Multistage delivery of active agents

• US 10,143,658 B2
• Filed: 05/29/2015
• Issued: 12/04/2018
• Est. Priority Date: 08/08/2006
• Status: Active Grant

• Current Assignee: Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: The Ohio State University Research Foundation, Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Ferrari, Mauro, Tasciotti, Ennio, Sakamoto, Jason
• Primary Examiner(s): EPPS -SMITH, JANET L
• Application Number:
  US14/725,570
• Publication Number:
  US 20160051481A1
• Time in Patent Office: 1,285 Days
• Field of Search: 514 34, 514 44 A, 424450, 424489
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/51 Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00

Abstract

Multistage delivery vehicles are disclosed which include a first stage particle and a second stage particle. The first stage particle is a micro or nanoparticle that contains the second stage particle. The second stage particle includes an active agent, such as a therapeutic agent or an imaging agent. The multistage delivery vehicle allows sequential overcoming or bypassing of biological barriers. The multistage delivery vehicle is administered as a part of a composition that includes a plurality of the vehicles. Methods of making the multistage delivery vehicles are also provided.

Claims

1. A multistage delivery composition comprising:

a first stage particle containing second stage particle, wherein the first stage particle, comprises;

(i) a body;

(ii) at least one surface with a surface charge; and

(iii) a plurality of nanoscale reservoirs in the body of the first stage particle,

wherein each reservoir is connected to at least one surface of the body through at least one channel,

wherein the at least one channel is in the form of a pore open to the surface,

wherein at least one of the plurality of the nanoscale reservoirs contains the second stage particle in the pore open to the surface, and wherein;

the first stage particle is biodegradable and has a selected non-spherical shape;

the first stage particle is a porous micro or nanoparticle with a size from about 100 nm to about 5 microns;

the second stage particle encapsulates a therapeutic agent;

the first stage particle is configured to overcome a first biological barrier; and

the second stage particle is configured to overcome a second biological barrier, wherein the first stage particle and the second stage particle are configured to sequentially overcome the first biological barrier and second biological barrier respectively.

2. The multistage delivery composition of claim 1 wherein the first stage particle is configured to release the second stage particle for delivery of the therapeutic agent.

3. The multistage delivery composition of claim 1 wherein the first stage particle is configured to release the second stage particle for delivery of the therapeutic agent via diffusion of the second stage particle through the channels in the first stage particle.

4. The multistage delivery composition of claim 1 wherein the first stage particle is configured to release the second stage particle for delivery of the therapeutic agent via degradation or erosion of the body the first stage particle.

5. The multistage delivery composition of claim 1 wherein the first biological barrier and the second biological barrier are each independently selected from the group of biological barriers consisting of a hemo-rheology barrier, a reticulo-endothelial system barrier, an endothelial barrier, a blood brain barrier, a tumor-associated osmotic interstitial pressure barrier, an ionic and molecular pump barrier, a cell membrane barrier, an enzymatic degradation barrier, a nuclear membrane barrier, and any combination of thereof.

6. The multistage delivery composition of claim 1 wherein the first stage particle comprises a chemical targeting moiety disposed on the surface of the first stage particle, wherein said chemical targeting moiety comprises at least one moiety selected from the group consisting of dendrimer, an aptamer, an antibody, a biomolecule and any combination thereof.

7. The multistage delivery composition of claim 1 wherein at least one of the plurality of nanoscale reservoirs contains at least one additional agent.

8. The composition of claim 7, wherein the at least one additional agent comprises at least one penetration enhancer, at least one additional active agent, or at least one targeting moiety.

9. The composition of claim 8, wherein the at least one penetration enhancer is selected from the group consisting of a basement membrane permeation enhancer, a tight junction protein (tjp) permeation enhancer and any combination thereof.

10. The composition of claim 1, wherein the first stage particle is configured to release the second stage particle in response to an external stimulus.

24. The multistage delivery composition of claim 1, wherein the second stage particle comprises a plurality of second stage particles stacked within the pore open to the surface.

27. The multistage delivery composition of claim 1, wherein the second stage particle comprises at least one constituent selected from the group consisting of a liposome, a micelle, an ethosome, a carbon nanotube, a fullerene nanoparticle, a metal nanoparticle, a semiconductor nanoparticle, a polymer nanoparticle, an oxide nanoparticle, a viral particle, a polyionic particle and a ceramic particle.

