Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-06-26
2003-03-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S489000, C424S469000, C424S488000, C424S493000, C424S485000, C424S486000, C424S484000
Reexamination Certificate
active
06534090
ABSTRACT:
The present invention relates to an oral osmotic controlled drug delivery system for a sparingly soluble drug.
BACKGROUND OF THE INVENTION
Carbamazepine, 5H-dibenz-[b,f]azepine-5-carboxamide, is used as an anti-convulsant and is available commercially in the form of tablets, syrups, chewable tablets and extended-release formulations. It is used in patients who do not respond satisfactorily to other forms of treatment. The drug appears to act by reducing polysynaptic responses and by blocking post-tetanic potentiation.
The therapeutic range of carbamazepine is about 4-12 &mgr;g/ml. Blood levels of carbamazepine below 4 &mgr;g/ml are ineffective in treating clinical disorders, while levels above 12 &mgr;g/ml are most likely to result in side-effects. The side-effects are seen to a greater extent in syrup formulations due to the presence of fine particles of the active ingredient, which dissolve rapidly leading to faster drug absorption and higher peak plasma levels. The tablet formulations are relatively free of this disadvantage.
The oral osmotic system (OROS®, Alza Corp.), described by F. Theeuwes in J. Pharm. Sci., Vol. 64, 12, 1987-1991 (1975), consists of a therapeutic system in the form of a coated and/or a laminated monocompartment system, comprising, a semi-permeable wall/coat covering a drug-containing core and a passageway through the wall for releasing the contents of the core. Water permeates from the surrounding body fluids through the semi-permeable wall/coat and the pressure that is built-up causes a solution or suspension of the drug in the core to be released from the passageway. When a suspension of the drug is released, the released drug crystals dissolve and the dissolved drug is available for absorption from the gastrointestinal fluids into the general circulation. Hereinafter, the term “release” is used while referring to release of a suspension of a drug from an osmotic system and the term “delivery” or “drug delivery” is used in reference to appearance of dissolved drug in dissolution fluids or gastrointestinal fluids.
The OROS® system is unsuitable for drugs like carbamazepine, which are sparingly soluble in water and thus the osmotic pressure generated by the drug on its own is too low to cause release of the drug formulation from the core at a constant rate. Incorporation of an osmotic agent other than the drug itself requires fabrication of a two-layered osmotic system, one layer containing the drug and a second layer containing the osmotic agent and a swelling agent. Osmotic influx of water causes the swelling of a swellable polymer in the core and expels the contents of the drug compartment through the orifice. As compared to single compartment systems, the manufacture of two-compartment systems is more complicated. Another problem is that anhydrous carbamazepine (amorphous or crystalline) gets converted to the dihydrate form in an aqueous environment. These dihydrate crystals are needle-shaped and grow to ca. 500 &mgr;m in size in the longitudinal direction. They affect the release of the drug formulation by blocking the passageway of the dosage form. Still another problem is that when known swelling agents such as polyvinylpyrrolidone, polyethylene oxide, polymethacrylate, etc are used in single compartment systems as the swellable polymer, the swelling pressure is so great that in contact with water the semi-permeable membrane bursts and the whole system disintegrates in the stomach after a short time.
The above mentioned drawbacks were overcome by a single compartment osmotic system disclosed in U.S. Pat. No. 4,857,336 ('336) reissued as RE 34990, assigned to Ciba-Geigy. The foregoing describe an oral therapeutic system comprising a core containing finely particulate anhydrous carbamazepine as a drug, hydroxypropyl methylcellulose (HPMC) as a protective colloid, a swellable hydrophilic polymer selected from the group consisting of poly-N-vinyl-2-pyrrolidone, polyvinyl alcohol, alkylene oxide homopolymers, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, a copolymer of vinyl pyrrolidone and vinyl acetate, a mixture of a copolymer of vinyl pyrrolidone and vinyl acetate, and a homopolymer of ethylene oxide, and a water-soluble compound for inducing osmosis. HPMC herein works as a protective colloid such that it inhibits the ability of carbamazepine to change from the anhydrous form to any other form. Thus, in the presence of HPMC, the anhydrous carbamazepine crystals within the system remain in their original fine state without converting to large crystals of the dihydrate, which block the drug formulation releasing orifice. It is explained in lines 35-39 of column 4 of the '336 patent that the therapeutic system is therefore able to release carbamazepine microcrystals having a size of up to about 20 &mgr;m.
