Solid dispersions of insoluble drug and preparation method thereof

Patent metadata

Field	Value
Publication number	US-2016346258-A1
Application number	US-201615231382-A
Country	US
Kind code	A1
Filing date	Aug 8, 2016
Priority date	Nov 7, 2012
Publication date	Dec 1, 2016
Grant date	—

Abstract

The present invention relates to a solid dispersion characterized in that it comprises carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as an active ingredient and a water-soluble polymer having a glass transition temperature lower than the melting point of the active ingredient as a carrier, and it is prepared via melt extrusion. The solid dispersion of the present invention remarkably increases the solubility and dissolution rate of the active ingredient which is an insoluble drug to efficiently improve the bioavailability when it is orally administered.

First claim

1 - 16 . (canceled)

17 . A method for treating a disease of central nervous system, comprising
administering to a patient in need thereof a pharmaceutically effective amount of a solid dispersion comprising:
carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, or a pharmaceutically acceptable salt or solvate thereof,
a water-soluble polymer, and
a plasticizer,
wherein the solid dispersion is prepared by melt extrusion, wherein the water-soluble polymer is selected from polyvinylpyrrolidone, hypromellose acetate succinate and a combination thereof, and wherein the plasticizer is selected from the group consisting of D-alpha-tocopheryl polyethylene glycol 1000 succinate, polyethylene glycol 400, and a combination thereof.

18 . The method of claim 17 , wherein the disease of central nervous system is a degenerative brain disease.

19 . The method of claim 17 , wherein the disease of central nervous system is a disease selected from the group consisting of ictus, Alzheimer's disease, Huntington's disease, Parkinson's disease, Pick's disease, Creutzfeld-Jacob disease, Parkinson-ALS-dementia complex of Guam, Wilson's disease, multiple sclerosis, progressive supranuclear palsy, neuropathic pain and bipolar disorder, corticobasal degeneration, schizophrenia, attention deficit hyperactivity disorder, dementia, amyotrophic lateral sclerosis, retinal disease, epilepsy, stroke, transient ischemic attacks, myocardial ischemia, myoischemia, ischemia caused by surgical technique associated with the extended stoppage of cerebral blood flow, head trauma, spinal cord trauma, hypoxia and depression.

20 . The method of claim 17 , wherein the solid dispersion is administered orally.

21 . The method of claim 17 , wherein the water-soluble polymer is contained in the amount of 30 wt % or more based on the total weight of the composition.

22 . The method of claim 17 , wherein the plasticizer is contained in the amount of 1 to 10 wt % or more based on the total weight of the composition.

23 . The method of claim 17 , wherein the solid dispersion comprises:
10 to 50 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, and 50 to 90 wt % of polyvinylpyrrolidone.

24 . The method of claim 17 , wherein the solid dispersion comprises:
10 to 50 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, 45 to 85 wt % of polyvinylpyrrolidone or hypromellose acetate succinate, and 1 to 5 wt % of D-alpha-tocopheryl polyethylene glycol 1000 succinate or polyethylene glycol 400.

25 . The method of claim 17 , wherein the solid dispersion comprises:
about 30 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, about 69 wt % of polyvinylpyrrolidone, and about 1 wt % of D-alpha-tocopheryl polyethylene glycol 1000 succinate.

26 . The method of claim 17 , wherein the solid dispersion comprises:
about 30 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, about 69 wt % of polyvinylpyrrolidone, and about 1 wt % of polyethylene glycol 400.

27 . The method of claim 17 , wherein the solid dispersion comprises:
about 15 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, about 84 wt % of hypromellose acetate succinate, and about 1 wt % of polyethylene glycol 400.

28 . The method of claim 17 , wherein the solid dispersion comprises:
about 50 wt % of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, about 40 wt % of hypromellose acetate succinate, and about 10 wt % of D-alpha-tocopheryl polyethylene glycol 1000 succinate.

29 . The method of claim 17 , wherein the solid dispersion melts at a temperature lower than the melting point of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester.

30 . A method for preparing a solid dispersion, comprising:
mixing carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester and a water-soluble polymer, and melt-extruding the mixture at a temperature lower than the melting point of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester.

31 . The method of claim 30 , wherein the mixture further comprises a plasticizer.

32 . The method of claim 31 , wherein the mixture is melted when it passes through four (4) or more heating blocks, wherein a temperature of the heating blocks is sequentially lowered.

33 . The method of claim 32 , wherein the heating blocks consist of a first, a second, a third, and a fourth heating blocks,
wherein a temperature of the first heating block is controlled to 160 to 145° C., wherein a temperature of the second heating block is controlled to 144 to 120° C., wherein a temperature of the third heating block is controlled to 119 to 80° C., and wherein a temperature of the fourth heating block is controlled to 79 to 70° C.

Assignees

• Sk Biopharmaceuticals Co Ltd

Inventors

• Baek Myoung Ki
• Pegan Augustin

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K9/146 Primary

  with organic macromolecular compounds · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title