Dosage forms and uses

Details Dosage forms and uses Dosage forms and uses

1998-09-11

2001-07-31

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S425000, C424S443000, C424S451000, C424S464000

Reexamination Certificate

active

06267980

ABSTRACT:

This application is a 371 continuation of PCT/GB97/00674 filed Mar. 11, 1997, which is a continuation of GB 9605074.5, filed Mar. 11, 1996.
1. Field of the Invention
This invention relates to verapamil and the discovery of novel pharmaceutical dosage forms thereof, and their use.
2. Background to the Invention
Verapamil (1) is presently in clinical use as a racemate and is used extensively for the treatment of hypertension. The opposite enantiomers of verapamil have different biological activities and different potencies. The pharmacological profile is determined by stereoselectivity of pharmacodynamics and pharmacokinetics. The (S)-enantiomer (levoverapamil) has the majority of the calcium channel antagonist activity (see DE-A-2059923), whilst the (R) -enantiomer (dexverapamil) differs in having greater sodium channel activity (see Bayer, Naunyn Schmiedeberg Arch. Pharmacol. (1975) 290: 81-97) and other cell-pump actions, in addition to higher bioavailability (plasma R:S ratio about 2.5), with slower clearance rate (plasma R:S ratio about 0.5). For the treatment of hypertension, the (S)-enantiomer may provide a safer treatment than the racemate, with an extended therapeutic window. The (R)-enantiomer may be of benefit for the reversal of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113); in this case hypotensive action by admixture with the (S)-enantiomer would be undesirable. Despite their different activities, it is conceivable that in some instances it may be advantageous to titrate the ratio of the two enantiomers to achieve a better therapeutic index.
Currently, verapamil is dosed as a racemic mixture both in immediate and controlled-release form, from which each enantiomer is released at the same rate. However, as reported by Longstreth in J.a. Clin. Pharmacol. (1993) 18 (2nd Edition): 315-336, the pharmacokinetic properties of each enantiomer are different, primarily due to differences in the rates at which they are metabolised. This has the effect that the ratio of the different enantiomers changes with time after initial dosing, which can lead to reduced efficacy of the drug. The actual enantiomeric ratio at any one time is dependent upon a number of factors and is complicated by the fact that different dosage forms provide different enantiomeric ratios.
SUMMARY OF THE INVENTION
According to the present invention, a pharmaceutical dosage form comprises, in one portion thereof, substantially single enantiomer (R)-verapamil and, in another, separate, portion thereof, substantially single enantiomer (S)-verapamil, wherein, in use, the different enantiomers are released at different rates from the dosage form.
The rates of release of the different enantiomers from the dosage form may be arranged such that their initial ratio, whether this is 50:50 or a non-racemic ratio, is maintained throughout the dosing period. By manipulating the administration of the different enantiomers in this way, presentation of the desired enantiomer to the target tissue is optimised, thereby increasing the clinical efficacy of the drug throughout the dosing period.
The present invention may also be beneficial if one of the enantiomers of verapamil is found to be responsible for causing an adverse side effect, as by altering the release from the dosage form of that enantiomer a significant reduction in that side effect may be achieved.
DESCRIPTION OF THE INVENTION
In the context of this Application, by substantially single enantiomer typically we mean that one enantiomer is in an excess of at least 70% by weight with respect to the other enantiomer, and is preferably in an excess of at least 80%, and more preferably 90%, or higher.
A number of different types of dosage form can be envisaged, for administration by a variety of routes, e.g. oral, rectal, transdermal, nasal, and ophthalmic.
One type of dosage form comprises a capsule containing two sets of multiparticulates having different release rates, one set containing (R)-verapamil and the other set containing (S) -verapamil. The multiparticulates themselves can be made by any of the conventional methods, including extrusion spheronisation, high shear granulation, non-pareil seeds, etc. The rates at which the different enantiomers are released from the multiparticulates can be achieved using any conventional controlled-release mechanism, for instance, matrix (ie. erosion diffusion), icoating, or osmotic. Dosage forms of this type are suitable for oral use.
Another type of dosage form comprises two tablets, i.e. as a combined product (kit), one tablet containing (R)-verapamil and the other tablet containing (S)-verapamil, the two tablets having different release rates. Again, conventional control-release technology can be used to achieve the desired effect. For example, two tablets having different release coatings or matrices may be used, or two osmotic pump tablets having different pumping rates. The tablets can then be administered in sequence, but preferably they are filled into a capsule for dosing simultaneously.
Another type of dosage form comprises an osmotic pump tablet comprising two distinct portions, typically two layers, one portion containing and pumping (R)-verapamil at one rate, and the other portion containing and pumping (S)-verapamil at another rate.
Another type of dosage form comprises a bi-layered tablet, one layer containing (R)-verapamil and the other layer containing (S)-verapamil, the two layers having different release rates for their respective enantiomers. Again, conventional control-release technology can be used to achieve the desired effect.
Another type of dosage form comprises a compressed coat tablet having a core containing one of (R)- and (S)-verapamil and, surrounding the core, a shell containing the other of (R)- and (S)-verapamil, the core and shell having different release rates for their respective enantiomers.
Another type of dosage form comprises a patch for placing adjacent a patient's skin, the patch comprising two distinct portions, one portion containing (R)-verapamil and the other portion containing (S)-verapamil, the two portions having different release rates for their respective enantiomers. Alternatively, two separate patches may be used, i.e. as a combined product (kit), one patch containing (R) -verapamil and the other patch containing (S) -verapamil, the two patches having different release rates.
Another type of dosage form comprises a polymer implant comprising two distinct portions, one portion containing (R)-verapamil and the other portion containing (S)-verapamil, the two portions having different release rates for their respective enantiomers. Alternatively, two separate polymer implants may be used, i.e. as a combined product (kit), one implant containing (R)-verapamil and the other implant containing (S)-verapamil, the two implants having different release rates.
Another type of dosage form comprises an aerosol containing two sets of microparticles having different release rates, one set containing (R)-verapamil and the other set containing (S)-verapamil. Alternatively, two separate aerosols may be used, one for each enantiomer, i.e. as a combined product (kit), the microparticles of each aerosol having different release rates.
The dosage forms of the present invention may be designed to release either of the enantiomers faster than the other, depending upon the condition to be treated, or the patient type. It may be desirable to maintain a constant ratio of the separate enantiomers at the target tissue over a specified period of time, for instance at least 8 hours a day, preferably at least 12 hours a day, and most preferably 24 hours a day. The ratio maintained may be 50:50, or a non-racemic ratio in which either the amount of (R)-verapamil is greater than (S)-verapamil, or vice versa.
Another option would be to vary the ratio of the two enantiomers throughout the treatment period, or at least for a portion of that period. For instance, the release rate of either or both enantiomers can be arranged to vary, so that either the relat

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