The oral osmotic dosage delivery form disclosed in U.S. Pat. No. 5,284,662 ('662) is an improvement over the system of the '336 patent and comprises a core comprising (i) carbamazepine, (ii) an effective amount of a crystal habit modifier for said carbamazepine selected from the group consisting of C
1-4
alkyl cellulose, hydroxypropyl-C
1-4
alkyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl C
1-4
alkyl cellulose, and gelatin, (iii) from about 2% to about 15% of the total core weight of a mixture of at least two different hydroxy-C
1
-C
4
-alkyl celluloses wherein the ratio of the higher viscosity to the lower viscosity hydroxy-C
1
-C
4
-alkyl cellulose is about 2:1, (iv) a C
6
sugar alcohol, (v) a mono-or di-saccharide, (vi) from 0 to an effective amount of a tabletting lubricant, and (vii) from 0 to an effective amount of a wetting agent, with the core surrounded by a semi-permeable wall with a hole that connects the core with the external environment. In comparison to the system of the '336 patent, the system disclosed in the '662 patent requires the presence of additional specific excipients, particularly a mono- or di-saccharide, more particularly a dextrate, and also requires the two different hydroxyalkyl celluloses to be present in a particular ratio of 2:1. These changes are said to result in a surprising and unexpectedly better product in that carbamazepine is released in a zero-order fashion over about 6 hours, whereas the system of the '336 patent having the two different hydroxyalkyl celluloses in a 1:1 ratio delivered only 33% of the carbamazepine in a zero-order fashion over a period of only about 4 hours. Although a broad group of cellulose-based polymers and gelatin are mentioned as crystal habit modifiers in the '662 patent, only hydroxypropyl methylcellulose is exemplified.
U.S. Pat. No. 4,992,278 ('278) discloses a peroral therapeutic system in tablet form for continuous and controlled administration of active ingredients that are sparingly soluble in water, and consists of (a) a casing made of a semi-permeable material, (b) a compressed core containing the active ingredient, a hydrophilic swelling polymer consisting of a mixture of a vinyl pyrrolidone/vinyl acetate copolymer with an ethylene oxide homopolymer, optionally a water soluble substance for inducing osmosis, and optionally other pharmaceutically acceptable adjuvants, and (c) a passage through the casing for transport of the components of the core to the surrounding aqueous body fluid. The patent teaches that when known swelling agents such as polyvinylpyrrolidone, polyethylene oxide, polymethacrylate and the like, are used in single compartment systems the swelling pressure is so great that in contact with water the semi-permeable membrane bursts and the whole system disintegrates in the stomach after a short time. The problem is said to be solved by the advantageous swelling polymer mixture of the '278 patent. However, the systems exemplified in the '278 patent use large quantities of polymer. It would be desirable to use swelling polymers having a high degree of swelling such that they are usable in small amounts and do not contribute to increa
Dharmadhikari Nitin B.
Karajgi Jayant S.
Menon Suma G.
Pilgaonkar Pratibha S.
Puthli Shivanand P.
Fubara Blessing
Page Thurman K.
Proskauer Rose LLP
Sun Pharmaceutical Advanced Research Centre Limited
LandOfFree
Oral osmotic controlled drug delivery system for a sparingly... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oral osmotic controlled drug delivery system for a sparingly..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oral osmotic controlled drug delivery system for a sparingly... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3007336