High-density lipoprotein, and delivery of drug to posterior segment of eye by ocular instillation of said cytophilic peptide-fused high-density lipoprotein

Patent metadata

Field	Value
Publication number	US-2018015171-A1
Application number	US-201515539276-A
Country	US
Kind code	A1
Filing date	Dec 25, 2015
Priority date	Dec 25, 2014
Publication date	Jan 18, 2018
Grant date	—

Abstract

The purpose of the present invention is to provide a novel system for the delivery of a drug to a posterior segment of the eye. The present invention relates to: a cytophilic peptide-fused high-density lipoprotein (cHDL) which can be used as a carrier for the delivery of a drug to a posterior segment of the eye; a method for producing the cytophilic peptide-fused high-density lipoprotein; a system of the delivery of a drug to a posterior segment of the eye, a pharmaceutical composition, and a system of the delivery of a drug to a posterior segment of the eye, each of which utilizes the cytophilic peptide-fused high-density lipoprotein; and a method for diagnosing, preventing or treating posterior ocular disease.

First claim

1 - 18 . (canceled)

19 . A cytophilic peptide-bound high-density lipoprotein, comprising a high-density lipoprotein and a cytophilic peptide,
wherein the cytophilic peptide is at least one kind selected from the group consisting of penetratin, polyarginine (R8), LL-37, transportan, Pep-1 and MTS.

20 . The cytophilic peptide-bound high-density lipoprotein according to claim 19 , wherein the high-density lipoprotein consists of apolipoprotein and at least one kind of phospholipid selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and di stearoylphosphatidylcholine (DSPC).

21 . The cytophilic peptide-bound high-density lipoprotein according to claim 19 , wherein the cytophilic peptide is penetratin or polyarginine (R8).

22 . The cytophilic peptide-bound high-density lipoprotein according to claim 19 , wherein the apolipoprotein is at least one kind selected from the group consisting of apolipoprotein A-I, apolipoprotein A-II, apolipoprotein C, apolipoprotein E, a partial fragment thereof, and a genetically modified apolipoprotein thereof.

23 . The cytophilic peptide-bound high-density lipoprotein according to claim 20 , wherein the cytophilic peptide-bound high-density lipoprotein consists of
a high-density lipoprotein consisting of apolipoprotein selected from the group consisting of apolipoprotein A-I and a genetically modified apolipoprotein thereof, and di stearoylphosphatidylcholine (DSPC), and penetratin.

24 . The cytophilic peptide-bound high-density lipoprotein according to claim 19 , having a particle size ranging from 10 to 20 nm in diameter.

25 . A complex comprising the high-density lipoprotein according to claim 19 , which further comprises at least one molecule of at least one of compound selected from a fluorescent labeling substance, a bioactive substance or a drug, per molecule of the high-density lipoprotein.

26 . A pharmaceutical composition for diagnosis, prevention or treatment of a disease of the posterior eye segment, comprising the high-density lipoprotein according to claim 19 , a drug effective for diagnosis, prevention or treatment of a disease of the posterior eye segment which is contained in the high-density lipoprotein, and a pharmaceutically acceptable additive.

27 . The pharmaceutical composition according to claim 26 , which is used for ocular instillation.

28 . The pharmaceutical composition for diagnosis, prevention or treatment of a disease of the posterior eye segment according to claim 26 , wherein the disease of the posterior eye segment is at least one disease selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, glaucoma, retinal artery or vein obstruction, retinal degenerative disease, degenerative myopia, macular hole, macular epithelium, retinal detachment, cataract, vitreous opacity and uveitis.

29 . The pharmaceutical composition for diagnosis, prevention or treatment of a disease of the posterior eye segment according to claim 26 ,
wherein the disease is at least one disease selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema and retinal artery or vein obstruction, and the drug is at least one compound selected from a compound which serves as a drug for suppressing choroidal neoangiogenesis or a diagnostic, prophylactic or therapeutic agent for a disease selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema and retinal artery or vein obstruction.

30 . The pharmaceutical composition according to claim 26 , wherein the drug is Pazopanib.

31 . The pharmaceutical composition according to claim 30 , which is used for ocular instillation for diagnosis, prevention or treatment of a disease of the posterior eye segment, which comprises
the cytophilic peptide-bound high-density lipoprotein consisting of
a high-density lipoprotein consisting of apolipoprotein selected from the group consisting of apolipoprotein A-I and a genetically modified apolipoprotein A-I thereof, and di stearoylphosphatidylcholine (DSPC), and
penetratin;
Pazopanib, and a pharmaceutically acceptable additive.

32 . The pharmaceutical composition which is used for ocular instillation for diagnosis, prevention or treatment of a disease of the posterior eye segment according to claim 31 , wherein the disease is at least one disease selected from the group consisting of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and retinal artery or vein obstruction.

33 . A method for diagnosis or treatment of a disease of the posterior eye segment, which comprises administering the pharmaceutical composition according to claim 26 to a subject.

34 . The method according to claim 33 , which is administered by an ocular instillation.

35 . A carrier for delivering a drug to the posterior eye segment comprising the cytophilic peptide-bound high-density lipoprotein according to claim 19 .

36 . The carrier for delivering a drug to the posterior eye segment according to claim 35 , which comprises the cytophilic peptide-bound high-density lipoprotein, wherein the cytophilic peptide-bound high-density lipoprotein consists of
a high-density lipoprotein consisting of apolipoprotein selected from the group consisting of apolipoprotein A-I and a genetically modified apolipoprotein A-I thereof, and di stearoylphosphatidylcholine (DSPC), and penetratin.

37 . A method for preparing the cytophilic peptide-bound high-density lipoprotein according to claim 19 , comprising
i) binding a cytophilic peptide to an apolipoprotein to obtain a bound protein; ii) a) blending a liposome containing a phospholipid, at least one compound selected from a fluorescent labeling substance, a bioactive substance or a drug, with the bound protein obtained in the above i) to produce a crude high-density lipoprotein having the cytophilic peptide bound thereto; or, b) mixing a cholate micelle obtained, with at least one compound selected from a bioactive substance or a drug to produce a crude high-density lipoprotein having the cytophilic peptide bound thereto; and iii) removing unreacted liposome, phospholipid micelle and/or apolipoprotein by an ultracentrifugation method to purify the crude high-density lipoprotein having the cytophilic peptide bound thereto.

38 . A method for preparing the complex according to claim 25 , comprising
i) binding a cytophilic peptide to an apolipoprotein to obtain a bound protein; ii) a) blending a liposome containing a phospholipid, at least one compound selected from a fluorescent labeling substance, a bioactive substance or a drug, with the bound protein obtained in the above i) to produce a crude high-density lipoprotein having the cytophilic peptide bound thereto; or, b) mixing a cholate micelle obtained, with at least one compound selected from a bioactive substance or a drug to produce a crude high-density lipoprotein having the cytophilic peptide bound thereto; and iii) removing unreacted liposome, phospholipid micelle and/or apolipoprotein by an ultracentrifugation method to purify the crude high-density lipoprotein having the cytophilic peptide bound thereto.

Assignees

• Univ Kyoto

Inventors

• Suda Kenji
• Murakami Tatsuya
• Yoshimura Nagahisa
• Gotoh Norimoto

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/10

  for accommodation disorders, e.g. myopia · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title