped with a porous membrane with a diameter of 20 μm, the prepared dispersed phase was injected to produce microspheres, and the microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0086] The temperature of the preparation container was maintained at 15°C for 24 hours, and 2,500 mL of 40.0% (w / v) ethyl alcohol was added to the dispersed phase to remove the organic solvent. The dispersed phase exchange process was carried out a total of 2 times with 5,000 mL of 0.5% (w / v) polyvinyl alcohol and 20.0% (w / v) ethyl alcohol aqueous solution. After the removal of the organic solvent was completed, the microsphere suspension was repeatedly washed several times with distilled water and then recovered and dried.

[0087] 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.

[0088] The types and amounts of polymers used in this production example, the amounts of drugs used, the amounts of pamoic acid used, the solvents used, the amounts of dispersed phase solvents used, and the amounts of continuous phases used are as shown in Table 3 below.

[0089]

Table 3

[0090] Production Example 4: Production of Sustained-Release Microspheres Containing Entecavir The dispersed phase is prepared by adding dichloromethane (manufactured by J.T Baker, USA) to a polymer obtained by mixing Resomer RG 858S (manufactured by Evonik, Germany) and Resomer R203H (manufactured by Evonik, Germany), which are biocompatible polymers, in a ratio of 7:3 or 5:5, and stirring until completely dissolved. Then, entecavir (manufactured by KB Pharm, South Korea) and dimethyl sulfoxide (manufactured by J.T Baker, USA) are added to pamoic acid, stirred until dissolved, and then the two solutions are mixed for use. The continuous phase is an aqueous solution of 0.5% polyvinyl alcohol with 5% (w / w) NaCl added. After installing a high-speed stirrer in the continuous phase, it is stirred at 3,000 rpm while injecting the dispersed phase to produce an emulsion in which the biodegradable polymer containing entecavir is dispersed. Immediately after production, it is sieved, recovered, and thoroughly washed. Then, it is transferred back to the preparation container, the suspension is stirred, and the remaining organic solvent is removed while maintaining at 45°C for 3 hours. Then, after lowering the temperature of the microsphere suspension to room temperature, it is filtered, the remaining polyvinyl alcohol is removed with triple-distilled water, and freeze-dried.

[0091] The types and amounts of polymers used in this production example, the amounts of drugs used, the amounts of pamoic acid used, the solvents used, the amounts of dispersed-phase solvents used, and the amounts of continuous phases used are as shown in Table 4 below.

[0092]

Table 4

[0093] Production Example 5: Production of Sustained-Release Microspheres Containing Octreotide The dispersed phase is prepared by putting a biocompatible polymer into dichloromethane (manufacturer: J.T Baker, USA) and stirring until it is completely dissolved. Then, octreotide (manufacturer: Hemmo, India) and dimethyl sulfoxide (manufacturer: J.T Baker, USA) are added to pamoic acid, followed by stirring until dissolved. After that, the two solutions are mixed for use. The continuous phase is an aqueous solution of 0.1% polyvinyl alcohol with 5% (w / w) NaCl added. 2,000 mL of the continuous phase is connected to an emulsification device equipped with a porous membrane with a diameter of 30 μm, and at the same time, the prepared dispersed phase is injected to produce microspheres. The suspension is stirred at 200 rpm. Then, the residual organic solvent is removed while maintaining the temperature at 40°C for 3 hours. After the removal is completed, the temperature of the microsphere suspension is lowered to room temperature, followed by filtration to remove the remaining polyvinyl alcohol with tertiary distilled water, and then freeze-dried.

[0094] The biocompatible polymers used as the 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 combination. The types and amounts of polymers used in this production example, the amounts of drugs used, the amounts of pamoic acid used, the solvents used, the amounts of dispersed phase solvents used, and the amounts of continuous phase used are as shown in Table 5 below.

[0095]

Table 5

[0096] Experimental Example 1. Measurement of Drug Content in Donepezil Sustained-Release Microspheres To measure the drug content of the microspheres produced in Production Example 1, 10 mg of the microspheres were completely dissolved in dimethyl sulfoxide and then diluted with the 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 phosphate buffer (pH 5.0) and acetonitrile mixed at a ratio of 60:40 (v / v). The measured encapsulation amount was shown in Table 6.

