Formulations Useful in the Treatment of Proliferative Diseases Affecting the Respiratory Tract

Patent metadata

Field	Value
Publication number	US-2016263232-A1
Application number	US-201415029736-A
Country	US
Kind code	A1
Filing date	Oct 16, 2014
Priority date	Oct 16, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

The present application provides a pharmaceutical formulation comprising a folate receptor (FR)-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation, wherein the FR-targeting antineoplastic substance or composition is comprised in a nanoparticle and wherein the nanoparticles are comprised in microparticles, and its use in the treatment of a proliferative disease affecting at least part of the respiratory tract. The present application further provides a pharmaceutical formulation comprising an antineoplastic agent and a FR-targeting excipient, for use in the treatment of a proliferative disease affecting at least part of the respiratory tract.

First claim

1 . A pharmaceutical formulation comprising a folate receptor (FR)-targeting antineoplastic substance or composition, wherein the pharmaceutical formulation is configured for administration by inhalation, wherein the FR-targeting antineoplastic substance or composition is comprised in a nanoparticle and wherein the nanoparticles are comprised in microparticles.

2 . The pharmaceutical formulation according to claim 1 , which is formulated as a dry powder.

3 . The pharmaceutical formulation according to claim 1 , wherein the FR-targeting antineoplastic substance or composition comprises at least one antineoplastic agent and at least one FR-targeting excipient.

4 . The pharmaceutical formulation according to claim 3 , wherein the antineoplastic agent and the FR-targeting excipient are comprised in a nanoparticle.

5 . The pharmaceutical formulation according to claim 1 , wherein the FR-targeting is effected by at least one folate moiety.

6 . The pharmaceutical formulation according to claim 3 , wherein the FR-targeting excipient is a folate-polysaccharide conjugate comprising at least one folate moiety covalently linked to a polysaccharide or functionally-modified polysaccharide.

7 . The pharmaceutical formulation according to claim 6 , wherein the polysaccharide or functionally-modified polysaccharide is selected from chitosan or functionally-modified chitosan; N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan (HTC) and its salts; N-trimethyl chitosan (TMC) and its salts; N,O-carboxymethyl chitosan (N,O-CMC) and its salts; N-carboxymethyl chitosan (N-CMC) and its salts; N,N-carboxymethyl chitosan (N,N-CMC) and its salts; O-carboxymethyl chitosan (O-CMC) and its salts; hydrophobically-modified chitosan (HMC) and its salts; dextran or functionally-modified dextran; hydrophobically-modified dextran (HMD) and its salts; starch or functionally-modified starch; hydroxypropyl starch; amylose or functionally-modified amylose; amylopectin or functionally-modified amylopectin; cellulose or functionally-modified cellulose; methylcellulose and its salts; carboxymethylcellulose and its salts; hydroxyethylcellulose and its salts; ethylcellulose and its salts; hydroxyethylmethylcellulose and its salts; hydroxypropylcellulose and its salts; hypromellose and its salts; hypromellose acetate succinate; hypromellose phthalate; croscarmellose and its salts; chitin; cyclodextrin; dextrate; dextrin; maltodextrin; pullulan; or guar gum.

8 . The pharmaceutical formulation according to claim 6 , wherein the polysaccharide or functionally-modified polysaccharide is covalently bound to the folate moiety via a single bond or via a linker, wherein the linker comprises a polyether, ether, amine, polyamine, amino acid, peptide, a polypeptide, a carbohydrate, or a combination of two or more thereof.

9 . The pharmaceutical formulation according to claim 3 , wherein the FR-targeting excipient is a folate-polysaccharide conjugate comprising at least one unit selected from the group consisting of units of Formula XIb, XIc, XId, and XIe, or a stereoisomer, tautomer, salt, hydrate or solvate thereof, or any subgroup thereof, wherein

Y 1 is —X 2 —X 1 —X 3 , or a group selected from —OR 10 , —N(R 100 )R 101 , or —N + (R 100 )(R 101 )R 102 ,
Y 2 is —X 2 —X 1 —X 3 , or a group selected from —OR 20 , —N(R 200 )R 201 , or —N + (R 200 )(R 201 )R 202 ,
Y 3 is —X 2 —X 1 —X 3 , or a group selected from —OR 30 , —N(R 300 )R 301 , or —N + (R 300 )(R 301 )R 302 ,
R 1 is —OR 11 or —X 2 —X 1 —X 3 ,
R 2 is —OR 21 or —X 2 —X 1 —X 3 ,
R 3 is —OR 31 or —X 2 —X 1 —X 3 ,
R 4 is —OR 41 or —X 2 —X 1 —X 3 ,
R 34 is —OR 31 or —X 2 —X 1 —X 3 ,
R 43 is —OR 41 or —X 2 —X 1 —X 3 ,
R 44 is —OR 41 or —X 2 —X 1 —X 3 ,
R 53 is —OR 51 or —X 2 —X 1 —X 3 ,
R 54 is —OR 51 or —X 2 —X 1 —X 3 ,
wherein at least one of Y 1 , R 1 , or R 2 is —X 2 —X 1 —X 3 ;
wherein at least one of Y 2 , R 3 , or R 4 is —X 2 —X 1 —X 3 ;
wherein at least one of Y 3 , R 43 , or R 53 is —X 2 —X 1 —X 3 ;
wherein at least one of R 34 , R 44 , or R 54 is —X 2 —X 1 —X 3 ;
wherein
R 10 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, —C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 11 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 20 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 21 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 30 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 31 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alkylenecarbonyl, hydroxyC 1-6 alkyl, carboxylC 6-12 arylenecarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 6-10 aryl, each group being optionally substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy, wherein R 12 is selected from hydrogen or C 1-6 alkyl;
R 41 is selected from hydrogen, a mono-, oligo-, or poly-glycosyl moiety, or a group consisting of C 1-25 alkyl, C 1-25 alkylcarbonyl, C 2-25 alkenylcarbonyl, C 1-6 alkylene-CO—OR 12 , carboxylC 1-6 alky

Assignees

• Université Libre de Bruxelles
• Univ Bruxelles

Inventors

• Amighi Karim
• Rosiére Rémi
• Wauthoz Nathalie
• Gelbecke Michel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/5161

  Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin · CPC title

• A61K9/5089

  Processes · CPC title

• A61K47/6939

  the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin · CPC title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title