Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-01-21
2002-02-12
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S470000, C514S772300, C514S779000, C514S781000
Reexamination Certificate
active
06346268
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to formulations for preparing sustained release drug forms useful for releasing pharmaceuticals at controlled rates, generally in the stomachs and/or gastrointestinal tracts of hosts. In particular the invention relates to an improved depot drug form useful in connection with preparing sustained release tablets.
BACKGROUND OF THE INVENTION
A zero order release profile for a drug from its controlled release dosage form sometimes is desirable in clinical use. The technology used to formulate zero order release dosage forms is well documented. The entrapment of a drug in a matrix is a common approach to formulate sustained release tablets with a zero order release profile.
It has been reported that depot drug formulations for controlled release of pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat. No. 5,132,295), using combinations of alginates and polyacrylates (see U.S. Pat. No. 5,230,901) and using combinations of alginates and a pH independent hydrocarbon gelling agent, such as, for example, hydroxypropylmethyl cellulose (see U.S. Pat. No. 4,792,452). It is also known that the use of alginates alone for this purpose often presents difficulties in tableting, film coating and storage.
Adding polyacrylates to the alginate formulation overcomes these difficulties to some extent; however, tablets formed using alginates and polyacrylates often have a pH dependent dissolution profile. In a low pH environment, alginates and polyacrylates do not swell and/or dissolve properly. This leads to drug release by a diffusion mechanism through non-viscous capillaries resulting in a different dissolution rate than in a high pH environment. On the other hand, in a high pH environment, alginates swell and become soluble while polyacrylates may or may not do the same. This leads to drug release both by erosion and diffusion at a rate which is different than the low pH release rate.
In formulations which include an alginate and a pH independent gelling polymer such as, for example, hydroxypropylmethyl cellulose, such polymers hydrate at low pH levels to create a viscous gel layer for drug release. At high pH levels, however, tablets become smaller and smaller during drug release due to polymer erosion, and this leads to a reduction in surface area which may affect dissolution rate.
SUMMARY OF THE INVENTION
A novelty of the present invention is the provision of a sustained release formulation which reduces, and perhaps eliminates these problems completely. In particular the invention provides a controlled release drug formulation which includes 1) a pH dependent gelling polymer such as, for example, an alginate material, a carboxyvinyl polymer or a sodium salt of carboxymethyl cellulose, 2) an enteric polymer, such as, for example, a cellulose acetate phthalate, a cellulose phthalate hydroxy propyl methyl ether, a polyvinyl acetate phthalate, a hydroxy propyl methyl cellulose acetate succinate, a cellulose acetate trimellitate, a shellac or apolyacrylate material such as Eudragit® or Eudragit® S, and 3) a pH independent gelling polymer, such as, for example, a hydroxy propyl methyl cellulose, a hydroxy propyl ethyl cellulose, a hydroxy propyl cellulose, a hydroxy ethyl cellulose, a methyl cellulose, a xantham gum or a polyethylene oxide. Such a combination of ingredients facilitates manufacturing procedures and improves drug dissolution profile.
In the formulation in accordance with the present invention, the pH dependent gelling polymer provides excellent binding and controlled release characteristics thereby facilitating the manufacturing processes. During dissolution, the pH independent gelling polymer hydrates to form a gel layer to control drug release at low pH levels. At high pH levels, the enteric polymer increases erosion rate so as to maintain a constant dissolution rate regardless of tablet size. So reduction in tablet size does not reduce release rate. Thus, the formulations of the present invention provide improved drug release profiles compared with the prior art formulations described above.
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Excerpts from theHandbook of Pharmaceutical Excipients, Second Edition, published by the American Pharmaceutical Association.
Ali Muhammad
Pinnamaraju Prasad
Zhang Guohua
Duramed Pharmaceuticals, Inc.
Marsh, Jr. James H.
Shook Hardy & Bacon L.L.P.
Spear James M.
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