[0097] Experimental Example 2. Measurement of drug content of rivastigmine sustained-release microspheres To measure the drug content of the microspheres produced in Production Example 2, 45 mg of the microspheres were completely dissolved in 25 mL of dimethyl sulfoxide and then diluted with the 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 phosphate buffer (pH 7.0) and acetonitrile mixed at a ratio of 77:23 (v / v). The measured encapsulation amount was shown in Table 6.

[0098] Experimental Example 3. Measurement of drug content of leuprolide acetate sustained-release microspheres To measure the drug content of the microspheres produced in Production Example 3, 10 mg of the microspheres were completely dissolved in 2.5 mL of acetonitrile, and then 7.5 mL of a 0.1% (w / w) trifluoroacetic acid aqueous solution was added for extraction. The solution filtered using a 0.45 μm filter was used as the test solution. 20 μL of the test solution was injected into 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 acetonitrile containing 0.1% (w / w) trifluoroacetic acid and a 0.1% (w / w) trifluoroacetic acid aqueous solution mixed at a ratio of 25:75 (v / v). The measured encapsulation amount was shown in Table 6.

[0099] Experimental Example 4. Measurement of drug content of entecavir sustained-release microspheres To measure the drug content of the microspheres produced in Production Example 4, 10 mg of the microspheres were completely dissolved in dimethyl sulfoxide and then diluted again with dimethyl sulfoxide. 5 μL of the diluted solution was injected into HPLC and determined 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 an aqueous solution of 0.1% (w / w) trifluoroacetic acid at a ratio of 91.5:8.5 (v / v). The measured encapsulation amount is shown in Table 6.

[0100] Experimental Example 5. Measurement of drug content of octreotide sustained-release microspheres To measure the drug content of the microspheres produced in Production Example 5, 10 mg of the microspheres were completely dissolved in dimethyl sulfoxide and then diluted again with dimethyl sulfoxide. 10 μL of the diluted solution was injected into HPLC and determined 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 an aqueous solution of 0.1% (w / w) trifluoroacetic acid at a ratio of 80:20 (v / v). The measured encapsulation amount is shown in Table 6.

[0101] Experimental Example 6. Particle size analysis of sustained-release microspheres To quantitatively measure the average particle size, distribution, and uniformity of the microspheres, a test was conducted using the laser diffraction method.

[0102] The particle size measurement results of the sustained-release microspheres produced in the above Examples and Comparative Examples are shown in Table 6 below.

[0103]

Table 6

[0104] Experimental Example 7: Measurement of sodium content in raw material pamoic acid To measure the sodium content of pamoic acid used in the above Examples and Comparative Examples, 300 mg of pamoic acid was mixed with 6 mL of a nitric acid aqueous solution mixed with ultrapure water in a 1:1 ratio and 3 mL of hydrogen peroxide. After that, it was heated at 100 °C or higher, and acid was added until the gas generated during the dissolution process changed from yellow to white. The sample thus obtained was weighed and dissolved in ultrapure water, and then injected into an inductively coupled plasma emission spectrometer (ICP-OES) (Thermo Scientific Co., iCAP 6300 Duo, UK) and measured at a detection wavelength of 598.5 nm. The measured contents are shown in Table 7.

[0105] Experimental Example 8: Measurement of Sodium Content in Sustained Release Microspheres To measure the sodium content of the microspheres produced in the above Examples and Comparative Examples, 300 mg of the Examples was used and measured in the same manner as in Experimental Example 7.

[0106]

Table 7

[0107] Experimental Example 9: In Vitro Initial Drug Release Measurement of Donepezil Microspheres According to Sodium Content In order to confirm the sodium content of pamoic acid used in the microspheres produced in Production Example 1 and the initial drug release of the microspheres according to the sodium content in the microspheres, the following experiment was conducted. 10 mg of microspheres was placed in an HDPE wide-mouth bottle, filled with 50 mL of the release test solution, and then stored in a 37 °C incubator. After 24 hours, 1 mL of this test solution was taken and centrifuged, and the supernatant obtained was analyzed for the donepezil content and release rate using HPLC under the same analysis conditions as in Experimental Example 1. The release test solution for this measurement used an aqueous solution of pH 7.4 containing phosphate and sodium azide. The results are shown in Table 8 and Figure 1.

[0108] Experimental Example 10: In Vivo Drug Release Measurement According to Sodium Content in Pamoic Acid To confirm the drug release of the microspheres according to the sodium content in pamoic acid used in the microspheres produced in the above examples, after a single administration of donepezil to SD rats, blood concentrations of donepezil were measured to confirm the pharmacokinetics.

