WO2023249465A1 - Formulation de microsphères à action prolongée contenant de l'entécavir, et son procédé de préparation - Google Patents

Formulation de microsphères à action prolongée contenant de l'entécavir, et son procédé de préparation Download PDF

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WO2023249465A1
WO2023249465A1 PCT/KR2023/008798 KR2023008798W WO2023249465A1 WO 2023249465 A1 WO2023249465 A1 WO 2023249465A1 KR 2023008798 W KR2023008798 W KR 2023008798W WO 2023249465 A1 WO2023249465 A1 WO 2023249465A1
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microspheres
entecavir
sustained
release
solvent
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Korean (ko)
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문성웅
김건호
이진우
설은영
이희용
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주식회사 지투지바이오
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to long-acting microspheres containing entecavir, pharmaceutical compositions containing the same, and methods for producing the same.
  • Entecavir is an antiviral medication used to treat hepatitis B virus (HBV) infection and is usually taken orally as a pill or solution. Hepatitis B accounts for 60-70% of chronic liver disease, and chronic hepatitis B often progresses to liver cirrhosis and liver cancer.
  • HBV hepatitis B virus
  • hepatitis B treatment If symptoms persist for more than 6 months or develop into chronic HBV, long-term treatment with hepatitis B treatment is required. In particular, if you stop taking the hepatitis B treatment or do not take it regularly, the level of the virus in the blood may increase, resulting in resistance or recurrence of hepatitis B.
  • prescriptions are usually given every 1-3 months for the first 1-2 years, and then every 6 months after HBV is stabilized.
  • approximately 70% of patients are treated to undetectable HBV after 1 year of treatment, and 90% of patients are treated to undetectable HBV after 3 years.
  • treatment of HBV infection requires long-term administration of entecavir preparations, but it has the disadvantage of poor compliance with daily oral administration, so there is a need for sustained-release preparations.
  • microsphere preparations using biocompatible polymers to develop sustained-release preparations have developed into a field of active research interest and clinical application.
  • the drug to be contained in the microspheres must be contained in a significantly high amount considering the administration period and dosage.
  • due to the characteristics of the drug it is difficult to encapsulate a sufficient amount of entecavir in biodegradable polymer microspheres.
  • a biocompatible polymer with a sufficiently long decomposition rate must be used.
  • the release period of microspheres containing a high content of entecavir is not long enough due to the high content of the drug, so the desired administration period cannot be met, or an 'initial burst' occurs in which the drug is released too quickly at the beginning of release.
  • various side effects may occur due to a rapid increase in blood concentration of the drug.
  • the content of the drug contained in the microspheres is lowered to solve this problem, the amount of the drug for treatment is not sufficient, so the amount of microspheres administered at one time is relatively increased excessively, reducing the patient's medication compliance. There is a problem that it may cause discomfort.
  • the present invention was designed to solve the problems of the prior art as described above, and provides a sustained-release microsphere preparation with stable drug release characteristics for a long period of time despite encapsulating a high content of entecavir in the microspheres, and a method for producing the same.
  • the purpose is to
  • the present invention used pamoic acid as a pharmaceutically usable salt or additive to improve the excessive initial release of high-dose drugs, and in particular, a sustained-release injectable drug with long-lasting drug effect by controlling the ratio of drug and pamoic acid contained in microspheres.
  • the purpose is to provide a method for manufacturing.
  • the active ingredient is entecavir or a pharmaceutically acceptable salt thereof; Sustained-release microspheres manufactured using pamoic acid and biocompatible polymers, wherein the molar ratio of the active ingredient: pamoic acid is 1:0.01 to 1:0.20 based on the free base form of the active ingredient, and the microspheres contain 4 as entecavir. It is possible to provide sustained-release microspheres having the characteristic of a daily cumulative release of less than 15%.
  • the molar ratio of the active ingredient: pamoic acid may be 1:0.01 to 1:0.20.
  • the microspheres may contain entecavir pamoate.
  • the content of entecavir in the microspheres may be 22% by weight or more based on the total weight of the microspheres.
  • the entecavir may be entecavir free base.
