Disintegratable core/shell silica particles for encapsulating and releasing bioactive macromolecules

A pharmaceutical or cosmetic composition comprising:

• a nanoencapsulated bioactive macromolecule consisting essentially of:
• (a) a disintegratable nanocapsule having a core/shell structure, wherein the shell of the nanocapsule is made of hybrid organosilica material comprising a three-dimensional framework of Si—O bonds, wherein at least a subset of Si atoms in the framework is connected to at least another Si atom in the framework through a linker having the following structure:
• *—R1—L-R2—*;
• wherein:
• each occurrence of * denotes a point of attachment to a Si atom in the framework;
• L represents a responsively cleavable covalent bond, and
• R1 and R2 independently represent an optionally substituted C1-20 alkylenyl moiety, an optionally substituted C1-20 heteroalkylenyl moiety, an optionally substituted ethylenyl moiety, —C≡C— or an optionally substituted phenyl moiety, wherein the C1-20 alkylenyl, C1-20 heteroalkylenyl or ethylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6 alkyl, —NO2, —CN, isocyano, —ORP, —N(RP)2 wherein each occurrence of RP independently represents H or C1-6 alkyl;
• and
• (b) a bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule, wherein the bioactive macromolecule(s) within the nanocapsule is/are in a conformation to carry on supposed biological activity of the bioactive macromolecule(s);
• and
• a pharmaceutically or cosmetically acceptable carrier, wherein the nanocapsule inner core does not contain a micellar phase.

A unit dosage form for local delivery of a bioactive macromolecule to a tissue of a subject, the unit dosage form comprising, a therapeutically effective amount of a nanoencapsulated bioactive macromolecule or bioactive macromolecule cluster consisting essentially of:

• (a) a disintegratable nanocapsule having a core/shell structure, wherein the shell of the nanocapsule is made of hybrid organosilica material comprising a three-dimensional framework of Si—O bonds, wherein at least a subset of Si atoms in the framework is connected to at least another Si atom in the framework through a linker having the following structure:
• *—R1—L-R2—*;
• wherein:
• each occurrence of * denotes a point of attachment to a Si atom in the framework;
• L represents a responsively cleavable covalent bond, and
• R1 and R2 independently represent an optionally substituted C1-20 alkylenyl moiety, an optionally substituted C1-20 heteroalkylenyl moiety, an optionally substituted ethylenyl moiety, —C≡C— or an optionally substituted phenyl moiety, wherein the C1-20 alkylenyl, C1-20 heteroalkylenyl or ethylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6 alkyl, —NO2, —CN, isocyano, —ORP, —N(RP)2 wherein each occurrence of RP independently represents H or C1-6 alkyl;
• and
• (b) a bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule, wherein the bioactive macromolecule(s) within the nanocapsule is/are in a conformation to carry on supposed biological activity of the bioactive macromolecule(s);
• and
• wherein the nanocapsule inner core does not contain a micellar phase;
• and
• wherein the macromolecule is selected from the group consisting of proteins, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, gene fragments, a hormone, a growth factor, a protease, an extra-cellular matrix protein, an enzyme, an infectious viral protein, an antisense oligonucleotide, a dsRNA, a ribozyme and a DNAzyme.

A delivery system for enhancing the circulation time of a bioactive macromolecule of therapeutic interest in vivo, the system comprising a nanoencapsulated bioactive macromolecule or bioactive macromolecule cluster consisting essentially of:

• (a) a disintegratable nanocapsule having a core/shell structure, wherein the shell of the nanocapsule is made of hybrid organosilica material comprising a three-dimensional framework of Si—O bonds, wherein at least a subset of Si atoms in the framework is connected to at least another Si atom in the framework through a linker having the following structure:
• *—R1—L-R2—*;
• wherein:
• each occurrence of * denotes a point of attachment to a Si atom in the framework;
• L represents a responsively cleavable covalent bond, and R1 and R2 independently represent an optionally substituted C1-20 alkylenyl moiety, an optionally substituted C1-20 heteroalkylenyl moiety, an optionally substituted ethylenyl moiety, —C≡C— or an optionally substituted phenyl moiety, wherein the C1-20 alkylenyl, C1-20 heteroalkylenyl or ethylenyl moiety may bear one or more substituents selected from halogen or —OR where R may represent H or C1-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, C1-6 alkyl, —NO2, —CN, isocyano, —ORP, —N(RP)2 wherein each occurrence of RP independently represents H or C1-6 alkyl;
• and
• (b) a bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule, wherein the bioactive macromolecule(s) within the nanocapsule is/are in a conformation to carry on supposed biological activity of the bioactive macromolecule(s);
• and
• wherein the nanocapsule inner core does not contain a micellar phase;
• and
• wherein the thickness of the nanocapsule shell is adapted to deliver the encapsulated bioactive macromolecule of therapeutic interest into in vivo circulation at a controlled rate of release.