Therapeutic calcium phosphate particles and methods of manufacture and use

Abstract

Novel calcium phosphate core particles, methods of making them, and methods of using them as vaccine adjuvants, as cores, as carriers of biologically active material, and as controlled release matrices for biologically active material are disclosed. The core particles may have a surface modifying agent and / or biologically active material, such as antigenic material or natural immunoenhancing factor, polynucleotide material, or therapeutic proteins or peptides, partially coating the particle or impregnated therein. The core particles have a diameter between about 300 nm and about 4000 nm, more particularly between about 300 nm and about 2000 nm, and even more particularly between about 300 nm and about 1000 nm, are substantially spherical in shape, and have a substantially smooth surface

Description

[0001] This application claims benefit of the filing dates of U.S. Provisional Application Ser. Nos. 60 / 118,356; 60 / 118,364; and 60 / 118,355, all filed Feb. 3, 1999, the entire contents of each of which are hereby incorporated by reference.BACKGROUND OF INVENTION[0002] 1. Field of the Invention[0003] The present invention relates to novel calcium phosphate core particles, to methods of making them, and to methods of using them as vaccine adjuvants, as cores or carriers for biologically active material, and as controlled release matrices for biologically active material.[0004] 2. Description of Related Art[0005] Nanometer scale particles have been proposed for use as carrier particles, as supports for biologically active molecules, such as proteins, and as decoy viruses. See U.S. Pat. Nos. 5,178,882; 5,219,577; 5,306,508; 5,334,394; 5,460,830; 5,460,831; 5,462,750; and 5,464,634, the entire contents of each of which are hereby incorporated by reference.[0006] The particles disclosed i...

AI Technical Summary

Problems solved by technology

Particles of this size are difficult to make with any degree of consistency, and their morphology is not described in any detail.

None of these patents disclose the use of nanoparticles as sustained release matrices.

Furthermore, these patents do not disclose the use of calcium phosphate particles as either (1) adjuvants for vaccines or viral decoys, or (2) controlled release matrices for delivery of pharmaceuticals or immunogenic materials.

There has been a suggestion in the literature to use calcium phosphate particles as vaccine adjuvants, but calcium phosphate particles have generally been considered an unsuitable alternative to other adjuvants due to inferior adjuvanting activity.

However, traditional vaccine methodologies may be undesirable as a result of their expense, instability, poor immunogenicity, limited heterogeneity and potential infectivity.

However, this approach may be undesirable for several reasons.

Also, viral vectors and modified pathogens have inherent risks that may hinder their use in humans (R. R. Redfield et al., New Engl.

For example, in live vector approaches, highly immunogenic vectors also tend to be highly pathogenic.

Thus, the system described by Wang et al., may be inappropriate for administration to humans.

However, this patent does not suggest the use of calcium phosphate particles as supports for DNA or RNA vaccines.

This patent also fails to suggest the use of calcium phosphate particles as controlled release matrices for genetic material.

For a number of therapeutic agents, delivery of the agent to a patient in need thereof can be difficult.

This is particularly true with proteins and peptides, which are difficult or impossible to administer orally, since they are easily digested or hydrolyzed by the enzymes and other components of gastric juices and other fluids secreted by the digestive tract.

Injection is often the primary alternative administration method, but is unpleasant, expensive and is not well tolerated by patients requiring treatment for chronic illnesses.

In particular, patients who are administered drugs on an out-patient basis, or who self-administer, are more likely to fail to comply with the required administration schedule.

However, preparation of suitable inhalable aerosols can be difficult for therapeutic agents where the blood level of the agent is critical, e.g., with insulin, because the amount of aerosol delivered to the deep lung tissue can be substantially variable, leading to inconsistent dosages of the drug to the patient.

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