  • the daily release amount of the active ingredient may be less than 10%.
  • the AUC of 1-day release compared to the total cumulative release period of microspheres in vivo may be 0.1 to 10%.
  • the active ingredient in the sustained-release microspheres may be released for 1 to 12 months.
  • the sustained-release microspheres may have an average particle diameter (Dv50) of 10 um or more and 100 um or less.
  • the biocompatible polymer is poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and their mixture; And it may be at least one selected from the group consisting of polyglycolide, polylactide, and polyglycolide and polylactide copolymer.
  • the microspheres may be for injection.
  • a pharmaceutical composition for preventing, improving, or treating hepatitis B containing sustained-release microspheres can be provided.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be an injectable preparation.
  • entecavir or a pharmaceutically acceptable salt thereof as an active ingredient; Preparing a dispersed phase by dissolving pamoic acid and a biocompatible polymer in a solvent for the 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) extracting the solvent for the dispersed phase in the dispersed phase of the emulsion prepared in step (b) into a continuous phase and evaporating the extracted solvent to form microspheres to prepare a suspension containing microspheres; and (d) preparing microspheres by recovering the microspheres from the suspension of step (c), wherein the molar ratio of the active ingredient: pamoic acid is 1:0.01 to 1:0.20 based on the free base form of the active ingredient.
  • a method for producing sustained-release microspheres can be provided, which is characterized in that:
  • the content of the active ingredient may be 22% by weight or more based on the total weight of the microspheres.
  • the entecavir in step (a), may be in a free base form.
  • step (a) may be performed by adding pamoic acid to the solution of the dispersed phase solvent and the active ingredient mixed.
  • the solvent for the dispersion phase is dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycofurol, It may include methyl isopropyl ketone, dimethyl carbonate, or a mixed solvent thereof.
  • the solvent for the dispersion phase is used as the first solvent, and additionally, chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, enmethyl pyrrolidone, methyl ethyl ketone, acetic acid, and methyl alcohol.
  • ethyl alcohol, propyl alcohol, benzyl alcohol, and mixed solvents thereof may be further included as a second solvent.
  • the sustained-release microsphere preparation according to the present invention can maintain the concentration of the drug in the therapeutic range for a long time without excessive initial release of the drug, thereby maximizing the treatment effect by increasing the medication compliance of hepatitis B patients.
  • Figure 1a is a scanning electron microscope image of microspheres containing entecavir according to Comparative Example 1.
  • Figure 1b is a scanning electron microscope image of microspheres containing entecavir according to Example 1.
  • Figure 2A is an optical microscope image of microspheres containing entecavir according to Example 1.
  • Figure 2b is an optical microscope image of microspheres containing entecavir according to Comparative Example 2.
  • Figure 3 is a graph showing the in vitro drug release results of microspheres containing entecavir according to Comparative Example 1 and Example 2.
  • Figure 4 is a graph showing the change in entecavir blood concentration over time after administration of microspheres containing entecavir according to Comparative Example and Examples 1 and 2 to rats.
  • the present invention includes entecavir or a pharmaceutically acceptable salt thereof as an active ingredient; pamoic acid; and sustained-release microspheres manufactured using biocompatible polymers.
  • the present invention provides entecavir or a pharmaceutically acceptable salt thereof as an active ingredient; pamoic acid; and sustained-release microspheres prepared using biocompatible polymers, wherein the molar ratio of entecavir and pamoic acid is 1:0.01 to 1:0.20.
  • the molar ratio of entecavir and pamoic acid may be 1:0.05 to 1:0.1.
  • microspheres relate to sustained-release microspheres for injectable preparations, which are entecavir and have a cumulative release rate of less than 15% over 4 days.
  • microsphere preparations using biocompatible polymers to develop sustained-release preparations have developed into a field of active research interest and clinical application.
  • entecavir In order to manufacture a microsphere preparation capable of sustained release of entecavir over a long period of time, entecavir must be included in a fairly high amount considering the administration period and dosage of the drug to be contained in the microspheres.
  • entecavir has a problem in that it is difficult to encapsulate a sufficient amount of drug into biodegradable polymer microspheres.
