Biodegradable targetable microparticle delivery system

Abstract

Copolymers designed for use as particulate carriers containing functionalizable amino acid subunits for coupling with targeting ligands are described. The copolymers are polyesters composed of α-hydroxy acid subunits such as D,L-lactide and pseudo-α-amino acid subunits which may be derived from serine or terpolymers of D,L-lactide and glycolide and pseudo-α-amino acid subunits which may be derived from serine. Stable vaccine preparations useful as delayed release formulations containing antigen or antigens and 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 and protective responses.

Description

REFERENCE TO RELATED APPLICATION [0001] This application is a continuation-in-part of copending U.S. patent Ser. No. 08 / 770,050 filed Dec. 20, 1996.FIELD OF THE INVENTION [0002] The present invention relates to biodegradable microparticles for delivery of a biologically active material and is particularly concerned with such microparticles that are targetable to particular cell types. BACKGROUND OF THE INVENTION [0003] Vaccines have been used for many years to protect humans and animals against a wide variety of infectious diseases. Such conventional vaccines consist of attenuated pathogens (for example, polio virus), killed pathogens (for example, Bordetella pertussis) or immunogenic components of the pathogen (for example, diphtheria toxoid and hepatitis B surface antigen). [0004] Some antigens are highly immunogenic and are capable alone of eliciting protective immune responses. Other antigens, however, fail to induce a protective immune response or induce only a weak immune resp...

AI Technical Summary

Benefits of technology

[0023] The present invention is directed towards the production of a novel and useful polymer that has properties suitable for manufacturing by various processes into microparticles and microspheres. In this invention, modifications of existing processing procedures results in significant improvement in encapsulation efficiencies.

[0052] The first water-in-oil emulsion may additionally comprise at least one organic solvent soluble adjuvant, which may be lipophilic. Such organic solvent adjuvant may be selected from the group consisting of BAY R1-005, tripalmitoyl cysteine and DC-chol. The presence of a lipophilic moiety serves to increase the encapsulation efficiency and to protect the antigen during formulation and release and enables the particles to present antigen to the immune system more efficiently than traditional formulation and hence provides a more efficacious vaccine.

[0053] The first water-in-oil emulsion also may additionally comprise at least one water soluble adjuvant, which may be a polymeric water soluble adjuvant, such as PCPP or a mucosal adjuvant, such as CT-X or subunit thereof or LT. The presence of the water soluble adjuvant serves to increase the encapsulation efficiency of the process and protects the antigen during formulation and release and prevents the antigen to the immune system more efficiently than traditional microparticle formulation, thereby providing a more efficancious vaccine.

[0057] (b) facilitated antigen presentation to the cells of the immune system resulting in improved antigen immunogenicity;

[0058] (c) improved formulating conditions which increase the bioavailability of the antigen.

Problems solved by technology

Other antigens, however, fail to induce a protective immune response or induce only a weak immune response.

This approach is suitable for infectious agents gaining access to the body via damaged skin (i.e. Tetanus), however, there are problems encountered due to side-effects and associated toxicity of many adjuvants administered in this fashion.

However, even these adjuvants are not suitable for use with all antigens and can also cause irritation at the site of injection.

There are other problems specific to the nature of the antigen being used.

Live attenuated vaccines and many nonliving liquid vaccines suffer from the need for controlled storage conditions and are susceptible to inactivation (e.g. thermal sensitivity).

There are also problems associated with combining vaccines in single dosage forms, due to adjuvant incompatibilities, pH, buffer type and the presence of salts.

However, most of these adjuvants are relatively poor in terms of improving immune responses to ingested antigens.

However, administration of antigens via these routes is generally ineffective in eliciting an immune response.

Although the above example illustrates the potential of these immunization modes, the development of vaccine formulations for use by these routes has been slow for various reasons.

However, U.S. Pat. No. 5,151,264 does not describe particulate carriers containing antigens for immunization and particularly does not describe particulate carriers for immunization via the orogastrointestinal, nasapharyngeal-respiratory and urogenital tracts and in the ocular orbits or other mucosal sites.

As is stated in this patent, in contrast, the oral administration of the same amount of unencapsulated antigen was ineffective at inducing specific antibodies of any isotype in any of the fluids tested.

Although time-delayed release of antigen was shown in the above work, difficulties were encountered when microparticles are manufactured by the described methods.

It may be also be difficult to scale-up the procedures.

Furthermore, hydrophilic antigens may be inefficiently encapsulated.

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