A sustained-release microgranule preparation containing caglirintide or a pharmaceutically acceptable salt thereof, and a method for producing the same.

Abstract

The present invention relates to a pharmaceutical composition comprising caglilintide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and sustained-release microspheres consisting of a biodegradable polymer, which eliminates the rapid initial release of the drug, contains a high drug content relative to its particle size, has high bioavailability, minimizes patient discomfort and inflammatory responses that may occur when administered to the human body, and is useful for the prevention or treatment of diabetes, beta-cell dysfunction, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, and Alzheimer's disease.

Claims

1. The active ingredients include (i) cadrylintide or a pharmaceutically acceptable salt thereof, or (ii) cadrylintide or a pharmaceutically acceptable salt thereof and semaglutide or a pharmaceutically acceptable salt thereof; Initial release inhibitors; and It contains sustained-release microspheres containing biodegradable polymers, The kaglirintide or a pharmaceutically acceptable salt thereof described in (i) above is included in an amount of 8% by weight or more of kaglirintide based on the total weight of the microglobules. The cadrylintide or a pharmaceutically acceptable salt thereof described in (ii) above is included in an amount of 4% by weight or more of cadrylintide based on the total weight of the microglobules. A pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, beta-cell dysfunction, obesity, or non-alcoholic steatohepatitis or Alzheimer's disease, comprising the initial release inhibitor in an amount of 10 to 2,000 ppm.

2. Sustained-release microspheres containing caglilintide or a pharmaceutically acceptable salt thereof as an active ingredient, an initial release inhibitor, and a biodegradable polymer; and The active ingredient is a combination of semaglutide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and sustained-release microspheres consisting of a biodegradable polymer. The aforementioned kaglirintide or a pharmaceutically acceptable salt thereof is included in an amount of 8% by weight or more of kaglirintide relative to the total weight of the microglobules. A pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, beta-cell dysfunction, obesity, or non-alcoholic steatohepatitis or Alzheimer's disease, comprising the initial release inhibitor in an amount of 10 to 2,000 ppm.

3. The pharmaceutical composition according to claim 1 or 2, wherein the release rate of kaglirintide or a pharmaceutically acceptable salt thereof from the microgranules is less than 20% within 24 hours when administered in vivo.

4. The pharmaceutical composition according to claim 1 or claim 2, wherein the release rate of kaglirintide or a pharmaceutically acceptable salt thereof from the microgranules is less than 15% within 24 hours when administered in vivo.

5. The pharmaceutical composition according to claim 1 or claim 2, wherein the release rate of kaglirintide or a pharmaceutically acceptable salt thereof from the microgranules is less than 10% within 24 hours when administered in vivo.

6. The biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide, PLGA) which is a copolymer of lactide and glycoside, polydioxanone (Polydioxanone), polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyaminoacid, polyalkylcyanoacrylate Polymers selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); copolymers or simple mixtures thereof of two or more of these; copolymers of the polymer with polyethylene glycol (PEG);The pharmaceutical composition according to claim 1 or claim 2, comprising one or more selected from the group consisting of the polymer or copolymer and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

7. The pharmaceutical composition according to claim 1 or 2, wherein the initial release inhibitor is one or more substances selected from alkali metals, alkaline earth metals, or ammonium phosphate salts, hydroxide salts, phosphine salts, phosphite salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrate salts, felicyanide salts, and nitride salts.

8. The pharmaceutical composition according to claim 1 or claim 2, wherein the average particle size of the microparticles containing the caglirintide or a pharmaceutically acceptable salt thereof and an initial release inhibitor is 5 μm to 100 μm.

9. The pharmaceutical composition according to claim 1 or claim 2, wherein the weight of microglobules containing the caglirintide or a pharmaceutically acceptable salt thereof and an initial release inhibitor is 20 to 1000 mg.

10. The pharmaceutical composition according to claim 1 or claim 2, wherein the intrinsic viscosity of the biodegradable polymer is 0.16 dL / g to 1.7 dL / g.

11. The pharmaceutical composition according to claim 1 or claim 2, wherein the microparticles further comprise one or more release regulators selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid.

12. The pharmaceutical composition according to claim 1, wherein the semaglutide or a pharmaceutically acceptable salt thereof described in (ii) is present in an amount of 4% by weight or more as semaglutide with respect to the total weight of the microspheres.