  • a biocompatible polymer with a sufficiently long decomposition rate must be applied, and the release period of microspheres containing such entecavir is not sufficiently long due to the high drug content, so the desired administration period If the dose cannot be adjusted, or an 'initial burst' occurs in which the drug is released too quickly at the beginning of release, various side effects may occur due to a rapid increase in the blood concentration of the drug.
  • therapeutic index (therapeutic) drugs such as entecavir may occur. Drugs with a low index may cause serious problems.
  • the present inventors found that when pamoic acid was added together with the drug when manufacturing microspheres containing entecavir, the encapsulation rate of the drug could be significantly increased even if the decomposition rate was unexpectedly long enough or a biodegradable polymer with a particularly large molecular weight was not used. It was confirmed that even if a high content of drug is contained in the microspheres, the problem of rapid initial release of the drug and the problem of the drug not being released for a sufficient period of time can be resolved.
  • the polymer is preferably poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof; And it may be at least one selected from the group consisting of polyglycolide, polylactide, and polyglycolide and polylactide copolymer, but is not limited thereto.
  • Entecavir i.e. the compound 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]- as shown in Formula 1 below:
  • 1H-Purin-6(9H)-one is a nucleoside type antiviral agent.
  • the entecavir is a drug that exhibits the highest anti-HBV activity among anti-HBV (hepatitis B virus) drugs available on the market.
  • the anti-HBV activity of entecavir is known to be more than 100 and 30 times higher than that of lamivudine and adefovir dipivoxil, respectively. In addition, it has few side effects and is effective in treating patients who are resistant to lamivudine. Therefore, entecavir is used as a useful treatment for hepatitis B.
  • the active ingredient in the microspheres according to the present invention may be present in the form of a pharmaceutically acceptable salt of entecavir.
  • a pharmaceutically acceptable salt of entecavir As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of the compound according to the present invention. means any organic or inorganic addition salt.
  • the content of the biocompatible polymer may be 50% by weight or more, 50 to 76% by weight, 55 to 70% by weight, or 60 to 70% by weight relative to the total weight of the microspheres, but is not limited thereto.
  • the biocompatible polymers include poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof; And it may be at least one selected from the group consisting of polyglycolide, polylactide, and polyglycolide and polylactide copolymer, but is not limited thereto.
  • the biocompatible polymer according to the present invention may be a combination of poly(lactide-co-glycolide) and polylactide.
  • the molar ratio of lactide to glycolide in the copolymer is 40:60 to 90:10, 45:55 to 85:15, or 50:50 to 75. :25, for example 45:55, 50:50, 75:25, or 85:15.
  • the types of polymers exemplified above may be a combination or blend of different polymers, but the same type of polymers may be composed of polymers having different intrinsic viscosity and/or monomer ratios.
  • a combination e.g. a combination or blend of two or more poly(lactide-co-glycolides) with different intrinsic viscosity
  • the same type of polymer with different end groups e.g.
  • biocompatible polymers examples include RG 502H, RG 503H, RG 504H, RG 502, RG 503, RG 504 from the Resomer series of Evonik Rohm GmbH, 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, Cobion's PDL 02A, PDL 02, PDL 04 , PDL 05, PDLG 7502A, PDLG 7502, PDLG 7507 PDLG 7510, PLG 8218, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG 5010, PL 10, PL 18, PL 24, PL 32, PL 38, PDL 2 0 , PDL
  • the sustained-release microspheres may additionally contain entecavir pamoate.
  • the sustained-release microspheres according to the present invention may contain entecavir, a pamoate form of entecavir, and/or pamoic acid.
  • the entecavir content contained in the microspheres can be increased and the encapsulation rate can be increased.
  • the drug release rate can be improved (released evenly rather than concentrated at a specific time) and the usability or applicability of low-viscosity polymers can be increased.
  • high-viscosity polymers are used alone, it is difficult to manufacture microspheres, which may lower yields and make it difficult to maintain the emission concentration for a certain period of time.
  • this problem can be solved to make it easier to manufacture microspheres, increase yield, and have the advantage of easy control of release characteristics.
  • the entecavir may be entecavir free base.
