Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-08-23
2003-05-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S422000, C424S426000, C424S490000, C424S491000, C424S493000, C424S497000, C424S499000, C424S130100, C424S184100, C424S204100, C424S234100, C424S237100, C424S244100
Reexamination Certificate
active
06565888
ABSTRACT:
BACKGROUND OF THE INVENTION
Antigen-containing sustained release devices, such as polymer-based devices and liposomes, can be administered to effectively stimulate an immune response. The devices, however, must be of a size sufficient to permit an antigen presenting cell, such as a macrophage, to engulf and then process the antigen for presentation to T lymphocytes. See, for example, U.S. Pat. Nos. 5,942,252, 6,024,983, 5,811,128, 5,814,344, and 5,853,763 to Tice et al., U.S. Pat. No. 6,015,576 to See et al. and Tabata, Y. and Ikada, Y., “Phagocytosis of Polymer Microspheres by Macrophages”
Adv. Polym. Sci.
1990, 94, 110-141, the entire contents of which are hereby incorporated by reference. Another method of delivery in which the size of the delivery device is critical, is the systemic delivery of efficacious levels of drugs by absorption of drug-containing delivery devices in the Peyer's patches of the gastrointestinal tract. This need for small delivery devices, presents difficulties and disadvantages in both processing and handling of these devices. Therefore, a need exists for improved methods and compositions for targeted delivery of biologically active agents where a small delivery device is needed to obtain delivery of sufficient levels of the agent.
SUMMARY OF THE INVENTION
The present invention relates to a sustained release composition for the targeted delivery of biologically active agents to specific tissues and cells. The composition comprises microparticles containing a biocompatible polymer, a water-soluble polymer and a biologically active agent. In one embodiment, the biologically active agent is an antigen. In another embodiment, the biologically active agent is a labile agent. In yet another embodiment, the biologically active agent is an immunomodulator. The microparticles have a number median diameter of greater than 20 microns upon administration. The water-soluble polymer can be present in the sustained released composition in at least about 20% of the dry weight of the microparticle. For example, the water-soluble polymer can be present in the sustained release composition at about 30% or more such as 40% or more of the dry weight of the microparticles. In a particular embodiment, the water-soluble polymer is present from about 40% to about 60% of the dry weight of the microparticles, such as from about 40% to 50%.
It has been found that the characteristics of the sustained release composition provide for the dissolution of the water-soluble polymer of the composition upon hydration, at a much greater rate than the degradation of the biocompatible polymer. This variance in solubility generates pseudo-microparticles which have a number median diameter which is substantially smaller than the size of the administered microparticles. For example, the pseudo-microparticles can have a number median diameter of less than about 20 microns such as less than about 10 microns. Preferably, the number median diameter of the pseudo-microparticles is less than about 5 microns, for example, from about 1 to about 5 microns. The pseudo-microparticles can be engulfed by antigen presenting cells of the immune system, or absorbed by the Peyer's patches in the gut. The generation of pseudo-microparticles following administration, therefore overcomes the problems associated with the processing and handling of small microparticles, for example, microparticles having a number median diameter of less than about 20 microns.
The sustained release composition can be used in a method for stimulating a systemic immune response in a mammal. As such, the invention relates to a method for stimulating a systemic immune response in a mammal. The method comprises administering to a mammal an effective amount of a sustained release composition comprising microparticles containing an antigen, a biocompatible polymer, and a water-soluble polymer wherein, the microparticles have a number median diameter of greater than about 20 microns, the water-soluble polymer represents at least about 20% of the dry weight of the microparticles such as 30% or more, for example 40% or more, such as from about 40% to about 60%, for example from about 40% to about 50%, and the microparticles generate pseudo-microparticles upon hydration, whereby sufficient pseudo-microparticles can be taken up by antigen presenting cells to stimulate a systemic immune response. Administration can be by any route which provides interaction between the antigen presenting cells and the pseudo-microparticles.
The sustained release composition can also be used in a method for modulating an immune response in a mammal. As such, the invention relates to a method for modulating an immune response in a mammal. The method comprises administering to a mammal an effective amount of a sustained release composition comprising microparticles containing an immunomodulator, a biocompatible polymer, and a water-soluble polymer wherein, the microparticles have a number median diameter of greater than about 20 microns, the water-soluble polymer represents at least about 20% of the dry weight of the microparticles, for example, 30% or more such as 40% or more, for example, from about 40% to about 60%, such as from about 40% to about 50%, and the microparticles generate pseudo-microparticles upon hydration, whereby sufficient pseudo-microparticles can be taken up by antigen presenting cells to modulate an immune response, such as an autoimmune response. Administration can be by any route which provides interaction between the antigen presenting cells and the pseudo-microparticles containing the immunomodulator.
Further, the sustained release composition can be used in a method for the systemic delivery of efficacious levels of labile agents to a mammal by uptake into the Peyer's patches of the gastrointestinal tract. As such, the invention further relates to a method for the systemic delivery of an effective amount of a labile agent to a mammal by uptake into the Peyer's patches of the gastrointestinal tract. The method comprises orally administering to the mammal an effective amount of the sustained release composition comprising microparticles containing a labile agent, a biocompatible polymer, and a water-soluble polymer wherein, the microparticles have a number median diameter of greater than 20 microns, the water soluble polymer represents at least about 20% of the dry weight of the microparticles and the microparticles generate pseudo-microparticles upon hydration, whereby sufficient pseudo-microparticles can be taken up into the Peyer's patches of the gastrointestinal tract.
The method of the invention for preparing a sustained release composition for the targeted delivery of a biologically active agent, comprises the steps of:
(a) forming a mixture comprising a labile agent or antigen, a biocompatible polymer, a water-soluble polymer and a solvent for the water soluble polymer and biocompatible polymer; and
(b) removing the solvent thereby forming a solid polymer/active agent matrix.
In a particular embodiment, the method can further comprise the step of forming droplets of the mixture prior to removal of the solvent. Further, the method can comprise freezing the droplets prior to removal of the solvent. According to the method of the invention, the droplets can be microdroplets. In a specific embodiment wherein droplets are formed of the mixture and then frozen, the solvent can be removed by an evaporation and/or extraction process.
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Scher David S.
Tracy Mark A.
Alkermes Controlled Therapeutics Inc.
Di Nola-Baron Liliana
Hamilton Brook Smith & Reynolds P.C.
Page Thurman K.
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