Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-11-06
2001-08-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S494000, C514S785000, C514S786000, C514S970000
Reexamination Certificate
active
06270805
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to controlled release unit dose formulations of water soluble drugs in general which are exemplified by diltiazem hydrochloride (diltiazem). There is a need for a means for varying the release rates of water soluble drugs from multiparticulate beads which have release membranes that are applied by a coating process. Diltiazem is sold commercially in extended release pharmaceutical dosage forms in order to maintain a therapeutic serum level of diltiazem and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. The minimum therapeutic plasma diltiazem concentrations are in the range of 50 to 200 ng/ml.
Cardizem® CD is described as a once-a-day extended release capsule containing diltiazem and fumaric acid. In the file history of U.S. Pat. No. 5,286,497, representations were made that the formulation disclosed in that patent is the formulation for Cardizem® CD. The formulation for Cardizem® CD is identified in the file history of U.S. Pat. No. 5,286,497 as having a “stair-step release profile” which has a rapid release bead and an extended release bead.
U.S. Pat. No. 5,567,441 also discloses a formulation of diltiazem which is bioequivalent to Cardizem® CD but has a different release profile in hydrochloric acid. That formulation exhibits a slower in vitro release profile in 0.1N hydrochloric acid than the slow release bead of the present invention but exhibits substantially the same in vivo release profile.
In U.S. Pat. No. 5,229,135 and in U.S. Pat. No. 5,529,791, once-a-day formulations are described that are based on a single pellet which is prepared with an active core which is coated with diltiazem and an inner and outer membrane. Other diltiazem formulations are disclosed in U.S. Pat. No. 4,721,619; U.S. Pat. No. 4,894,240; U.S. Pat. No. 5,002,776; U.S. Pat. Nos. 5,364,620; 4,891,230; U.S. Pat. No. 4,917,899; U.S. Pat. No. 5,288,505; and U.S. Pat. No. 5,336,504.
The present invention provides novel water soluble pharmaceutical formulations which are two-pellet based capsule formulations. The diltiazem formulations made according to the present invention do not have a “stair-step release profile” but do provide a “two- peak pharmacokinetic profile”. Moreover, the diltiazem formulations of the present invention does not require the presence of fumaric acid or any other organic acid in the core. The present invention also provides a means for varying the release rates of water soluble to allow for faster in vitro release of the drug.
SUMMARY OF THE INVENTION
The present invention is directed to a once-a-day controlled release water soluble pharmaceutical formulation which comprises:
(a) from 20 to 50% by weight of polymeric enteric coated pellets comprising a polymer membrane coated core which comprises a biologically inert core which is coated with a first layer which consists essentially of a water soluble drug and a polymeric binder; and a second layer which comprises a membrane comprising a polymeric enteric coating material; and
(b) from 50% to 80% by weight of delayed pulse polymeric membrane coated pellets comprising a polymeric membrane coated core which comprises a biologically inert core which is coated with a combined first layer which consists essentially of a water soluble drug and a polymeric binder and a second layer which comprises a polymeric membrane and an alkaline earth metal stearate said second layer being capable of substantially maintaining its integrity in the varying pH conditions of the gastrointestinal tract and being permeable to said water soluble drug; and
(c) a unit dose containment system.
The present invention also provides a dosage form of diltiazem which exhibits in 0.1N HCl, a release rate profile which is initially a relatively slow, zero order release rate that continues for up to about 12-14 hours. Thereafter, there is a sharp increase in the rate of release which can be characterized as a delayed pulse.
It is surprising and unexpected that the combined zero order-delayed pulse in vitro release characteristics of the diltiazem dosage form of the present invention provides substantially the same in vivo “two peak” plasma levels of diltiazem which is provided by a commercial formulation which exhibits in vitro a stair-step type of release profile.
It is an object of the invention to provide a once-a-day water soluble drug dosage system.
It is also an object of the present invention to provide a once-a-day water soluble drug dosage system which is free of any organic acid component.
It is also an object of this invention to provide an organic acid free, once-a-day diltiazem dosage system which is therapeutically or biologically equivalent to a once-a-day stair step diltiazem dosage system which contains an organic acid.
It is also an object of this invention to provide a once a day diltiazem dosage system which is bioequivalent to Cardizem® CD but has a different in vitro release profile when the release profile is determined in 0.1N hydrochloric acid.
These and other objects of the invention will become apparent from the appended specification.
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patent: 5567441 (1996-10-01), Chen
patent: 5830503 (1998-11-01), Chen
patent: 5834023 (1998-11-01), Chen
patent: 5840329 (1998-11-01), Bai
patent: 6033687 (2000-03-01), Heinicke et al.
Chen Chih-Ming
Cheng Xiu Xiu
Andrx Pharmaceuticals Inc.
Hedman & Costigan ,P.C.
Page Thurman K.
Seidleck Brian K.
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