  • the content of entecavir, as entecavir free base may be 22% by weight or more, 22 to 46% by weight, 22 to 40% by weight, or 25 to 40% by weight relative to the total weight of microspheres, but is limited thereto. That is not the case.
  • the content of pamoic acid may be 1% by weight or more, 1 to 18% by weight, 1.5 to 15% by weight, or 1.5 to 10% by weight based on the total weight of the microspheres, but is not limited thereto.
  • microspheres of the present invention have uniform particle distribution. Microspheres with uniform particle distribution have less variation during injection and can be administered in a more accurate amount compared to non-uniform microspheres.
  • the span value of the microspheres of the present invention is 1.2 or less.
  • span value used in the present invention is an indicator of the uniformity of the particle size of microspheres, and the span value means the value obtained by Equation 1 below.
  • Dv0.1 is the particle size corresponding to 10% of the volume % in the particle size distribution curve of the microspheres
  • Dv0.5 is the particle size corresponding to 50% of the volume % in the particle size distribution curve of the microspheres
  • Dv0.9 is the particle size distribution of the microspheres. It refers to the particle size corresponding to 90% of the volume% in the curve.
  • the average particle diameter (Dv50) of the microspheres according to the present invention may be 10 um or more, 15 um or more, 20 um or more, 30 um or more, or 10 to 100 um, but is preferably 40 to 90 um, 45 to 90 um. , 45 to 85um, 50 to 90um, 50 to 85um, or 55 to 85um, and more preferably 60 to 80um.
  • the drug in microspheres may have an initial daily release rate of less than 10%.
  • the initial release rate may be, but is not limited to, less than 9%, less than 8%, or less than 7%.
  • the AUC for one-day release of microspheres in vivo may be 0.1% to 10% of the total AUC.
  • the AUC upon daily release is 0.1% to 9%, 0.3% to 9%, 0.3% to 8%, 0.5% to 8%, 0.5% to 7%, 0.8% to 7%, 0.8% to 0.8%. It may be 6%, 1.0% to 6%, 1.0% to 5%, or 1.2% to 5%, and more preferably, the AUC upon daily release may be 1.5% to 4%, but is not limited thereto. .
  • entecavir or a pharmaceutically acceptable salt thereof in sustained-release microspheres according to the present invention may be released for 1 to 12 months.
  • sustained-release microspheres according to the present invention may be for injection.
  • the present invention relates to a pharmaceutical composition for preventing, improving, or treating hepatitis B, comprising the sustained-release microspheres.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be an injectable formulation.
  • the microspheres according to the present invention may be sustained-release microspheres containing 22% by weight or more of entecavir with a molar ratio of pamoic acid to entecavir of 0.01 to 0.20.
  • entecavir or a pharmaceutically acceptable salt thereof in sustained-release microspheres according to the present invention may be released for 1 to 12 months.
  • sustained-release microspheres according to the present invention may be for injection.
  • the present invention relates to a pharmaceutical composition for preventing, improving, or treating hepatitis B, comprising the sustained-release microspheres.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be an injectable formulation.
  • Sustained-release microspheres according to the present invention may be produced using, for example, a “solvent extraction and evaporation method,” but the production method is not limited thereto.
  • a method for producing sustained-release microspheres comprising the following steps:
  • step (b) preparing an emulsion by adding the dispersed phase prepared in step (a) to an aqueous solution containing a surfactant as a continuous phase;
  • step (c) extracting the solvent for the dispersed phase in the dispersed phase of the emulsion prepared in step (b) into a continuous phase and evaporating the extracted solvent to form microspheres to prepare a suspension containing microspheres;
  • step (d) recovering the microspheres from the suspension of step (c) to prepare microspheres
  • the molar ratio of the active ingredient: pamoic acid is 1:0.01 to 1:0.20 based on the free base form of the active ingredient.
  • the content of the active ingredient may be 22% by weight or more based on the total weight of the microspheres.
  • the content of the biocompatible polymer may be 50% by weight or more based on the total weight of the microspheres.
  • the content of pamoic acid may be 4% by weight or more based on the total weight of the microspheres.
