Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-04-29
2002-02-26
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S472000, C424S452000, C424S489000, C514S960000
Reexamination Certificate
active
06350470
ABSTRACT:
BACKGROUND OF THE INVENTION
Many orally-administered drugs display poor bioavailability when administered in conventional dosage forms, i.e., the rate and extent to which the drugs are absorbed is less than desirable. With several drugs, absorption may be as little as 30% or less of the orally administered dose. To compensate for this effect, a very large dose is often administered so that absorption of the therapeutically required quantity of the drug can occur. This technique may prove costly with expensive drugs; and the nonabsorbed drug may also have undesirable side effects within the gastrointestinal tract. In addition, poorly absorbed drugs often display large inter- and intrasubject variability in bioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-987, 1993. Specific examples (with the average bioavailability given in parentheses) include methyldopa (25%) with a range of 8% to 62%. See Kwan, K. C., Folz, E. L., Breault, G. O., Baer, J. E., Totaro, J. A., J. Pharmacol. Exp. Ther., 198:264-277, 1976; and nalbuphine (approximately 17%) with a range of 6% to 40%. See Lo. M.-W, Schary, W. L., Whitney, C. C., Jr., J. Clin. Pharmacol., 27:866-873, 1987. Such variation in the amount of drug absorbed does not allow for good control of the disease condition.
To improve the bioavailability of poorly absorbed drugs, penetration enhancers have also been employed. However, many of the penetration enhancers referred to in the current literature damage the absorbing tissues and thus are not a practical solution to the problem of poor bioavailability. In fact, it has been suggested that the damage to the mucosa caused by these agents may be the factor responsible for the improved absorption. See LeCluyse, E. L. and Sutton, S. C., Advanced Drug Delivery Reviews, 23:163-183, 1997.
Other techniques which have been employed to improve bioavailability include using enteric coated tablets having effervescence to rapidly dissolve or disperse the dosage form in the stomach. See U.S. Pat. Nos. 4,503,031; 4,289,751; and 3,961,041.
SUMMARY OF THE INVENTION
The pharmaceutical compositions of the present invention comprise orally administerable dosage forms that use effervescence as a penetration enhancer for drugs known, or suspected, of having poor bioavailability. Effervescence can occur in the stomach, once the tablet or other dosage form is ingested. In addition to effervescence in the stomach, or as alternative technique, by the use of appropriate coatings and other techniques, the effervescence can occur in other parts of the gastrointestinal tract, including, but not limited to, the esophagus, duodenum, intestinal and colon. The site of effervescence and drug release is chosen to correspond with the segment of the gastrointestinal tract displaying maximal absorption of the formulated drug, or to gain some other therapeutic advantage. Desirably, such site is not in the mouth of the subject.
REFERENCES:
patent: 3961041 (1976-06-01), Nishimura et al.
patent: 4289751 (1981-09-01), Windheuser
patent: 4503031 (1985-03-01), Glassman
patent: 5178878 (1993-01-01), Wehling et al.
Eichman, J.D., and Robinson, J.R., “Mechanistic Studies on Effervescent-Induced Permeability Enhancement” Pharm. Res. 15(6):925-30 (1998).
Eichman, J.D., Thesis “Mechanistic Studies on Effervescent-Induced Permeability Enhancement” (catalogued at the University of Wisconsin-Madiosn on Sep. 18, 1998) (on file with the University of Wisconsin-Madison).
K. Sashara et al., Dosage Form Design for Improvement of Bioavailability of Levodopa IV: Possible Causes of Low Bioavailability of Oral Levodopa in Dogs, J. Pharm. Sci., (7)70:730-733 (1981).
K. Sasahara et al., Dosage Form Design for Improvement of Bioavailability of Levodopa III: Influence of Dose on Pharmacokinetic Behavior of Levodopa in Dogs and Parkinsonian Patients, J. Pharm. Sci., (12)69:1374-1378 (1980).
K. Sashara et al., Dosage Form Designe for Improvement of Bioavailability of Levodopa II: Bioavailability of Marketed Levodopa Preparations in Dogs and Parkinsonian Patients, J. Pharm. Sci., (3)69 261-265 (1980).
K. Sasahara et al., Dosage form Design for Improvement of Bioavailability of Levodopa V: Absorption and Metabolism of Levodopa in Intestinal Segments of Dogs, J. Pharm. Sci., (10)70 1157-1160 (1981).
K. Nishimura et al. Dosage Form Design for Improvement of Bioavailibility for Levodopa VI: Formulation of Effervescent Enteric-Coated Tablets, J. Pharm. Sci., (7)73 942-946 (1984).
Eichman Jonathan D.
Gupte Sangeeta V.
Hontz John
Khankari Rajendra K.
Pather S. Indiran
Cima Labs Inc.
Lerner David Littenberg Krumholz & Mentlik LLP
Spear James M.
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