Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1997-04-17
2003-12-02
Webman, Edward J (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S500000, C424S501000, C424S484000, C424S485000, C424S486000, C424S488000, 91, 91
Reexamination Certificate
active
06656508
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to sustained-release formulations using alginate gel beads and methods thereof.
BACKGROUND
With the advances in genetic and cell engineering technologies, the availability of recombinant proteins has engendered advances in the use of proteins as medicaments for therapeutic applications. Many illnesses or conditions treated with pharmaceutical proteins require sustained protein levels to achieve the most effective therapeutic result. However, as with most protein pharmaceuticals, the generally short biological half-life requires frequent administration. These repeated injections are given at various intervals which result in fluctuating medication levels at a significant physical and monetary burden on the patients. Since many conditions respond better to controlled levels of a pharmaceutical, a need exists for controlled release of a medicament to provide longer periods of consistent release. Such sustained-release medicaments would provide the patient with not only enhanced prophylactic, therapeutic or diagnostic effects, but also a decrease in the frequency of injections as well as in overall costs.
Current attempts to sustain medication levels in humans or animals between doses have included the use of biodegradable polymers as matrices to control medicament release. For example, Great Britain Patent No. 1,388,580 discloses the use of hydrogels for sustained-release of insulin. U.S. Pat. No. 4,789,550 discloses the use of polylysine coated alginate microcapsules for delivery of protein by encapsulating living cells. Sustained-release attempts have also utilized anionic or cationic polymer compositions surrounded by ionic polymers of the opposite charge for encapsulating cells capable of producing biologically active compositions. U.S. Pat. No. 4,744,933. Likewise, multiple coats of anionic or cationic cross-linking polymers have also been disclosed as means for obtaining controlled release. U.S. Pat. Nos. 4,690,682 and 4,789,516. In addition, further attempts disclose the use of alginates alone, or alginates coated with other biodegradable polymers, for controlled release of polypeptide compositions or cation precipitates thereof. PCT WO 96/00081, PCT WO 95/29664 and PCT WO 96/03116.
These attempts, however, have provided insufficient means for obtaining sustained-release delivery of desired protein pharmaceuticals. It is generally known that the use of certain biodegradable polymers, e.g., polylactide co-glycolide, under in vivo conditions, exhibit high initial bursts of medicament release. Johnson, O. et al., Nature Med., 2/7: 795 (1996). Furthermore, it is generally known that proteins used with current forms of sustained-release preparations can undergo denaturation and lose their bioactivity upon exposure to the encapsulating agents. Such preparations use organic solvents which can have deleterious effects on the protein of choice. Finally, as discussed below, use of alginate alone has not provided the desired controlled protein release necessary for effective therapeutic results.
In general, alginates are well known, naturally occurring, anionic, polysaccharides comprised of 1,4-linked-&bgr;-D-mannuronic acid and &agr;-L-guluronic acid. Smidsrod O. et al., Trends in Biotechnology, 8: 71-78 (1990); Aslani, P. et al., J. Microencapsulation, 13/5: 601-614 (1996). Alginates typically vary from 70% mannuronic acid and 30% guluronic acid, to 30% mannuronic acid and 70% guluronic acid. Smidsrod, supra. Alginic acid is water insoluble whereas salts formed with monovalent ions like sodium, potassium and ammonium are water soluble. McDowell, R. H., “Properties of Alginates” (London, Alginate Industries Ltd, 2nd edition 1961). Polyvalent cations are known to react with alginates and to spontaneously form gels.
Alginates have a wide variety of applications such as food additives, adhesives, pharmaceutical tablets and wound dressings. Alginates have also been recommended for protein separation techniques. For example, Gray, C. J. et al., in Biotechnology and Bioengineering, 31: 607-612 (1988) entrapped insulin in zinc/calcium alginate gels for separation of insulin from other serum proteins.
Alginate matrices have also been well documented for drug delivery systems, see for example U.S. Pat. No. 4,695,463 disclosing an alginate based chewing gum delivery system and pharmaceutical preparations. Alginate beads have been used for controlled release of various proteins such as: tumor necrosis factor receptor in cation-alginate beads coated with polycations, Wee, S. F, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 21: 730-31 (1994); transforming growth factor encapsulated in alginate beads, Puolakkainen, P. A. et al., Gastroenterology, 107: 1319-1326 (1994); angiogenic factors entrapped in calcium-alginate beads, Downs, E. C. et al., J. of Cellular Physiology, 152: 422-429 (1992); albumin entrapped in chitosan-alginate microcapsules, Polk, A. et al., J. Pharmaceutical Sciences, 83/2: 178-185 (1994) or chitosan-calcium alginate beads coated with polymers, Okhamafe, A. O. et al., J. Microencapsulation, 13/5: 497-508 (1996); hemoglobulin encapsulated with chitosan-calcium alginate beads, Huguet, M. L. et al., J. Applied Polymer Science, 51: 1427-1432 (1994), Huguet, M. L. et al., Process Biochemistry, 31: 745-751 (1996); and interleukin-2 encapsulated in alginatechitosan microspheres, Liu, L. S. et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater, 22: 542-543 (1995).
Systems using alginate gel beads, or alginate/calcium gel beads, to entrap proteins suffer from lack of any sustained-release effect due to rapid release of the protein from the alginate beads. Liu, L. et al., J. Control. Rel., 43: 65-74 (1997). To avoid such rapid release, a number of the above systems attempt to use polycation polymer coatings (e.g., polylysine, chitosan) to retard the release of the protein alginate beads. See, e.g., Wheatley, M. A. et al., J. Applied Polymer Science, 43: 2123-2135 (1991); Wee, S. F. et al. supra; Liu, L. S. et al. supra; Wee, S. F. et al., Controlled Release Society, 22: 566-567 (1995) and Lim, et al. supra.
Polycations, such as polylysine, are positively charged polyelectrolytes which interact with the negatively charged alginate molecules to form a polyelectrolyte complexes that act as diffusion barriers on the bead surface. Problems can occur with the use of polycations in that: (1) such formulations maybe cytotoxic due to the polycations (Huguet, M. L. et al., suDra; Zimmermann, Ulrich, Electrophoresis, 13: 269 (1992); Bergmann, P. et al., Clincial Science, 67: 35 (1984)); (2) polycations are prone to oxidation; (3) beads with polycation coatings tend not to be erodible and build up in the body; (4) such formulations are made via laborious coating procedures which include multiple coatings of the polycation polylysine (Padol, et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater, 2: 216 (1986) and (5) ionic interactions between the protein and the polycations can result in loss of protein activity or cause protein instability.
Accordingly, a need exists to develop pharmaceutical formulations which achieve a better means of sustained-release for clinical applications. Numerous recombinant or natural proteins could benefit from constant long term release and thereby provide more effective clinical results.
The present invention provides such advances. Pharmaceutical compositions of the present invention are capable of providing protein protection, decreased degradation and slow release with increased protein stability and potency. Also, pharmaceutical compositions of the present invention provide a simple, rapid and inexpensive means of controlled recombinant protein release for effective prophylactic, therapeutic or diagnostic results.
SUMMARY OF THE INVENTION
The present invention relates to sustained-release formulations using alginate gel beads or particles, and methods thereof. In particular, the formation of the sustained-release gels includes the co-precipitation of alginate gel beads with a biologically act
Beekman Alice C.
Goldenberg Merrill Seymour
Amgen Inc.
Eggert Joan D.
Levy Ron K.
Watt Stuart L.
Webman Edward J
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