[0109] The dosage of donepezil administered was measured such that the microspheres would be 26.04 mg / head, dispersed in 0.3 mL of suspension, and then intramuscularly injected into SD rats. Blood samples of 0.25 - 0.5 mL were collected at pre-planned times, and the blood concentration of donepezil was measured using HPLC. The drug concentrations (ng / mL) corresponding to the times of Examples 5, 6, and 7 are shown in Figure 2.

[0110] Experimental Example 11: In vitro measurement of the initial drug release of rivastigmine microspheres according to the sodium content The following experiment was conducted to confirm the initial drug release of the microspheres according to the sodium content in pamoic acid used in the microspheres produced in Production Example 2 and the sodium content in the microspheres.

[0111] 22 mg of microspheres were placed in an HDPE wide-mouth bottle, filled with 50 mL of the release test solution, and then stored in a 37°C incubator. After 24 hours, 1 mL of this solution was taken, centrifuged, and the supernatant obtained was analyzed for the rivastigmine content and release rate using HPLC under the same analytical conditions as in Experimental Example 2. The release test solution for this measurement used an aqueous solution of pH 7.4 containing phosphate and sodium azide. The results are shown in Table 8.

[0112]

Table 8

[0113] As can be confirmed in Table 8 above, when the sodium content in the pamonic acid used for the production of the microspheres is 10% by weight or more based on the weight of the pamonic acid and the sodium content in the microspheres is 1,600 ppm or more, it was confirmed that excessive initial drug release occurred on the first day. Only when sodium is present in the pamonate used for the microspheres at less than a certain content in the microspheres, it was possible to confirm that the 1-day release rate at the time of microsphere administration is 15% or less, and the drug is gradually released over a long period without the problem of excessive initial drug release, which is preferable in terms of drug release.

[0114] Therefore, only when sodium is present in the pamonate used for the microspheres at less than a certain content in the microspheres, it was possible to confirm that the 1-day release rate at the time of microsphere administration is 15% or less, and the drug is gradually released over a long period without the problem of excessive initial drug release, which is preferable in terms of drug release.

Claims

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

2. A sustained-release microsphere produced by using a drug, pamoic acid, and a biocompatible polymer, wherein the molar ratio of the drug to pamoic acid is from 1:0.01 to 1:1, and the sodium content contained in the pamoic acid is 10% by weight or less 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 sodium content in the microsphere is less than 1,600 ppm.

4. The sustained-release microsphere according to claim 3, wherein the sustained-release microsphere further contains a pamoate of the drug.

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

6. The sustained-release microsphere 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 microsphere according to any one of claims 1 to 3, wherein the initial release rate of the drug per day is less than 15%.

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

9. The sustained-release microsphere according to any one of claims 1 to 3, wherein the drug in the sustained-release microsphere is released over a period of 1 month to 6 months.

10. The sustained-release microsphere according to any one of claims 1 to 3, 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 copolymers of polyglycolide and polylactide.

11. The sustained-release microsphere according to any one of claims 1 to 3, which is for injection.

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

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

14. The pharmaceutical composition according to claim 12, which is an injection preparation.

15. (a) A drug; a step of dissolving pamoic acid and a biocompatible polymer in a dispersion phase solvent to produce a dispersion phase; (b) A step of adding the dispersion phase produced in the step (a) to an aqueous solution containing a surfactant as a continuous phase to produce an emulsion; (c) A step of extracting the dispersion phase solvent from the dispersion phase of the emulsion produced in the step (b) with the continuous phase, evaporating the extracted solvent to form microspheres, and producing a suspension containing the microspheres; and (d) A step of recovering the microspheres from the suspension of the step (c) to produce microspheres, At this time, the sodium content in the pamoic acid is 10% by weight or less based on the weight of the pamoic acid, and the method for producing the sustained-release microspheres according to any one of claims 1 to 3 is characterized in that.

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

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

18. The production method according to claim 15, which is carried out by adding pamoic acid to a solution of the drug dissolved in a dispersion phase solvent in the step (a).

19. The dispersion phase solvent includes dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycol formal, methyl isopropyl ketone, dimethyl carbonate, or a mixed solvent thereof, and the production method according to claim 15 is characterized in that.

20. The production method according to claim 15, wherein the solvent 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, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, and a mixed solvent thereof.

21. The production 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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