13. The pharmaceutical composition according to claim 2, wherein the semaglutide or a pharmaceutically acceptable salt thereof is present in an amount of 8% by weight or more as semaglutide with respect to the total weight of the microglobules.

14. (a) A step of preparing an oil phase (O phase) as a dispersed phase, in which (i) cadrylintide or a pharmaceutically acceptable salt thereof or (ii) cadrylintide or a pharmaceutically acceptable salt thereof and semaglutide or a pharmaceutically acceptable salt thereof, and one or more biodegradable polymers are dissolved in an organic solvent as the active ingredient; (b) A step of preparing a continuous phase (W phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a) above to produce a dispersed phase in an emulsion state; (c) A step of extracting and evaporating an organic solvent from the emulsion-like dispersed phase produced in step (b) as a continuous phase (W phase) to form microspheres; and A method for producing microspheres in an O / W emulsion containing an active ingredient, an initial release inhibitor, and a biodegradable polymer, comprising the step of (d) recovering the microspheres.

15. (a') A step of preparing a primary aqueous phase (W1 phase) by dissolving (i) cadrylintide or a pharmaceutically acceptable salt thereof or (ii) cadrylintide or a pharmaceutically acceptable salt thereof and semaglutide or a pharmaceutically acceptable salt thereof in an aqueous solution as an active ingredient, and preparing an oil phase (O phase) by dissolving one or more biodegradable polymers in an organic solvent, and then preparing a primary W1 / O emulsion as a dispersed phase by mixing the aqueous phase (W1 phase) and the oil phase (O phase); (b') A step of preparing a continuous phase (W2 phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a') above to produce a dispersed phase in a secondary W1 / O / W2 emulsion state; (c') A step of extracting and / or evaporating an organic solvent from the dispersed phase in the secondary W1 / O / W2 emulsion state of step (b') as a continuous phase (W2 phase) to form microspheres; and A method for producing microspheres in a W / O / W emulsion containing an active ingredient, an initial release inhibitor, and a biodegradable polymer, comprising the step of (d') recovering the microspheres.

16. The biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone (Polydioxanone), polycaprolactone (PCL), polylactide-co-glycolide-cocaprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyaminoacid, polyalkylcyanoacrylate Polymers selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); copolymers or simple mixtures thereof of two or more of these; copolymers of the polymer with polyethylene glycol (PEG);The manufacturing method according to claim 14 or claim 15, wherein the material is one or more selected from the group consisting of the polymer or copolymer and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

17. The method for producing a product according to claim 14 or 15, wherein the dispersed phase of step (a) or (a') further comprises one or more release regulators selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, hydroxynaphthoic acid, napadisylic acid, and pamoic acid.

18. The production method according to claim 14 or claim 15, wherein the organic solvent in step (a) or (a') is one or more organic solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol.

19. The manufacturing method according to claim 14 or claim 15, wherein the surfactant in step (b) or (b') is polyvinyl alcohol.

20. The manufacturing method according to claim 14 or 15, wherein the continuous phase of step (b) or (b') further comprises one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.

21. The manufacturing method according to claim 14 or claim 15, wherein the continuous phase of step (b) is used by adding an initial release inhibitor to an aqueous solution containing a surfactant so that the final concentration is 0.1 to 5.0 (w / v)%.

22. The manufacturing method according to claim, claim 14, or claim 15, wherein the initial release inhibitor is one or more selected from the group consisting of two or more alkali metal phosphate salts, one or more alkali metal bicarbonate salts, and one or more alkali metal carbonate salts.

23. The manufacturing method according to claim 14 or claim 15, wherein the pH of the continuous phase in step (b) or (b') is 7 or higher.

24. The manufacturing method according to claim 14 or claim 15, wherein when the manufactured sustained-release microglobulins are administered in vivo, the release rate of caglirintide or a pharmaceutically acceptable salt thereof within 24 hours is less than 15%.

25. The manufacturing method according to claim 14 or claim 15, wherein when the manufactured sustained-release microglobulins are administered in vivo, the release rate of caglirintide or a pharmaceutically acceptable salt thereof within 24 hours is less than 10%.

Images