Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1992-03-26
1994-04-19
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
423161, 423592, 423604, 423605, 423606, 423624, 423632, 423641, 530400, A61K 914
Patent
active
053043820
DESCRIPTION:
BRIEF SUMMARY
Disclosed herein are inventions relating to compositions encapsulated in a protein shell, more specifically such inventions comprise ferritin analogs, methods of making ferritin analogs and methods of using ferritin analogs, e.g. to produce nanosized (e.g. about 1-50 nanometers) particles and monolithic articles such as ceramics. Also disclosed are inventions relating to substantially uniform spherules of a monomodal size distribution prepared from ferritin analogs and methods of making and using such spherules.
BACKGROUND OF THE INVENTION
Among the tougher ceramic materials are those comprising ultra-small particles. Such particles are conventionally prepared by grinding larger particles and classifying the resultant mix of particles of wide ranging sizes and shapes, e.g. lumps, discs and needles, etc. The variety of shapes are difficult to separate and inhibit close packing of particles in use. For instance, when ceramics are produced from such particles, the disparate shapes provide discontinuities and stress risers which can result in failure of the ceramic article. Some attempts to produce high performance ceramics have focused on uniformity and fineness of particles. For instance, Eastman et al. in Research and Development pp 56-60 (January 1989) report the production of ultrafine powders of alumina, rutile etc. by condensing evaporated atoms in a low pressure inert gas, followed by compaction; the particles have a typical grain size distribution from about 5 to 25 nanometers (50-250 Angstroms). Also, Wusirika in U.S. Pat. No. 4,778,671 discloses the production of substantially unagglomerated metal oxide particles of up to about 1 micron mean diameter by precisely controlled precipitation of chelated solutes. The production of ultrafine particles of substantially monomodal size distribution has eluded practioners in the ceramics but remains an objective in efforts to provide high performance ceramics.
Substantially uniform nanosized particles are ubiquitous in nature, i.e. in the form of the mineral core of the natural iron storage molecule, commonly known as "ferritin". Although iron is essential for most forms of plant and animal life, free or too much iron can be harmful. In nature ferritin serves to accumulate, store and dispense iron in response to the flux of iron entering or leaving the plant or animal. The structure and characteristics of ferritin is discussed by Ford et al. in "Ferritin: design and formation of an iron-storage molecule", B 304 Phil. Trans. R. Soc. Lond. 551-565 (1984). Ferritin is characterized as a hybrid polymer comprising a protein shell, assembled from 24 structurally equivalent protein subunits, forming a nearly spherical hollow shell surrounding a hydrous ferric oxide core, commonly known as "ferrihydrite", which is reported to have a diameter of about 5-8 nanometers (50 to 80 Angstroms) which corresponds to about 4500 iron atoms. It is believed that ions permeate through intersubunit channels in the protein shell to nucleation sites on the inside surface of the protein shell where the ferrihydrite core grows from the outside in.
Since ferritin is concentrated in the spleen and liver of higher animals, horse spleen provides a common source of ferritin for many applications. Stefanini et al. in "On the Mechanism of Horse Spleen Apoferritin Assembly: A Sedimentation Velocity and Circular Dichroism Study", 26 Biochemistry 1831-1837 (1987), discloses disassembly in acid of ferritin into protein subunits and liberated iron core. After the iron core is dissolved in acid the protein subunits can then be reassembled to provide a hollow protein shell, commonly known as "apoferritin".
Ferritin has been proposed for a variety of uses. For instance Zimmerman et al. in U.S. Pat. No. 4,269,826 discloses the preparation of magnetic field concentratable tumor treating agents by incorporating ferritin into erythrocytes.
Shukla, et al. in Anal. Chem. Symp Ser. 14 (Chromatogr. Mass. Spectrum. Biomed. Sci., 2) 179-86 (1983) discloses attempts to provide cancer therapy compounds by comp
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Kelley Thomas E.
Kishore G. S.
Monsanto Company
Page Thurman K.
Wachter Mark F.
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