  • the active ingredient in step (a), may be in the form of a free base, and the pamoic acid may be in the form of a powder.
  • step (a) may be performed by adding pamoic acid to a solution of the active ingredient dissolved in the solvent for the dispersion phase.
  • the solvent that is immiscible with water is contained in an amount of 10 to 55 (w/w)%, preferably 15 to 53 (w/w)%, more preferably 20 to 50%, based on the total weight of the solvent for the dispersed phase. (w/w)%, most preferably 25 to 50 (w/w)%, but is not limited thereto.
  • solvent for this dispersion phase there is no limitation to the solvent for this dispersion phase, but dichloromethane, ethyl acetate, ethyl formate, methyl acetate, methyl formate, butyl acetate, n-propyl acetate, isopropyl acetate, n-propyl formate, glycofurol, methyl isopropyl. It may contain one or more first solvents selected from the group consisting of ketones, dimethyl carbonate, and mixed solvents thereof.
  • the solvent for the dispersion phase includes the first solvent, chloroform, acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, enmethyl pyrrolidone, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, and One or more types selected from the group consisting of mixed solvents thereof may be further included as a second solvent.
  • the method of homogeneously 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, in-line mixer, membrane emulsion method, microfluidics emulsion method, etc. .
  • a high-speed stirrer or in-line mixer it is difficult to obtain a uniform emulsion, so it is desirable to perform an additional sieving process between steps (c) and (d), which will be described later.
  • It is more preferable to use the membrane emulsion method and the microfluidics emulsion method because an emulsion of uniform size can be obtained and no additional sieving process is required between steps (c) and (d), which will be described later.
  • the type of surfactant used in step (b) is not particularly limited, and any dispersed phase can be used as long as it can help form a stable liquid droplet dispersed phase within the continuous phase.
  • the surfactant is preferably a group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, and mixtures thereof. It can be selected from, and most preferably polyvinyl alcohol can be used.
  • the continuous phase may be used at 5,000% (v/w) to 50,000% (v/w) compared to the dispersed phase solvent, but is not limited thereto.
  • the content of the surfactant in the continuous phase containing the surfactant is 0.01 w/v% to 20 w/v%, preferably 0.1 w/v, based on the total volume of the continuous phase containing the surfactant. v% to 5 w/v%. If the surfactant content is less than 0.01 w/v%, a dispersed phase or emulsion in the form of droplets may not be formed in the continuous phase, and if the surfactant content exceeds 20 w/v%, an excessive amount of surfactant may be present. Because of this, it may be difficult to remove the surfactant after fine particles are formed in the continuous phase.
  • Water can be used as the solvent for the continuous phase used in step (b), and in order to control the extraction rate of the organic solvent from the dispersed phase in the emulsion state, one selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate. Water containing some or more of these species can be used.
  • step (c) the emulsion comprising 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 can be extracted from the dispersed phase in the form of droplets into the continuous phase. Some of the organic solvent extracted in the continuous phase may evaporate from the surface. As the organic solvent is extracted from the droplet-shaped dispersed phase, the droplet-shaped dispersed phase may solidify to form microspheres.
  • heat may be applied to the temperature of the continuous phase for a certain period of time.
  • step (d) the method of recovering microspheres according to the present invention may be performed using various known techniques, for example, methods such as filtration or centrifugation may be used.
  • the remaining surfactant can be removed through filtration and washing, and the microspheres can be recovered by filtering again.
  • the washing step to remove the remaining surfactant can typically be performed using water, and the washing step can be repeated several times.
  • uniform microspheres can be obtained by additionally using a sieving process between steps (c) and (d). You can.
  • the sieving process can be performed using known techniques, and microspheres of uniform size can be obtained by filtering out microspheres of small and large particles using sieve membranes of different sizes.
  • step (d) or after the filtration and washing steps the obtained microspheres are dried using a conventional drying method to obtain finally dried microspheres.
