Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-06-21
2004-04-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S464000, C424S465000, C424S468000, C424S474000, C424S475000, C424S479000
Reexamination Certificate
active
06720005
ABSTRACT:
FIELD
This invention concerns a tablet adapted for controlled release of various pharmaceuticals.
BACKGROUND
It, Controlled release pharmaceutical dosage forms are commercially available. Zero order drug release from dosage forms is desired in order to provide a uniform and sustained drug delivery to a patient, but this is not easily achieved. Osmotic pump tablets are known (U.S. Pat. No. 5,545,413), and do a good job of providing zero order drug release. These tablets comprise a rigid coating membrane having an aperture formed therethrough using a laser. Gastrointestinal fluids penetrate the semipermeable coating membrane, and the core of the device generates sufficient pressure to force drug out through the laser-drilled aperture. These tablets generally provide a lag time of up to about two hours before beginning to release drug because some time is required for gastrointestinal fluids to penetrate the semipermeable coating membrane, and for the core of the device to generate sufficient pressure to begin forcing drug out through the aperture.
The osmotic pump tablets provide several advantages, including drug release which is independent of both pH and ionic strength. Moreover, drug release is not affected by erosion as a result of peristaltic gastrointestinal motion. Although these dosage forms provide zero-order drug release, they suffer from many problems in large-scale production. The semipermeable membranes which control water flow into the tablet, but block water flow out of the tablet, must be cast using organic solvents which are environmental pollutants closely regulated by the Environmental Protection Agency. This alone makes the process very expensive and undesirable. Moreover, laser equipment is required to drill the effluent hole in each tablet through which the drug must exit. Special equipment is required to position each tablet, one-at-a-time, correct side up, to drill the laser hole.
There also are problems associated with drug delivery using these osmotic pump tablets. For example, since drug can exit the tablet only through the aperture, any tablet which becomes trapped with the aperture against the gastrointestinal wall will pump drug directly into a localized spot on the mucous membrane. Thus, mucosal irritants, such as indomethacin and other non-steroidal anti-inflammatory drugs, should not be administered using osmotic pump tablets. Osmotic tablets do not release drug in some desirable ways, such as sustained fashion in the lower intestine, e.g., sustained colonic drug delivery without prior delivery of much of the drug in the upper gastrointestinal tract.
Hydrophilic-gum-matrix, controlled-release tablets are much easier to produce than osmotic pumps and provide sustained drug release. However, such tablets do not provide good zero-order drug release and cannot provide a lag time prior to drug release. These tablets do not provide pulsatile drug delivery. Further, hydrophilic gum matrix tablets undergo erosion in the gastrointestinal tract as a result of peristaltic activity such that drug release is much faster during times of high GI activity, which occurs with meals, than when the GI tract is quiescent, such as during fasting (Bertil Abrahamsson, Magne Alpsten, Gjorn Bake, Ulf 3onsson, Maria Eriksson-Lepkowska and Annhild Larsson, “Drug Absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of food”, Journal of Controlled Release, 52, pp. 301-310 (1998)). There is no lag time for drug release from hydrophilic matrix ER tablets, and gastric erosion speeds up drug release to an undesirable extent as shown by Abrahamsson, et al.
A discussion of matrix tablet formation and difficulties associated with obtaining the desired drug release rate can be found in U.S. Pat. No. 5,783,212. This patent also points out problems with multilayer matrix tablets containing swellable layers which are not erodible, and erodible layers which are not swellable, including the lack of desired control over drug release rate from hydrophilic matrix gum tablets. U.S. Pat. No. 5,783,212 then describes multiple compression of at least three layers of swellable erodible polymers to form a tablet which controls drug release. U.S. Pat. No. 4,839,177 discloses multiple layer tablets containing a) a deposit-core of active substance, a high degree of swelling polymer and/or a swelling and gelling polymer and b) an aqueous insoluble support platform partially covering the deposit-core. The deposit-core tablet hydrates, swells, and erodes but the aqueous insoluble support platform remains attached to the core tablet for a prolonged time. These hydrophilic gum matrix tablets differ from known hydrophilic gum matrix tablets at least by virtue of their aqueous insoluble support platforms which leave at least one surface exposed and uncoated prior to administration. A particularly good review in this area is “Multi-layered hydrophilic matrices as constant release devices (Geomatrix Systems”, U. Conte, L. Maggi, P. Colombo, and A. La Manna, Journal of Controlled Release, 26 (1993) 39-47.
Conte, et al., identify the advantages of tablets described in U.S. Pat. No. 4,839,177 and point out the need to identify a method for industrial production of the devices described. The key to practicing the '177 patent is to only partially cover the tablet so there is at all times an uncoated area which allows drug to be released. However, this key feature is impossible to achieve using modem tablet spray coating chambers. Conte, et al., states that “the application by casting of an impermeable film on a portion of the matrix tablet could only be obtained manually. To overcome this drawback which does not allow for the automatic production of the system, different approaches were tried”. That is, the key requirement for practicing the invention of only partially covering the tablet to expose a fixed portion of the tablet results in the impossibility of automatic production by casting or spray coating with impermeable films because such commercial processes cover the entire tablet. Thus, Conte, et al. used a multi-layer compression process known in the art to produce two layer tablets, three layer tablets, or even compression coated tablets which can produce a tablet completely surrounded by an outer compression coat. This process does allow automatic production of multi-layer tablets with characteristics of the '177 patent, but creates a new problem which is real and significant. That is, multiple layer tablets and compression coating both require special equipment which is very expensive and not widely available. And, such tablets are known to suffer from problems including splitting, cracking, or separation, especially the compression coated tablets. Coats of less than 1 mm are not possible because thinner coats crack at the core tablet edges. This coating thickness requirement can make an already large tablet too large to swallow.
Drug release from hydrophilic gum matrix core tablets partially coated by manual casting of an impermeable film (Conte, et al.) was described by the equation Q/Q=kt
n
where Q/Q=fraction of drug released at time t, k=kinetic constant, and n=exponent of drug release. When n=1, drug release is zero-order. The n values reported by Conte, et al. were 0.66, 0.64, 0.79, 0.84, and 0.76. Drug release is considered to be approximately zero order when the calculated n value for average dissolution results is greater than at least 0.70. Expected n values associated with drug release from an osmotic pump tablet are closer to 1.0. And, none of the partially covered, hand cast impermeable film coated matrix tablets provided a lag time prior to release of drug. Only the relatively difficult to produce compression coated core tablet was able to provide a lag time prior to drug release. The partially support coated tablets cannot be used for prevention of drug release in the stomach or upper small intestine.
Film coats have been applied to hydrophilic matrix tablets but they ar
Kishore Gollamudi S.
Klarquist & Sparkman, LLP
Oh Simon J.
The State of Oregon acting by and through the State Board of Hig
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