Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1998-08-18
2001-05-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S451000, C424S489000, C424S493000, C424S497000, C424S499000, C264S004100
Reexamination Certificate
active
06238677
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to microscopic-sized starch-based shells (microspheres) and their use in forming microcapsules having utility as delivery systems for drugs, pharmaceuticals, cosmetics and other active agents. These microcapsules (coated droplets) are dispersible in an aqueous carrier and can be used in the preparation of aqueous-based delivery systems of active agents that are lipophilic and water-insoluble in nature. The resultant delivery systems are particularly useful for administration of active agents by injection.
2. Description of the Prior Art
In a three part series of articles discussing the manufacturing techniques for producing microspheres and microcapsules, Arshady [Polymer Eng. & Sci. 29:1746-1758 (1989); and Polymer Eng. & Sci. 30:905-924 (1990)] describes three principal techniques in current practice: (1) suspension cross-linking; (2) coacervation; and (3) solvent evaporation. In suspension cross-linking, a stable droplet suspension of a polymer solution (or melt) is produced in an immiscible liquid, and the droplets are gradually hardened by covalent cross-linking. This process may involve cross-linking of polysaccharides, proteins, or synthetic polymers. Coacervation involves macromolecular aggregation (or phase separation) brought about by partial desolvation of fully solvated macromolecules. Gelatin, gum arabic, and ethylcellulose are commonly used in this process. The solvent extraction/solvent evaporation processes involve droplet formation followed by solvent removal. The extraction or evaporation of the solvent is accompanied by a corresponding decrease in the volume and increase in the viscosity of the individual droplets. Various polysaccharides, polysaccharide derivatives, and synthetic polymers can be used in this technique.
Use of starch as a vehicle for the delivery of drugs and pharmaceuticals is currently limited to only a few specific areas, for example: (1) use of powdered starch (or starch derivatives) in the formulation and pressing of tablets, which are then ingested to deliver their active ingredient; (2) use of capsules that are prepared by molding starch in the presence of plasticizing agents such as water. Capsules are then filled with active ingredient in a separate step. These capsules are thick-walled, have large diameters and also must be ingested to deliver their active ingredient. Neither of these two technologies can be used to deliver drugs or pharmaceuticals by injection.
U.S. Pat. No. 5,676,994, which is incorporated herein by reference, describes compositions prepared by mixing starch, water and a lipophilic component at room temperature and then passing this mixture through an excess steam jet cooker. The resulting jet cooked compositions are stable with respect to separation and coagulation of oil droplets and are comprised of microscopic droplets of oil, about 1-10 microns in diameter, uniformly distributed in the starch-water phase. No emulsifying agents, dispersing agents or surface-active agents are used in the process. The amount of oil in the formulation generally does not exceed 65 parts per 100 parts of starch by weight (about 40% of the total product), and preferred compositions are comprised of about 20-40 parts of oil per 100 parts of starch (17-29%, by weight). The one embodiment that produced a composite containing as much as 90% oil was prepared from a starch-soy protein mixture, rather than pure starch (Example 38 in U.S. Pat. No. 5,676,994). The resulting jet cooked dispersions are useful for a number of end-use applications and are characterized by the following properties: (1) they do not phase separate into their oil and water components on prolonged standing; (2) when cooled, they form soft gels that can be easily converted back to pourable fluids by the application of heat; (3) they may be dried, for example by drum drying, to yield solid compositions that are not oily to the touch; and (4) dried compositions hydrate rapidly and are easily redispersed in water to form smooth, stable, lump-free dispersions that are similar in properties and appearance to aqueous compositions that have never been dried. The electron micrographs in a publication by Eskins et al. (
Carbohydrate Polymers,
29: 233-239, 1996) show what appears to be a boundary layer of unknown composition surrounding the lipophilic droplets prepared by the same method as the aforementioned patent. The nature of that boundary layer has not heretofore been characterized.
SUMMARY OF THE INVENTION
We have now discovered a method for making microscopic-sized polysaccharide-based shells having use for forming water-dispersible microcapsular delivery systems for both hydrophilic and lipophilic drugs, pharmaceuticals, cosmetics and other active agents.
This invention is based on the discovery that when a completely solubilized natural polysaccharide and a water-immiscible material are intimately combined under high shear conditions, it is possible to isolate discrete polysaccharide-coated lipophilic droplets without the use of cross-linking agents. These droplets are conveniently separated from the predominantly-polysaccharide fraction of the jet-cooked dispersion by diluting the dispersion with water and then either centrifuging the diluted dispersion or allowing it to stand for a period of time sufficient for the layers to separate under the force of gravity according to their relative densities. Polysaccharide-coated lipophilic droplets are then isolated from either the surface of the dispersion or from the denser layer that settles to the bottom. The isolated droplets may be further purified by washing with water. The polysaccharide coating that surrounds each droplet is stable and prevents the droplets from coalescing when they are isolated, washed, and used for various end-use applications. The polysaccharide coating also causes these droplets to disperse instantly with minimum agitation when they are diluted with water. Moreover, if a volatile lipophilic material is used, hollow spheres can be recovered by permitting the lipophile to evaporate.
In accordance with this discovery, it is an object of this invention to provide new and novel compositions of matter comprised of microscopic-sized, fully biodegradable, natural polysaccharide-based shells useful as microcapsular delivery systems.
It is also an object of the invention to provide micron-sized lipophilic droplets, each droplet being coated with a thin layer of polysaccharide.
Another object of this invention to provide a process for the preparation of the aforementioned lipophile/polysaccharide compositions.
A further object of the invention is to provide injectable drugs and pharmaceuticals comprising aqueous dispersions of the aforementioned microcapsular delivery systems comprising polysaccharide-based shells containing hydrophilic or lipophilic active agents.
Other objects and advantages of the invention will become apparent from the following discussion.
REFERENCES:
patent: 4256834 (1981-03-01), Zuk et al.
patent: 4972000 (1990-11-01), Kawashima et al.
patent: 5112688 (1992-05-01), Michael
patent: 5183690 (1993-02-01), Carr et al.
patent: 5260002 (1993-11-01), Wang
patent: 5292507 (1994-03-01), Charley
patent: 5456985 (1995-10-01), Zgoulli et al.
patent: 5549908 (1996-08-01), Smith et al.
patent: 5676994 (1997-10-01), Eskins et al.
patent: 5733566 (1998-03-01), Lewis
patent: 5993855 (1999-11-01), Yoshimato et al.
Arshady, R., “Microspheres and Microcapsules: A Survey of Manufacturing Techniques. Part 1:Suspension Cross-Linking”,polymer Engineering and Science, Dec. 1989, vol. 29, No. 24, pp. 1746-1758.
Arshady, Reza, “Microspheres and Microcapsules, a Survey of Manufacturing Tecnhiques Part II: Coacervation”,Polymer Engineering and Science, Mid-Aug. 1990, vol. 30, No. 15, pp. 905-914.
Arshady, Reza, “Microspheres and Microcapsules, a Survey of Manufacturing Techniques: Part III Solvent Evaporation”,Polymer Engineering and Science, Mid-Aug. 1990, vol. 30, No. 15, pp. 915-924.
Knutson, C.A., “Isolation of Water
Eskins Kenneth
Fanta George F.
Felker Frederick C.
Knutson Clarence A.
Fado John D.
Page Thurman K.
Ribando Curtis P.
Silverstein M. Howard
The United States of America as represented by the Secretary of
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