  • the dispersed phase was composed of 0.715 g of biocompatible polymers ResomerRG 858S (manufacturer: Evonik, Germany) and ResomerR 203H (manufacturer: Evonik, Germany) mixed in a 7:3 ratio, and 3.7 g of dichloromethane (manufacturer: J.T Baker, USA). Add and stir until sufficiently dissolved. Afterwards, 4.2 g of dimethyl sulfoxide (manufacturer: J.T Baker, USA) was added to 0.25 g of entecavir (manufacturer: Kyungbo Pharmaceutical, Korea) and 0.035 g of pamoic acid, stirred to dissolve, and then the two solutions were mixed and used.
  • a 0.5% polyvinyl alcohol aqueous solution with 5% w/w NaCl added was used as the continuous phase.
  • An emulsion in which biodegradable polymers containing entecavir were dispersed was prepared by injecting the dispersed phase into the continuous phase, and immediately after preparation it was recovered through a sieve and thoroughly washed. Afterwards, the suspension was transferred back to the preparation container, stirred, and maintained at 45°C for 3 hours to remove the remaining organic solvent. Afterwards, the temperature of the microparticle suspension was lowered to room temperature, filtered, residual polyvinyl alcohol was removed with tertiary distilled water, and freeze-dried.
  • the above manufacturing method shows the manufacturing method of Example 1, and for the remaining examples, the same manufacturing method as that of Example 1 was used, but the polymer type, amount used, amount of drug used, amount of pamoic acid used, solvent used, The amount of solvent used in the dispersed phase and the amount used in the continuous phase were as shown in Table 1.
  • Table 1 the molar ratio of drug:pamoic acid is shown based on the free base form of the drug.
  • the dispersed phase is a mixture of biocompatible polymers ResomerRG 858S (manufacturer: Evonik, Germany) and ResomerR 502H (manufacturer: Evonik, Germany) in a 7:3 ratio, and dichloromethane (manufacturer: JT Baker, USA) is added until sufficiently dissolved. It was stirred. Afterwards, dimethyl sulfoxide (manufacturer: JT Baker, USA) was added to entecavir (manufacturer: Kyungbo Pharmaceutical, Korea) and stirred to dissolve, and then the two solutions were mixed and used. A 0.5 (w/w)% polyvinyl alcohol aqueous solution was used as the continuous phase.
  • An emulsion in which biodegradable polymers containing entecavir were dispersed was prepared by injecting the dispersed phase into the continuous phase, and immediately after preparation it was recovered through a sieve and thoroughly washed. Afterwards, the suspension was transferred back to the preparation container, stirred, and maintained at 45°C for 3 hours to remove the remaining organic solvent. Afterwards, the temperature of the microparticle suspension was lowered to room temperature, filtered, residual polyvinyl alcohol was removed with tertiary distilled water, and freeze-dried.
  • the manufacturing method shows the manufacturing method of Comparative Example 1, and in the case of Comparative Example 2, the same manufacturing method as Comparative Example 1 was used, but the polymer type, amount used, amount of drug used, amount of pamoic acid used, solvent used, and dispersed phase were used.
  • the amount of solvent and continuous phase used is as shown in Table 1.
  • Table 1 the molar ratio of drug:pamoic acid is shown based on the free base form of the drug.
  • the dispersed phase is a mixture of biocompatible polymers ResomerRG 858S (manufacturer: Evonik, Germany) and ResomerR 202H (manufacturer: Evonik, Germany) in a 7:3 ratio, and dichloromethane (manufacturer: JT Baker, USA) is added until sufficiently dissolved. It was stirred. Afterwards, entecavir (manufacturer: Kyungbo Pharmaceutical, Korea) and dimethyl sulfoxide (manufacturer: JT Baker, USA) were added to pamoic acid, stirred to dissolve, and then the two solutions were mixed and used.
  • the continuous phase used was a 0.5% polyvinyl alcohol aqueous solution to which 5% w/w NaCl was added.
  • An emulsion in which biodegradable polymers containing entecavir were dispersed was prepared by injecting the dispersed phase into the continuous phase, and immediately after preparation it was recovered through a sieve and thoroughly washed. Afterwards, the suspension was transferred back to the preparation container, stirred, and maintained at 45°C for 3 hours to remove the remaining organic solvent. Afterwards, the temperature of the microparticle suspension was lowered to room temperature, filtered, residual polyvinyl alcohol was removed with tertiary distilled water, and freeze-dried.
