Functionalized liposomes useful for the delivery of bioactive compounds

Patent metadata

Field	Value
Publication number	US-9744247-B2
Application number	US-201314411097-A
Country	US
Kind code	B2
Filing date	Jun 28, 2013
Priority date	Jun 29, 2012
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The invention relates to conjugates in which a sterol is functionalized by an ether bond with a water-soluble polymer to which a guiding ligand is bound. These conjugates improve the physico-chemical and delivery properties of their carrying vesicles, making these more stable, homogeneous and effective. A method for their preparation, a pharmaceutical composition containing said liposomes, and their therapeutic use are described as well.

First claim

The invention claimed is:

1. A conjugate, comprising:
i) a sterol;
ii) a chain of polyethylene glycol having a proximal end and a distal end wherein said chain of polyethylene glycol is covalently bound by its proximal end to i) via an alkyl ether bond; and
iii) a guiding ligand, capable of selectively binding to one or several receptors present in a target cell, said guiding ligand being covalently bound to the distal end of ii);
wherein the guiding ligand is a peptide.

2. The conjugate of claim 1 wherein the sterol is cholesterol.

3. The conjugate of claim 1 wherein the chain of polyethylene glycol has a number of repetitions from 2 to 10.

4. The conjugate of claim 1 wherein the guiding ligand comprises an RGD sequence.

5. The conjugate of claim 4 wherein the guiding ligand is the peptide of sequence SEQ ID NO: 1.

6. A liposome comprising the conjugate of claim 1 .

7. The liposome of claim 6 , having a monomodal particle size distribution.

8. The liposome of claim 7 wherein the average particle size is from 25 up to 500 nanometers, and the average Z potential in absolute value is from 20 up to 90 mV.

9. The liposome of claim 6 , further comprising a therapeutic agent.

10. The liposome of claim 9 wherein the therapeutic agent is α-galactosidase.

11. A method of delivering a therapeutic agent to a subject comprising administering the liposome of claim 9 to the subject.

12. A method of treatment comprising administering a therapeutically effective amount of the liposome of claim 9 together with pharmaceutically acceptable excipients or carriers, to a subject having Fabry disease.

13. A pharmaceutical composition comprising a therapeutically effective amount of the liposome of claim 9 , together with pharmaceutically acceptable excipients and/or carriers.

14. A method for the preparation of the conjugate of claim 1 comprising the following steps:
a) reacting a sterol with a sulfonyl halide in the presence of a base and a solvent to give the corresponding sulfonyl ester;
b) reacting the compound obtained in the step a) with a polyethylene glycol with a number of repetitions from 2 to 10 in the presence of a solvent;
c) activating the compound obtained in the step b) with disuccinimidyl carbonate; and
d) reacting the compound resulting from the step c) with a peptide comprising the RGD sequence in the presence of a base and a solvent.

15. A method for the preparation of the liposome of claim 6 comprising the following steps:
a) preparing an aqueous solution which may optionally include a surfactant;
b) preparing a solution comprising:
I) a conjugate, the conjugate comprising:
i) a sterol;
ii) a chain of polyethylene glycol having a proximal end and a distal end wherein said chain of polyethylene glycol is covalently bound by its proximal end to i) via an alkyl ether bond; and
iii) a guiding ligand, capable of selectively binding to one or several receptors present in a target cell, said guiding ligand being covalently bound to the distal end of ii); and

II) cholesterol and, optionally, a phospholipid dissolved in an organic solvent, where the organic solution is expanded with a compressed fluid;

c) optionally, adding a therapeutic agent either to the solution of step a), or to the solution of the step b) before expanding this solution; and
d) depressurizing the solution resulting from step b) over the resulting solution of step a).

16. A liposome comprising the conjugate of claim 4 .

17. The liposome of claim 16 , further comprising a therapeutic agent.

18. The liposome of claim 16 , wherein the therapeutic agent is α-galactosidase.

19. A method of treatment comprising administering therapeutically effective amount of the liposome of claim 17 , together with pharmaceutically acceptable excipients or carriers, to a subject having Fabry disease.

Assignees

• Consejo Superior De Investig Científicas (Csic)
• Fundació Parc Científic De Barcelona
• Centro De Investigación Biomédica En Red
• Fundació Inst De Recerca Biomèdica (Irb Barcelona)
• Univ Barcelona
• Fundació Hospital Univ Vall D'Hebron-Institut De Recerca
• UNIV AUTòNOMA DE BARCELONA
• Fundació Hospital Univ Vall D'Hebron—Institut De Recerca

Inventors

• Ventosa Rull Leonor
• Veciana Miró Jaume
• Cabrera Puig Ingrid
• Elizondo Saez De Vicuña Elisa
• Melgarejo Diaz Marta
• Royo Expósito Miriam
• Albericio Palomera Fernando
• Pulido Martinez Daniel
• Sala Vergés Santiago
• Corchero Nieto Jose Luis
• Schwartz Navarro Simón
• Abasolo Olaortua Ibane
• Villaverde Corrales Antonio Pedro

Classifications

• A61K47/646 Primary

  the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title