Dosage forms

Details Dosage forms Dosage forms

2000-01-05

2001-04-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S489000, C424S451000, C424S472000, C424S449000, C424S426000, C424S045000

Reexamination Certificate

active

06221394

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the discovery of novel pharmaceutical dosage forms of chiral drugs.
BACKGROUND TO THE INVENTION
The separate enantiomers of some chiral drugs have different therapeutic properties, and/or mechanisms of action and yet in some cases it may still be desirable to dose both enantiomers together. However, where the pharmacokinetic properties of the separate enantiomers are different, for instance due to differences in the rates at which they are metabolised, 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 may be dependent upon a number of factors, and may be further complicated if different dosage forms provide different enantiomeric ratios. Effects such as these have been observed with the different enantiomers of Verapamil, for instance see Longstreth, J. A. Clin. Pharmacol. (1993) 18 (2nd Edition): 315-336 and Gupta et al., Eur. J. Pharm. Biopharm. (1996) 42(1): 74-81.
SUMMARY OF THE INVENTION
According to the present invention, a pharmaceutical dosage form comprises, in one portion thereof, a substantially single (+)-enantiomer of a chiral drug other than verapamil and , in another, separate, portion thereof, a substantially single (−)-enantiomer of the drug, wherein, in use, the different enantiomers are released at different rates from the dosage form.
Where the different enantiomers of the chiral drug are absorbed, metabolised, distributed or secreted by the body at different rates, their rates of release from the dosage form may be arranged such that their initial ratio, whether this is 50:50 or a non-racemic ratio, is maintained, ideally throughout the dosing period. By manipulating the administration of the different enantiomers in this way, presentation of the desired enantiomer to the target organ is optimised, thereby increasing the clinical efficacy of the drug throughout the dosing period.
The present invention may also be beneficial in administering chiral drugs whose individual enantiomers have different efficacies, different modes of action, different selectivities, e.g. to receptors or enzymes, or different toxicities.
The present invention may also be beneficial in administering chiral drugs which have a side effect associated therewith, but where the side effect resides in only one of the drug's two individual enantiomers. In this case, it may be desirable to have a different release rate for the enantiomer causing the side effect, although this will depend upon the nature of the side effect.
Examples of chiral drugs where both enantiomers have a valid pharmacological input, and where a clinical benefit may be realised by controlling the release rates of those enantiomers, include warfarin, tramadol, mianserin, carvedilol, citalopram, dobutamine, aminoglutethimide, alfuzosin, celiprolol, cisapride, disopyramide, fenoldopam, flecainide, hydroxychloroquine, ifosfamide, labetolol, mexiletine, propafenone, tegafur, terazosin, thioctic acid, thiopental and zacopride, and in particular warfarin and tramadol, and most particularly tramadol.


REFERENCES:
patent: 5204116 (1993-04-01), Edgren e al.
patent: 624366 (1994-11-01), None
patent: 9600075 (1996-01-01), None

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