  • the manufacturing method shows the manufacturing method of Comparative Example 3, and in the case of Comparative Example 4, it was prepared in the same manner as Comparative Example 3, except that the type of polymer, amount used, amount of drug used, amount of pamoic acid used, solvent used, and amount of dispersion phase solvent were used. and the amount of continuous phase used was as shown in Table 1.
  • Table 1 the molar ratio of drug:pamoic acid is shown based on the free base form of the drug.
  • the dispersed phase is a polymer mixed with biocompatible polymers Purac 7510 (manufacturer: Corbion, Netherlands) and ResomeR 202H (manufacturer: Evonik, Germany) in an 8:2 ratio, and dichloromethane (manufacturer: J.T Baker, USA) is added and fully dissolved. It was stirred until. Afterwards, dimethyl sulfoxide (manufacturer: J.T Baker, USA) was added to entecavir (manufacturer: Kyungbo Pharmaceutical, Korea) and pamoic acid, stirred to dissolve, and then the two solutions were mixed and used. A 0.5% polyvinyl alcohol aqueous solution with 5% w/w NaCl added was used as the continuous phase.
  • An emulsion in which biodegradable polymers containing entecavir were dispersed was prepared by injecting the dispersed phase into the continuous phase, and immediately after preparation it was recovered through a sieve and thoroughly washed. Afterwards, the suspension was transferred back to the preparation container, stirred, and maintained at 45°C for 3 hours to remove the remaining organic solvent. Afterwards, the temperature of the microparticle suspension was lowered to room temperature, filtered, residual polyvinyl alcohol was removed with tertiary distilled water, and freeze-dried.
  • the above manufacturing method shows the manufacturing method of Example 14, and for the remaining manufacturing examples, in the manufacturing method of Example 14, the type of polymer, amount used, amount of drug used, amount of pamoic acid used, solvent used, amount of dispersed phase solvent used, and continuous
  • the amount of phase used is as shown in Table 1.
  • Table 1 the molar ratio of drug:pamoic acid is shown based on the free base form of the drug.
  • Example 1 RG858S:203H(7:3) 0.25 0.035 1:0.1 0.715 1:1.13 7.90 1,000
  • Example 2 RG858S:203H(7:3) 0.30 0.042 1:0.1 0.658 1:1.13 7.90 1,000
  • Example 3 RG858S:202H(5:5) 0.25 0.035 1:0.1 0.715 1:1.40 6.96
  • Example 4 RG858S:203H(5:5) 0.25 0.035 1:0.1 0.715 1:1.42 7.01 1,000
  • Example 5 7510:PDL02A(8:2) 0.60 0.084 1:0.1 1.316 1:1.74 12.78 1,500
  • Example 6 7510:PDL04A(8:2) 0.60 0.084 1:0.1 1.316 1:1.54 13.37 1,500
  • Example 7 7510 0.30 0.042 1:0.1:0.1 0.715 1:1.13 7.90
  • Example 2 RG858S:203H(7:3) 0.30 0.042 1:0.1 0.658 1:1.13 7.90 1,000
  • Example 3
  • Comparative Example 1 which is a microsphere containing entecavir without adding pamoic acid
  • the size of the microspheres is not constant and many of the microspheres do not maintain a spherical shape, whereas pamoic acid is added.
  • the added entecavir microspheres of Example 1 it was confirmed that the spherical shape was well maintained.
  • Example 1 Optical microscopy was observed to analyze the morphological characteristics of the microspheres prepared in Example 1 and Comparative Example 3, and the results are shown in Figures 2A and 2B.
  • the microspheres according to Example 1 which are microspheres containing entecavir by adding pamoic acid, have a constant size and the microspheres maintain a spherical shape, while the addition ratio of pamoic acid It was confirmed that in the case of microspheres containing entecavir according to Comparative Example 3 prepared by increasing the microspheres, the microspheres were not formed properly.
