Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-04-23
2004-10-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S451000, C424S457000, C424S458000, C424S464000, C424S468000, C424S474000
Reexamination Certificate
active
06805881
ABSTRACT:
The present invention relates to orally administrable multiple-unit sustained-release dose forms having controlled and agitation-independent release and processes for their production using a selected erodable hydrophilic polymer.
For many medicaments, it is desirable that they guarantee a controlled, long-lasting and uniform release of the active compound after administration once daily. In this way, the desired plasma concentration can be maintained over a relatively long period without great variations and thus the medicament safety and the patient compliance are increased. Formulations which release the active compound over a defined period in this manner are called sustained-release formulations. Various techniques for their production are already known.
Very often, single-unit matrix tablets which contain the active compound in a matrix of polymers and some pharmaceutical excipients are employed for this purpose. The polymer can either be hydrophilic or hydrophobic or a mixture thereof. Meanwhile, matrix tablets containing hydrophilic polymers have become very popular, since these are comparatively inexpensive, non-toxic, processable in conventional plants, etc.
A further method is the coating of preparation forms with buffered or pH-dependent coatings which are intended to guarantee a controlled release in certain areas of the gastrointestinal tract.
While the erosion matrix tablets are susceptible to mechanical stress, in particular hydrodynamic stresses, the pH-controlled formulations are susceptible to pH changes in the gastrointestinal tract. While the tablet moves through the gastrointestinal tract, both the pH and the mechanical stress vary, in particular also as a function of the nature and amount of the filling of the stomach and of the digestive tract. This dependence of the active compound release is called the “agitation dependence” or the “food effect”. It is seen that the release rate of most sustained-release formulations is dependent on the food intake and thus different profiles of action occur depending on whether the medicament is taken before, during or after a meal.
There have been numerous attempts to exclude or to minimize the undesirable variability of this “food effect”. For erosion-controlled preparations, an approximately agitation-independent single-unit system has been described which, however, is technically very complicated and therefore impracticable (cf. W. D. Lindner et al. Farm., 51 (1996) 263). As a further possibility of an agitation-independent preparation, a single-unit osmotic pump system has been described and in some cases successfully marketed. Here, the active compound is squeezed outwards through defined openings or pores of a chamber, the squeezing pressure being produced by a swelling polymer whose water absorption is osmotically controlled (cf. U.S. Pat. Nos. 4,449,983, 4,203,400 and 4,327,725).
The problems and disadvantages of the previously proposed and employed agitation-independent sustained-release formulations are known and presented, inter alia, in the description of EP 0 425 298.A2. According to this application, it is attempted to achieve the agitation independence of salt-forming active compounds by means of different coatings with poorly soluble polymers. The disadvantages of this process likewise lie in the technically complicated process measures and in the fact that only certain salt-forming and thus easily soluble active compounds can be employed.
Multiple-unit formulations are designated as those formulations which, in contrast to so-called single-unit formulations such as tablets, consist of a number of small particles, e.g. pellets, granules, minitablets or grains which are contained, for example, in a capsule. In the gastrointestinal tract, these particles are then present independently of one another. Such multiple-unit formulations have a number of advantages in comparison to single-unit formulations. They provide for a more uniform absorption of the active compound and for smaller inter- and intraindividual variations of the pharmacokinetic profiles. Furthermore, different active compounds and dosages can thus be simply inserted, for example, into capsules. These formulations can thus be tailored to the different medicinal requirements without a great outlay.
The object of the present invention is to be seen as making available agitation-independent multiple unit sustained-release formulations, i.e. formulations without an interfering food effect, which can be produced in a simple manner for all types of active compounds, in particular for poorly soluble active compounds.
Multiple-unit sustained-release formulations according to the present invention are formulations which, in the USP paddle test using apparatus II, release 80% of the active compound within 4 to 14 hours, preferably within 6 to 12 hours, relative to the total amount of active compound in the formulation.
Agitation-independent formulations according to the present invention are those which, in the USP XXII paddle test with 900 ml of release medium, pH 6.8 at a stirren speed of 50 rpm and of 150 rpm, have a maximum release difference of ±10%, preferably ±5%.
The stirren speed of the paddle test according to USP was selected with regard to the publication B. Abrahamsson et al., Eur. J. Pharm. Sci., 46 (1998) 69, according to which the mechanical stress of a tablet in the gastrointestinal tract is to be compared, for example, with the conditions which correspond to a stirring motion in the paddle test at up to about 150 rpm.
This object can be achieved according to the invention in that
a) the hydrophilic polymer employed is hydroxypropylcellulose (HPC) having an average molecular weight of 250000 to 1200000, preferably 350000 to 1150000, in an amount from 40 to 95% by weight, preferably 45 to 90% by weight, based on the active compound-polymer mixture, and a molar degree of substitution of ≧3 as a release-sustaining erosion material and
b) the active compound-polymer combination is converted into small particles such as pellets, granules or minitablets having a maximum diameter of 0.2 to 3.0 mm, preferably of 0.5 to 2 mm.
HPC having an average molecular weight of 700000 to 1200000, preferably 850000 to 1150000, can also be employed.
Maximum diameter is here understood as meaning the greatest longitudinal dimension of the particle; according to the invention it is 0.2 to 3 mm.
If desired, the miniparticles can be lacquered and further customary pharmaceutical excipients can also be added.
These sustained-release miniparticles can be produced and administered in a simple manner in the desired dose units as multiple-unit sustained-release dose forms, e.g. in hard gelatin capsules, as sachets or are modified to give tablets which decompose into the miniparticles again immediately after administration and thus behave like a multiple-unit dose form.
With knowledge of the prior art, it was not obvious that, as a result of the selection of the abovementioned erodable hydrophilic polymer HPC and simultaneous limitation of the maximum size of the active compound-containing polymer particles to at most 3 mm diameter, an agitation-independent sustained-release formulation can be produced. It was rather to be expected that erodable hydrophilic polymers especially would exhibit a particularly strong agitation effect or food effect. It is known, for example, that nifedipine-containing matrix tablets having diameters of 9 or 10 mm, which contain HPC or HPMC (hydroxypropylmethylcellulose) as hydrophilic polymer, are strongly agitation-dependent and exhibit a strong food effect (cf. Adalat CC®; EP 0 299 211 and B. Abrahamsson et al., J. Controlled Rel., 52 (1998) 301).
On the other hand, minitablets for oral administration have been known and described for some time (cf. Colombo et al., Acta Technol. Legis. med. 1992, 3 (3), 137). However, it was previously not known that the particles according to the invention having a maximum diameter of 3 mm are agitation-independent sustained-release formulations.
To achieve the object according to
Brendel Erich
Chantraine Ernst
Kanikanti Venkata-Rangarao
Rupp Roland
Weisemann Claus
Bayer Aktiengesellschaft
Page Thurman K.
Sheikh Humera N.
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