Biodegradable targetable microparticle delivery system

• US 6,471,996 B1
• Filed: 02/11/2000
• Issued: 10/29/2002
• Est. Priority Date: 12/20/1996
• Status: Expired due to Fees

• Current Assignee: Aventis Pasteur Limited (Sanofi )
• Original Assignee: Aventis Pasteur Limited (Sanofi )
• Inventors: Chong, Pele, Klein, Michel H., Sokoll, Kenneth K.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/499,532
• Time in Patent Office: 991 Days
• Field of Search: 424/501, 424/426, 424/428, 514/951-952, 264/4.1
• US Class Current: 424/501
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: C08G 63/6852 derived from hydroxy carboxylic acids
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/816 Attached to the carrier via a bridging agent
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Copolymers designed for use as particulate carriers containing functionalizable amino acid subunits for coupling with targeting ligand are described. The copolymers are polyesters composed of α-hydroxy acid subunits such as D,L-lactide and α-amino acid subunits such as serine or in the preferred embodiment, terpolymers of D,L-lactide and glycolide and α-amino acid subunits such as serine. Stable vaccine preparations useful as delayed release formulations containing antigen(s) or antigen(s) and co-adjuvants encapsulated within or physically mixed with polymeric microparticles are described. The particulate carriers are useful for delivering agents to the immune system of a subject by mucosal or parenteral routes to produce immune responses, including antibody responses.

Claims

1. A process for making a particulate carrier for the delivery of at least one biologically active material to a host, comprising the steps of:

(a) mixing an organic solvent phase comprising an α

-hydroxy acid polymer with an aqueous composition comprising dispersed or dissolved biologically active material to form a first water-in-oil emulsion, said α

-hydroxy acid polymer having a molecular weight of about 5,000 to about 40,000 daltons and having the general formula;

 

wherein;

R₁, R₂ and R₅ are selected independently and are selected from the group consisting of H, linear or branched alkyl groups;

R₃ and R₄ are H;

R₆ is H;

X is selected from the group consisting of an O or S group; and

x and y are integers such that at least 95% of the polymer is comprised of α

-hydroxy acid residues;

(b) dispersing the first water-in-oil emulsion into an aqueous detergent phase to form a second water-in-oil-in-water double emulsion;

(c) removing water from the second double emulsion to form microspheres; and

(d) collecting the microspheres and having said biological material entrapped therein.

2. The process of claim 1, wherein said polymer is selected from the group consisting of poly-D,L-lactide-co-glycolide-co-pseudo-Z-serine ester (PLGpZS) and poly-P,L-lactide-co-glycolide-co-pseudo-serine ester (PLGpS).

3. The process of claim 1, wherein said organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, acetone and mixtures thereof.

4. The process of claim 1 wherein said aqueous detergent phase comprises at least one non-ionic emulsion stabilizer.

5. The process of claim 4, wherein said at least one non-ionic emulsion stabilizer is selected from the group consisting of poly vinyl alcohol, methyl cellulose and Triton X-100.

6. The process of claim 1, wherein said first water-in-oil emulsion additionally comprises at least one adjuvant.

7. The process of claim 6, wherein said adjuvant is selected from the group consisting of BAY R1-005 and tripalmitoyl cysteine.

8. The process of claim 1, wherein said first water-in-oil emulsion additionally comprises at least one surfactant.

9. The process of claim 8, wherein said surfactant is selected from the group consisting of sucrose, mannose, trehalose and gelatin.

10. The process of claim 1 wherein said at least one biologically active material is selected from the group consisting of cell bioadhesion groups, macrophage stimulators, poly amino acids and polyethylene glycol.

11. The process of claim 1 wherein said at least one biologically active material is capable of eliciting an immune response.

12. The process of claim 11 wherein said at least one biologically active material comprises at least one Haemophilus influenzae protein.

13. The process of claim 12 wherein said Haemophilus influenzae protein is selected from the group consisting of a non-proteolytic Hin-47 analog, D15, P1, P2, P6 and mixtures thereof.

14. The process of claim 11 wherein said at least one biologically active material comprises at least one influenzae virus type A protein or a component thereof.