  • Example 1 division Drug content (%w/w) Drug inclusion rate (%) Microsphere size (D50, ⁇ m) Span value Example 1 24.4 97.6 64.06 1.13 Example 2 28.1 93.7 68.05 1.05 Comparative Example 1 22.2 74.0 75.91 1.07
  • the drug encapsulation rates in the sustained-release microspheres containing entecavir according to Examples 1 and 2 were 97.6% and 93.7%, respectively, showing a considerably high encapsulation rate, while the microspheres according to Comparative Example 1
  • the drug encapsulation rate was quite low at 74.0%.
  • Example 1 0.00 0.3
  • Example 2 1.11 2.1
  • Example 3 0.6
  • Example 4 0.4
  • Example 7 1.5
  • Example 8 3.6
  • Example 9 2.2 4.7
  • Example 10 4.6 9.1 Comparative Example 1 10.9 -
  • Figure 3 is a graph showing the initial release rate (%) over time for Example 2 and Comparative Example 1.
  • Comparative Example 1 showed a fairly high level of initial release with a drug release rate of 10.9%, while Example 2 did not show an initial burst. Based on these results, it was confirmed that when pamoic acid was added when preparing microspheres containing entecavir, the drug was slowly released over a long period of time without excessive initial release, which was desirable in terms of drug release.
  • the concentration of entecavir in the blood was measured over time after administration to rats.
  • Microspheres were measured according to the set entecavir administration dose, suspended in 0.3 mL dispersion solvent, and then injected subcutaneously into SD rats.
  • Blood collection from the rats was performed at 0.04 days, 0.25 days, 1 day, 4 days, 7 days, 10 days, 14 days, 17 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days after administration. This was performed after 63, 70, 77, 84, 91, 98, 105, and 112 days, respectively.
  • Example 1 division Day 1 AUC % of drug Example 1 0.4 Example 2 3.7 Example 3 2.7 Example 4 1.6 Example 5 1.9 Example 6 1.5 Example 7 1.3 Example 8 3.2 Example 9 2.6 Example 10 3.7 Example 11 0.3 Example 12 1.2 Example 13 0.4 Comparative Example 1 16.3

Abstract

L'invention concerne : des microsphères à libération prolongée contenant de l'entécavir, de l'acide pamoïque et un polymère biocompatible ; une composition pharmaceutique contenant les microsphères à libération prolongée, pour prévenir, atténuer ou traiter l'hépatite B ; et un procédé de préparation des microsphères à libération prolongée.
PCT/KR2023/008798 2022-06-23 2023-06-23 Formulation de microsphères à action prolongée contenant de l'entécavir, et son procédé de préparation WO2023249465A1 (fr)

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Citations (5)

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KR20130100464A (ko) * 2012-03-02 2013-09-11 동국제약 주식회사 엔테카비어 미립구 및 이를 포함하는 비경구투여용 약제학적 조성물
KR20140086722A (ko) * 2012-12-28 2014-07-08 주식회사 종근당 양이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물
KR20150100576A (ko) * 2014-02-25 2015-09-02 동아에스티 주식회사 용법이 개선된 엔테카비어를 함유하는 약학적 조성물
KR20210007924A (ko) * 2019-07-12 2021-01-20 주식회사 지투지바이오 리바스티그민을 포함하는 장기지속형 제제 및 이의 제조방법
WO2022042641A1 (fr) * 2020-08-26 2022-03-03 上海博志研新药物技术有限公司 Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130100464A (ko) * 2012-03-02 2013-09-11 동국제약 주식회사 엔테카비어 미립구 및 이를 포함하는 비경구투여용 약제학적 조성물
KR20140086722A (ko) * 2012-12-28 2014-07-08 주식회사 종근당 양이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물
KR20150100576A (ko) * 2014-02-25 2015-09-02 동아에스티 주식회사 용법이 개선된 엔테카비어를 함유하는 약학적 조성물
KR20210007924A (ko) * 2019-07-12 2021-01-20 주식회사 지투지바이오 리바스티그민을 포함하는 장기지속형 제제 및 이의 제조방법
WO2022042641A1 (fr) * 2020-08-26 2022-03-03 上海博志研新药物技术有限公司 Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée

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