Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals

Patent metadata

Field	Value
Publication number	US-9492400-B2
Application number	US-66690805-A
Country	US
Kind code	B2
Filing date	Nov 4, 2005
Priority date	Nov 4, 2004
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

A composition for delivering an active agent to a patient. The composition includes a polymer core encapsulating the active agent and a mucoadhesive coating disposed about the core. The polymer may include covalently linked poly(ethylene glycol) chains, and the mucoadhesive coating may be selected to facilitate transfer of the particle through the intestinal mucosa. A molecular weight and cross-link density of the polymer may be selected such that the polymer core will decompose in a predetermined time interval. The fraction of the dose of the drug entering the system at circulation during the predetermined time interval may be between about 0.25% and about 25%. The composition may be formulated as a plurality of nanoparticles or microparticles that are combined with a pharmaceutically acceptable carrier to produce an edible or inhalable drug product.

First claim

What is claimed is:

1. A composition comprising
(i) a plurality of nanoparticles having a diameter between about 10 nm and 1000 nm, the nanoparticles comprising
(a) an amphiphilic block co-polymer core encapsulating an active agent,
(b) a mucoadhesive coating comprising a material selected from the group consisting of lectins and positively charged polymers, the coating being present on the core and interacting through electrostatic interactions with the amphiphilic block co-polymer to form a coated nanoparticle, and
(c) a targeting agent; and

(ii) a pharmaceutically acceptable carrier.

2. The composition of claim 1 , wherein the amphiphilic block co-polymer is functionalized with one or more groups selected from the group consisting of hydroxyl, amine, carboxy, maleimide, thiol, N-hydroxy-succinimide (NHS) esters, and azide groups.

3. The composition of claim 2 , wherein the amphiphilic block co-polymer is functionalized with carboxy groups.

4. The composition of claim 1 , wherein the targeting agent is disposed at a surface portion of the polymer core.

5. The composition of claim 1 , wherein the targeting agent is disposed on the surface portion of the polymer core and within the interior of the polymer core.

6. The composition of claim 1 , wherein the targeting agent is selected from the group consisting of nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences.

7. The composition of claim 1 , providing controlled release of the active agent.

8. The composition of claim 1 , wherein the mucoadhesive coating is dislodged from the particle core at pH of about 7.4.

9. The composition of claim 1 , wherein the amphiphilic block co-polymer comprises a poly(alkylene glycol) block.

10. The composition of claim 9 , wherein the poly(alkylene glycol) is poly(ethylene glycol) or poly(propylene glycol).

11. The composition of claim 1 , wherein the amphiphilic block co-polymer core comprises PEGylated poly(lactic acid).

12. The composition of claim 9 , wherein the poly(alkylene glycol) is carboxylated.

13. The composition of claim 9 , wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 7000 Daltons.

14. The composition of claim 13 , wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 1000 Daltons.

15. The composition of claim 13 , wherein the poly(alkylene glycol) has a molecular weight between about 1000 and about 3500 Daltons.

16. The composition of claim 13 , wherein the poly(alkylene glycol) has a molecular weight between about 3500 and 7000 Daltons.

17. The composition of claim 1 , wherein the amphiphilic block co-polymer comprises a biodegradable polymer block.

18. The composition of claim 17 , wherein the biodegradable polymer block is selected from the group consisting of poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(ortho esters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyphosphazenes, polyamino acids, polyethers, polyacetals, polylactides, polyhydroxyalkanoates, polyglycolides, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polycarbonates, polyorthocarbonates, poly(vinyl pyrrolidone), biodegradable polycyanoacrylates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), poly(ethylene imine), poly(acrylic acid), poly(maleic anhydride), biodegradable polyurethanes, polysaccharides, and mixtures of the above.

19. The composition of claim 1 , wherein the amphiphilic block co-polymer comprises a non-biodegradable polymer block selected from the group consisting of polystyrene, polyesters, non-biodegradable polyurethanes, polyureas, poly(vinyl alcohol), polyamides, poly(tetrafluoroethylene), poly(ethylene vinyl acetate), polypropylene, polyacrylate, non-biodegradable polycyanoacrylates, polymethacrylate, poly(methyl methacrylate), polyethylene, polypyrrole, polyanilines, polythiophene, poly(ethylene oxide), co-polymers of the above, and mixtures of the above.

20. The composition of claim 1 , wherein the material positively charged polymers are selected from the group consisting of chitosan, poly(lysine), poly(ethylene imine), and combinations thereof.

21. The composition of claim 20 , wherein the coating comprises chitosan, lectin, or both.

22. The composition of claim 1 , wherein the coating is a block co-polymer having a mucoadhesive block and a block that is adapted to participate in an interaction selected from the group consisting of electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions.

23. The composition of claim 1 , wherein the active agent is selected from the group consisting of a drug, vaccine, and polynucleotide.

24. The composition of claim 23 , wherein the active agent is a vaccine.

25. The composition of claim 1 , wherein the active agent is a protein.

26. The composition of claim 25 , wherein the active agent is insulin.

27. A method for administering an active agent to an individual, comprising:
orally or nasally administering to the patient a composition comprising:
(i) a plurality of nanoparticles having a size between about 10 nm and 1000 nm, the nanoparticles comprising
(a) an amphiphilic block co-polymer core encapsulating active agent;
(b) a mucoadhesive coating comprising a material selected from the group consisting of lectins and positively charged polymers, the coating present on the amphiphilic block co-polymer core and interacting through electrostatic interactions with the amphiphilic polymer to form a coated nanoparticle, and
(c) a targeting agent; and

(ii) a pharmaceutically acceptable carrier.

28. The method of claim 27 , wherein the amphiphilic block co-polymer is functionalized with one or more groups selected from hydroxyl, amine, carboxy, maleimide, thiol, N-hydroxy-succinimide (NHS) esters, and azide groups.

29. The method of claim 27 , wherein the amphiphilic block co-polymer is functionalized with carboxy groups.

30. The method of claim 27 , wherein the targeting agent is disposed at a surface portion of the polymer core.

31. The method of claim 27 , wherein the targeting agent is disposed at a surface portion of the polymer core and within the interior portion of the polymer core.

32. The method of claim 27 , wherein the targeting agent is selected from the group consisting of nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences.

33. The method of claim 27 , wherein the amphiphilic block co-polymer comprises a poly(alkylene glycol) block.

34. The method of claim 33 , wherein the poly(alkylene glycol) is poly(ethylene glycol) or poly(propylene glycol).

35. The method of claim 33 , wherein the core comprises PEGylated poly(lactic acid).

36. The method of claim 33 , wherein the poly(alkylene glycol) is carboxylated.

37. The method of claim 33 , wherein the poly(alkylene glycol) has a molecular weight

Assignees

• Jon Sangyong
• Farokhazd Omid C
• Langer Robert S
• Cheng Jianjun
• Massachusetts Inst Technology
• Brigham & Womens Hospital Inc

Inventors

• Jon Sangyong
• Farokhazd Omid C
• Langer Robert S
• Cheng Jianjun

Classifications

• A61K9/5192 Primary

  Processes · CPC title

• A61K9/0065

  Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus · CPC title

• A61K9/5036

  Polysaccharides, e.g. gums, alginate; Cyclodextrin · CPC title

• A61K9/0043

  Nose · CPC title

• A61K9/5153 Primary

  Polyesters, e.g. poly(lactide-co-glycolide) · CPC title