Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1997-08-29
1999-03-09
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424465, 424474, 514770, 514772, 5147723, 514781, 514934, A61K 928
Patent
active
058797068
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB96/00111 filed Jan. 19, 1996.
This invention relates to a tablet of the antiviral drug valaciclovir. acyclovir possesses potent antiviral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group in humans (see, for example, Schaeffer et al, Nature, 272, 583-585 (1978), UK Patent No. 1523865, U.S. Pat. No. 4,199,574). However, acyclovir is poorly absorbed from the gastrointestinal tract upon oral administration and this low bioavailability means that multiple high doses or oral drug may need to be administered, especially for the treatment of less sensitive viruses or infections in order to achieve and maintain effective anti-viral levels in the plasma.
The L-valine ester of acyclovir (herein referred to as valaciclovir) has been shown to possess much improved bioavailability whilst retaining the anti-viral properties of acyclovir. A preferred form of this compound is its hydrochloride salt which is herein referred to as valaciclovir hydrochloride. Valaciclovir and its salts including the hydrochloride salt are disclosed in U.S. Pat. No. 4,957,924 (see particular example 1B), European Patent No. 0308065 (see particularly example IB) and Beauchamp et al, Antiviral Chemistry and Chemotherapy, 3(3), 157-164 (1992) (see particularly page 162 column 1). Tablets of valaciclovir are also generally disclosed in the U.S. Pat. No. 4,957,924 and European Patent No. 0308065.
During development of a tablet formulation containing a high proportion of valaciclovir, we often encountered difficulties in obtaining tablets of sufficient hardness and friability for pharmaceutical handling and for film coating.
If the tablet is too friable, it will chip or break during packaging and transport. The US Pharmacopoeia (USP) no. 23, 1995, p1981 at monograph 1216 requires that pharmaceutical tablets have a friability not exceeding 1%. If the tablet is too soft, it will crumble during, tumbling in the film coating pan.
In the reference manual `Problem Solver` (compiles by FMC Corporation) at pages 8 and 9, the remedies for low tablet hardness are given inter alia as increasing the compression force applied to form the tablet, or decreasing the proportion of lubricant in the tablet formulation.
We tried to increase the hardness and friability of valaciclovir tablets by increasing the compression force, by decreasing the proportion of lubricant and increasing the proportion of biner, but found in each case that a sufficiently hard and non-friable tablet could not be produced in a practical way.
Furthermore, cracks were found in some tablets as a result of increasing the compression force. Additionally, valaciclovir has `adhesive` properties in that it can stick to tablet dies and therefore needs to be efficiently lubricated. It is difficult therefore to reduce the proportion of lubricant without causing the tablets to stick. Furthermore, the disintegration time of the valaciclovir tablet is also quite long and therefore any possible solution to the hardness and friability problem should not have a substantial deleterious effect on either the disintegration time or lubrication (as measured by the ejection force) of the table formulation.
It is therefore an object of the invention to provide a robust tablet formulation of valaciclovir and salts thereof which is capable of being film coated and consistently providing tablets having a friability not exceeding 1%, a hardness of at least 9 kP and an ejection force not exceeding 1000 Newtons (1 kN).
The hardness of the tablet should be such that it not only has an acceptable crushing force (as measured by the kP value), but also that the tablet does not break during tumbling.
It is a further preferred object of the invention to provide a robust formulation which is capable of consistently providing tablets substantially free of cracks.
We have now found an effective method of overcoming both of the above friability and hardness problems which involves the extragranular use o
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Carter Barry Howard
Tillman Lloyd Gary
Glaxo Wellcome Inc.
Page Thurman K.
Spear James M.
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