Biodegradable injectable nanoparticles

• US 5,543,158 A
• Filed: 07/23/1993
• Issued: 08/06/1996
• Est. Priority Date: 07/23/1993
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Minamitake, Yoshiharu, Langer, Robert S., Gref, Ruxandra
• Primary Examiner(s): Azpuru, Carlos
• Application Number:
  US08/096,370
• Time in Patent Office: 1,110 Days
• Field of Search: 424/489, 424/497, 424/498, 424/501, 424/502, 424/451, 424/462, 424/78.08, 514/963, 428/402.21, 428/402.24, 428/403
• US Class Current: 424/501
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 51/1241 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
• CPC Class Codes: A61K 51/1251 micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42
• CPC Class Codes: C08J 2300/16 Biodegradable polymers
• CPC Class Codes: C08J 2367/04 Polyesters derived from hydroxy carboxylic acids, e.g. lactones C08J2367/06 takes precedence
• CPC Class Codes: C08J 2371/02 Polyalkylene oxides
• CPC Class Codes: C08J 3/14 by precipitation from solutions C08J3/122 takes precedence
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]
• CPC Class Codes: Y10T 428/2991 : Coated

Abstract

Particles are provided that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system, and that can be modified to achieve variable release rates or to target specific cells or organs. The particles have a biodegradable solid core containing a biologically active material and poly(alkylene glycol) moieties on the surface. The terminal hydroxyl group of the poly(alkylene glycol) can be used to covalently attach onto the surface of the particles biologically active molecules, including antibodies targeted to specific cells or organs, or molecules affecting the charge, lipophilicity or hydrophilicity of the particle. The surface of the particle can also be modified by attaching biodegradable polymers of the same structure as those forming the core of the particles.

Claims

1. A nonoparticle or microparticle formed of a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer selected from the group consisting of polyanhydride, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, and copolymers prepared from the monomers of these polymers, wherein the biodegradable moieties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface of the resulting particle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system.

8. The nanoparticle or microparticle of claim 1, 2 or 3 further comprising molecules covalently bound to the surface of the particle via the terminal hydroxyl group of the poly(alkylene glycol), wherein the molecules are selected from the group consisting of molecules which have biological activity, molecules which can be detected, targeting molecules, and molecules affecting the charge, lipophilicity or hydrophilicity of the particle.

9. The nanoparticle or microparticle of claim 8, wherein the targeting molecule is selected from the group consisting of compounds specifically reactive with a cell surface component.

10. The nanoparticle or microparticle of claim 9, wherein the poly(alkylene glycol) is covalently bound to the targeting molecules.

11. The nanoparticle or microparticle of claim 1, 2 or 3 wherein the surface of the nanoparticle or microparticle is modified by attaching biodegradable polymers of the same structure as those forming the core of the injectable particles by covalently linking the biodegradable polymers to the poly(alkylene glycol) moieties on the surface of the particle.

14. The nanoparticle or microparticle of claim 1, 2 or 3 further comprising a biologically active or detectable substance.

17. The nanoparticle or microparticle of claim 14 wherein the substance is a biologically active substance selected from the group consisting of synthetic inorganic or organic molecules that cause a biological effect when administered in vivo to an animal, peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides, and combinations thereof.

2. A nanoparticle or microparticle formed of a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer selected from the group consisting of polyanhydrides, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid) and copolymers prepared from the monomers of these polymers, wherein the biodegradable moieties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface of the resulting nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system, and wherein the copolymer is a diblock or multiblock copolymer comprising two or more poly(alkylene glycol) blocks.

3. A nanoparticle or microparticle formed of a block copolymer consisting essentially of poly(alkylene glycol) and a polymer selected from the group consisting of poly(lactic-co-glycolic acid), poly(lactic acid), and poly(glycolic acid), wherein the copolymer is blended with poly(lactic-co-glycolic acid) prior to forming the particle, and wherein the biodegradable moieties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moleties are on the surface of the resulting nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle. by the reticuloendothelial system.

4. A method for making a nanoparticle or microparticle with a core and a surface comprising:

(i) preparing a solution of a block copolymer consisting essentially of poly(alkylene glycol) and biodegradable polymer selected from the group consisting of polyanhydride, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, and copolymers prepared from the monomers of these polymers; and

(ii) precipitating the polymer from a solvent system such that the biodegradable moleties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface of the resulting nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system.

12. The method of claim 4 further comprising covalently binding to the surface of the nanoparticle or microparticle via the terminal hydroxyl group of the poly(alkylene glycol) molecules selected from the group consisting of molecules which have biological activity, molecules which can be detected, targeting molecules, and molecules affecting the charge, lipophilicity or hydrophilicity of the particle.

13. The method of claim 4 wherein the surface of the nanoparticles or microparticles is modified by attaching biodegradable polymers of the same structure as those forming the core of the injectable particles by covalently linking the biodegradable polymers to the poly(alkylene glycol) moieties on the surface of the nanoparticle or microparticle.

15. The method of claim 4 further comprising incorporating into or onto the particles a biologically active or detectable substance.

18. The method of claim 15 wherein the substance is a biologically active substance when administered to an animal or human in need thereof in a therapeutically or diagnostically effective amount selected from the group consisting of synthetic inorganic or organic molecules that cause a biological effect when administered in vivo to an animal, peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides, and combinations thereof.

19. The method of claim 12 wherein the targeting molecule is a compound specifically reactive with a cell surface component.

5. A method for making a nanoparticle or microparticle with a core and a surface comprising:

(i) preparing a solution of a block copolymer consisting essentially of poly(alkylene glycol) and biodegradable polymer selected from the group consisting of polyanhydride, polyhydroxybutyfic acid, polyorthoesters, polysiloxanes, polycaprolactone, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid) and copolymers prepared from the monomers of these polymers, and

(ii) precipitating the polymer from a solvent system such that the biodegradable moleties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface of the resulting nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system,

wherein the copolymer is a diblock or multiblock copolymer comprising two or more blocks of poly(alkylene glycol).

6. A method for making a nanoparticle or microparticle with a core and a surface comprising:

(i) preparing a solution of a block copolymer consisting essentially of poly(alkylene glycol) and biodegradable polymer selected from the group consisting of poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid) and copolymers prepared from the rrtonomers of these polymers, and

(ii) precipitating the polymer from a solvent system such that the biodegradable moieties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface of the resulting nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system,

wherein the copolymer is blended with poly(lactic-co-glycotic acid) prior to forming the nanoparticles or microparticles.

16. The method of claim 6 wherein the copolymer is insoluble in water.

7. A method for delivering a substance to a patient comprising administering to the patient a composition comprising nanoparticles or microparticles comprising a therapeutic or detectable amount of a substance to be delivered to a patient in need thereof and a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer selected from the group consisting of polyanhydride, polyhydroxybutyric acid, polyorthoesters, polysiloxanes, polycaprolactone, and copolymers prepared from the monomers of these polymers, wherein the biodegradable moieties of the copolymer are in the core of the resulting particle, and the poly(alkylene glycol) moieties are on the surface or the resulting particle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system.

20. The method of claim 7 wherein the substance is a biologically active substance selected from the group consisting of synthetic inorganic or organic molecules that cause a biological effect when administered in vivo to an animal, peptides, proteins, carbohydrates, nucleic acids, lipids, polysaccharides, and combinations thereof which is present in a therapeutically effective amount in the particles.