Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-02-28
2003-06-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S468000, C424S470000, C424S474000, C424S475000, C424S484000, C424S486000, C424S489000, C424S451000, C424S452000, C424S457000, C424S458000, C424S460000, C424S461000, C424S462000
Reexamination Certificate
active
06576260
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to forms of administration of tramadol, retarded by a coating, which contain the active substance tramadol as tramadol saccharinate, optionally together with other auxiliary substances.
The very readily water-soluble tramadol hydrochloride—(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride—is often used for the control of intense and moderately intense pain.
The administration of tramadol hydrochloride in the form of sustained-release preparations represents a therapeutic improvement for this active substance. Even for this active substance with its relatively short half-life in the organism, retardation makes it possible to provide a preparation with a long-lasting action and also, through more constant blood levels, to reduce side effects and improve the patients' observance of the dosage instructions.
The active substance tramadol hydrochloride can be retarded e.g. by the application of sustained-release film coatings to pharmaceutical forms containing tramadol hydrochloride. However, retardation of this active substance with the aid of film coatings is relatively expensive because film coatings from aqueous coating systems for very readily water-soluble active substances of this kind frequently constitute an inadequate diffusion barrier and the permeability of these film coatings for tramadol hydrochloride usually changes during storage (P. B. O'Donnell, J. W. McGinity, “Mechanical Properties of Polymeric Films, Prepared from Aqueous Polymeric Dispersions in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms”, Drugs and the Pharmaceutical Science, vol. 79, ed. J. W. McGinity, Marcel Decker, New York, Basle, Hong Kong 1997).
The manufacture of these retarded tramadol hydrochloride preparations therefore requires relatively expensive coating processes with multilayer films or time-consuming tempering processes, as described in U.S. Pat. Nos. 5,645,858, 5,580,578, 5,681,585 or U.S. Pat. No. 5,472,712, in K. Bauer, “Coated Pharmaceutical Dosage Forms”, Medpharm Scientific Publishers, Stuttgart 1998, B. Sutter, Thesis, University of Düsseldorf, 1987, or in F. N. Christensen, Proceed. Intern. Symp. Contr. Rel. Bioact. Mater. 17, 124, 1990. If such coatings are applied from organic solvents, the associated environmental and solvent residue problems further increase the gcost of retarding tramadol hydrochloride.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The object of the invention was therefore to provide a form of administration, or a pharmaceutical formulation, of the active substance tramadol, retarded with the aid of a coating, whose active substance release profile immediately after preparation is stable on storage without the need for laborious and expensive coating processes or time-consuming and hence cost-intensive tempering processes.
According to the invention, this object is achieved by the preparation of forms of administration, provided with a sustained-release coating, which contain the active substance tramadol as tramadol saccharinate, optionally together with other pharmaceutically acceptable auxiliary substances or excipients.
Surprisingly, the active substance release profile of the retarded forms of administration according to the invention immediately after preparation is stable on storage without the sustained-release coating having to undergo tempering after the conventional drying.
To prepare the tramadol saccharinate, tramadol—(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol—and/or at least one appropriate, preferably water-soluble salt are reacted with saccharin and/or at least one, preferably water-soluble saccharin salt. The tramadol salt used is preferably tramadol hydrochloride and the saccharin salt used is preferably the sodium, potassium, calcium or ammonium salt and particularly preferably the sodium salt.
The tramadol saccharinate can also be formed in situ during the preparation of the forms of administration.
In terms of the present invention, in situ formation means that a readily water-soluble salt of tramadol is mixed with a water-soluble salt of saccharin, moistened and granulated several times, optionally extruded and/or formulated under some other energy input, preferably under pressure and/or with the application of heat.
For the in situ formation of tramadol saccharinate, the tramadol can be used as a water-soluble, pharmaceutically acceptable salt, preferably as tramadol hydrochloride, and the water-soluble, pharmaceutically acceptable salt of saccharin used is preferably the sodium, potassium, calcium or ammonium salt and particularly preferably the sodium salt.
The forms of administration according to the invention, provided with a sustained-release coating film, are preferentially suitable for oral administration.
In one preferred embodiment of the present invention, the forms of administration according to the invention are tablets, capsules or suspensions.
In another preferred embodiment of the present invention, the forms of administration according to the invention are multiparticulate, preferably in the form of microtablets, microcapsules, micropellets, granules, active substance crystals or pellets, optionally filled into capsules or compressed to tablets, or in a hydrophilic or lipophilic liquid, preferably as a homogeneous suspension, and particularly preferably in the form of juices or oral dispersions. If the forms of administration according to the invention are granules or pellets, they can preferably have a size in the range 0.1 to 3 mm and particularly preferably in the range 0.5 to 2 mm.
If the forms of administration according to the invention are microtablets, they can preferably have a diameter in the range 0.5 to 5 mm, particularly preferably in the range 1 to 3 mm and very particularly preferably in the range 1 to 2 mm.
If the forms of administration according to the invention are active substance crystals, microparticles, micropellets or microcapsules, they can preferably have a diameter in the range 10 &mgr;m to 1 mm, particularly preferably in the range 15 &mgr;m to 0.5 mm and very particularly preferably in the range 30 &mgr;m to 200 &mgr;m.
Depending on the embodiment, the forms of administration according to the invention can also contain, as additional constituents, the conventional auxiliary substances known to those skilled in the art.
If the forms of administration according to the invention are tablets or microtablets, they can preferably contain, as additional auxiliary substances, microcrystalline cellulose, cellulose ethers, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogenphosphate and the conventional binders, flow regulators, lubricants and optionally disintegrants known to those skilled in the art.
If the forms of administration according to the invention are pellets, granules or micropellets, they can preferably contain, as additional auxiliary substances, microcrystalline cellulose, cellulose ethers, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogenphosphate, fatty alcohols, glycerol esters or fatty acid esters.
If the forms of administration according to the invention are microcapsules or microparticles, they can contain the conventional auxiliary substances known to those skilled in the art, depending on the type of production process.
The various forms of administration according to the invention can be produced by different methods known to those skilled in the art.
If the form of administration according to the invention is tablets, they can be produced for example by the compression of granules produced by means of moist, dry or hot-melt granulation, or by direct tableting of the tramadol saccharinate, optionally with additional auxiliary substances. The tablets can also be produced by the compression of coated pellets, active substance crystals, microparticles or microcapsules.
The pellet form of administration according to the invention can be produced by extrusion and spheronization, by
Bartholomaeus Johannes
Kugelmann Heinrich
Ziegler Iris
Bennett Rachel M.
Crowell & Moring LLP
Gruenenthal GmbH
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