11. A method comprising administering to a subject a composition comprising:

a first stage particle containing a second stage particle, wherein the first stage particle comprises;

(i) a body;

(ii) at least one surface with a surface charge; and

(iii) a plurality of nanoscale reservoirs in the body of the first stage particle,

wherein each reservoir is connected to at least one surface of the body through at least one channel,

wherein the at least one channel is in the form of a pore open to the surface,

wherein at least one of the plurality of the nanoscale reservoirs contains the second stage particle in the pore open to the surface, and wherein;

the first stage particle is biodegradable and has a selected non-spherical shape;

the first stage particle is a porous micro or nanoparticle with a size from about 100 nm to about 5 microns;

the second stage particle encapsulates a therapeutic agent;

the first stage particle is configured to overcome a first biological barrier; and

the second stage particle is configured to overcome a second biological barrier, wherein the first stage particle and the second stage particle are configured to sequentially overcome the first biological barrier and second biological barrier respectively.

12. The method of claim 11 wherein the first stage particle is configured to release the second stage particle for delivery of the therapeutic agent.

13. The method of claim 11 wherein the first biological barrier and the second biological barrier are each independently selected from the group of biological barriers consisting of a hemo-rheology barrier, a reticulo-endothelial system barrier, an endothelial barrier, a blood brain barrier, a tumor-associated osmotic interstitial pressure barrier, an ionic and molecular pump barrier, a cell membrane barrier, an enzymatic degradation barrier, a nuclear membrane barrier, and any combination of thereof.

14. The method of claim 11 wherein the first stage particle comprises a chemical targeting moiety disposed on the surface of the first stage particle, wherein said chemical targeting moiety comprises at least one moiety selected from the group consisting of dendrimer, an aptamer, an antibody, a biomolecule and any combination thereof.

15. The method of claim 11 wherein the at least one of the plurality of nanoscale reservoirs contains at least one additional agent.

16. The method of claim 11 wherein the at least one additional agent comprises at least one penetration enhancer, at least one additional active agent, or at least one targeting moiety.

17. The method of claim 11 wherein the composition is administered intravascularly.

25. The method of claim 11, wherein the second stage particle comprises a plurality of second stage particles stacked within the pore open to the surface.

28. The method of claim 11, wherein the second stage particle comprises at least one constituent selected from the group consisting of a liposome, a micelle, an ethosome, a carbon nanotube, a fullerene nanoparticle, a metal nanoparticle, a semiconductor nanoparticle, a polymer nanoparticle, an oxide nanoparticle, a viral particle, a polyionic particle and a ceramic particle.

18. A method of fabricating a multistage delivery composition, comprising:

(a) providing a first stage particle, wherein the first stage particle comprises;

(i) a body;

(ii) at least one surface with a surface charge; and

(iii) a plurality of nanoscale reservoirs in the body of the first stage particle,

wherein each reservoir is connected to at least one surface of the body through at least one channel,

wherein the at least one channel is in the form of a pore open to the surface, and wherein;

the first stage particle is biodegradable and has a selected non-spherical shape;

the first stage particle is a porous micro or nanoparticle with a size from about 100 nm to about 5 microns;

(b) providing a second stage particle;

and

(c) loading the second stage particle inside one of the plurality of nanoscale reservoirs of the first stage particle such that the nanoscale reservoir contains the second stage particle in the pore open to the surface, and such that the first stage particle is configured to overcome a first biological barrier and the second stage particle is configured to overcome a second biological barrier, wherein the first stage particle and the second stage particle are configured to sequentially overcome the first biological barrier and second biological barrier respectively.

19. The method of claim 18, wherein loading the second stage particle inside one of the plurality of nanoscale reservoirs of the first stage particle comprises placing the first stage particle and the second stage particle in a sealed chamber having a pressure above atmospheric pressure.

20. The method of claim 19 wherein first stage particle and the second stage particle are submerged in a solution in the sealed chamber.

21. The method of claim 20 wherein the first stage particle is subjected to reduced pressure prior to being placed in the solution in the sealed chamber.

22. The of method claim 18, wherein loading the second stage particle inside one of the plurality of nanoscale reservoirs of the first stage particle comprises loading via passive diffusion or capillary convection, or by a combination of those.

23. The method of claim 18 wherein loading the second stage particle inside one of the plurality of nanoscale reservoirs of the first stage particle comprises modifying a surface charge of the first particle or the second particle.

26. The method of claim 18, wherein the second stage particle comprises a plurality of second stage particles stacked within the pore open to the surface.