United States Patent:   5,985,309

Assignee:  Massachusetts Institute of Technology (Cambridge, MA)

Filed:  November 17, 1997

Particles incorporating a surfactant and/or a hydrophilic or hydrophobic complex of a positively or negatively charged therapeutic agent and a charged molecule of opposite charge for drug delivery to the pulmonary system, and methods for their synthesis and administration are provided. In a preferred embodiment, the particles are made of a biodegradable material and have a tap density less than 0.4 g/cm³ and a mass mean diameter between 5 .mu.m and 30 .mu.m, which together yield an aerodynamic diameter of the particles of between approximately one and three microns. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of poly(lactic acid) or poly(glycolic acid) or copolymers thereof. Alternatively, the particles may be formed solely of a therapeutic or diagnostic agent and a surfactant. Surfactants can be incorporated on the particle surface for example by coating the particle after particle formation, or by incorporating the surfactant in the material forming the particle prior to formation of the particle. Exemplary surfactants include phosphoglycerides such as dipalmitoyl phosphatidylcholine (DPPC). The particles can be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of wide a variety of therapeutic agents. Formation of complexes of positively or negatively charged therapeutic agents with molecules of opposite charge can allow control of the release rate of the agents into the blood stream following administration.

SUMMARY OF THE INVENTION

Particles incorporating a surfactant and/or a hydrophilic or hydrophobic complex of a positively or negatively charged therapeutic agent and a charged molecule of opposite charge for delivery of therapeutic or diagnostic agents to the pulmonary system, and methods for their synthesis and administration, are provided. Exemplary surfactants include naturally occurring phosphatidylcholines, such as dipalmitoylphosphatidylcholine ("DPPC"). Exemplary hydrophilic or hydrophobic complexes include insulin (negatively charged) and protamine (positively charged). In a preferred embodiment, the particles are aerodynamically light particles, which are made of a biodegradable material, and have a tap density less than 0.4 g/cm³. The "aerodynamically light" particles generally have a mean diameter between 5 .mu.m and 30 .mu.m. The tap density less than 0.4 g/cm³ and mean diameter between 5 .mu.m and 30 .mu.m, are designed to yield particles with an aerodynamic diameter between approximately one and five microns, preferably between approximately one and three microns. The particles may be formed of biodegradable materials such as biodegradable polymers, proteins, or other water soluble or non-water soluble materials. Particles can also be formed of water-soluble excipients, such as trehalose or lactose, or proteins, such as the proteins to be delivered. In one embodiment, the particles include only a therapeutic or diagnostic agent to be delivered to a patient in a complex with another charged molecule. In a second embodiment, the particles include only the agent and a surfactant. In a third embodiment, particles include surfactant and charged molecules forming a complex, which provides for sustained release.

The particles can be used for enhanced delivery of a therapeutic agent to the airways or the alveolar region of the lung. The particles may be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of a wide variety of therapeutic agents. They also optionally may be co-delivered with larger carrier particles, not carrying a therapeutic agent, having, for example, a mean diameter ranging between about 50 .mu.m and 100 .mu.m. The particles can be used to form a composition that includes the particles and a pharmaceutically acceptable carrier for administration to a patient, preferably for administration via inhalation.

Claim 1 of 27 Claims

1. Particles for drug delivery to the pulmonary system consisting of a therapeutic agent and a material selected from the group consisting of surfactant and a molecule having a charge opposite to the charge of the therapeutic agent and forming a complex thereto, wherein the particles have a tap density less than 0.4 g/cm³ and a mean diameter between 5 .mu.m and 30 .mu.m effective to yield an aerodynamic diameter of the particles of between approximately one and five microns.

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