Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-08-09
2004-08-03
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S468000, C424S449000
Reexamination Certificate
active
06770295
ABSTRACT:
The present invention relates to an improved method of treating unstable or overactive urinary bladder as well as a formulation therefor.
A substantial part (5-10%) of the adult population suffers from urinary incontinence, and the prevalence, particularly of so-called urge incontinence, increases with age. The symptoms of an unstable or overactive bladder comprise urge incontinence, urgency and urinary frequency. It is assumed that unstable or overactive bladder is caused by uncontrolled contractions of the bundles of smooth muscle fibres forming the muscular coat of the urinary bladder (the detrusor muscle) during the filling phase of the bladder. These contractions are mainly controlled by cholinergic muscarinic receptors, and the pharmacological treatment of unstable or overactive bladder has been based on muscarinic receptor antagonists. The drug of choice has for a long time been oxybutynin.
Oxybutynin, which chemically is the DL-racemic form of 4-diethylamino-2-butynyl-phenylcyclohexylglycolate, is given orally, usually as a tablet or syrup. Oxybutynin, usually administered as the chloride salt, is metabolized to an active metabolite, N-desethyl-oxybutynin. The drug is rapidly absorbed from the gastrointestinal tract following administration and has a duration of from three to six hours. While the effectiveness of oxybutynin has been well documented, its usefulness is limited by classical antimuscarinic side-effects, particularly dry mouth, which often leads to discontinuation of treatment.
WO 96/12477 discloses a controlled release delivery system for oxybutynin, which delivery system is said not only to be of convenience to the patient by reducing the administration to a once daily regimen, but also to reduce adverse side-effects by limiting the initial peak concentrations of oxybutynin and active metabolite in the blood of the patient.
The alleged relief of side-effects by reducing or eliminating peak concentrations through administration of the controlled release delivery system is, however, contradicted by a later published clinical report, Nilsson, C. G., et al., Neurourology and Urodynamics 16 (1997) 533-542, which describes clinical tests performed with the controlled release delivery system disclosed in WO 96/12477 above. In the clinical tests reported, a 10 mg controlled release oxybutynin tablet was compared with the administration of a conventional (immediate release) 5 mg tablet given twice daily to urge incontinent patients. While high peak levels of the drug obviously were eliminated with the controlled release oxybutynin tablet, no difference in side-effects between the controlled release tablet and the conventional tablet was observed. The advantage of the controlled release tablet thus resided merely in enhancing treatment compliance by its once-a-day dosage rather than also reducing side-effects as stated in WO 96/12477.
Recently, an improved muscarinic receptor antagonist, tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, has been marketed for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. Both tolterodine and its major, active metabolite, the 5-hydroxymethyl derivative of tolterodine, which significantly contributes to the therapeutic effect, have considerably less side-effects than oxybutynin, especially regarding the propensity to cause dry mouth. While tolterodine is equipotent with oxybutynin in the bladder, its affinity for muscarinic receptors of the salivary gland is eight times lower than that of oxybutynin; see, for example, Nilvebrant, L., et al., European Journal of Pharmacology 327 (1997) 195-207. The selective effect of tolterodine in humans is described in Stahl, M. M. S., et al., Neurourology and Urodynamics 14 (1995) 647-655, and Bryne, N., International Journal of Clinical Pharmacology and Therapeutics, Vol. 35, No. 7 (1995) 287-295.
The currently marketed administration form of tolterodine is filmcoated tablets containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dosage usually being 2 mg twice a day. While, as mentioned, the side-effects, such as dry mouth, are much lower than for oxybutynin, they still exist, especially at higher dosages.
According to the present invention it has now surprisingly been found that, contrary to the case of oxybutynin, the substantial elimination of peak serum levels of tolterodine and its active metabolite through controlled release of tolterodine for an extended period of time, such as through a once-daily administration form, while maintaining the desired effect on the bladder, indeed gives a significant reduction of the (already low) side-effects, particularly dry mouth, compared with those obtained for the same total dosage of immediate release tablets over the same period. In other words, eliminating the peak serum levels of the active moiety affects the adverse effects, and particularly dry mouth, more than the desired effect on the detrusor activity, simultaneously as the flattening of the serum concentration does not lead to loss of activity or increased incidence of urinary retention or other safety concerns. Thus, in addition to the convenience advantage of controlled release administration, one may either (i) for a given total dosage of tolterodine, reduce the side-effects, such as dry mouth, or (ii) for a given level of acceptable side-effects, increase the dosage of tolterodine to obtain an increased effect on the bladder, if desired.
In one aspect, the present invention therefore provides a method of treating unstable or overactive urinary bladder, which method comprises administering to a (mammal) patient in need of such treatment tolterodine or a tolterodine-related compound, or a pharmaceutically acceptable salt thereof, through a controlled release formulation that administers tolterodine or said tolterodine-related compound, or salt thereof, at a controlled rate for at least 24 hours. It is preferred that the dosage form formulation is capable of maintaining a substantially constant serum level of the active moiety or moieties for said at least 24 hours.
Overactive urinary bladder encompasses detrusor instability, detrusor hyperreflexia, urge incontinence, urgency and urinary frequency.
As mentioned above, the chemical name of tolterodine is (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine. The term “tolterodine-related compound” is meant to encompass the major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine; the corresponding (S)-enantiomer to tolterodine, i.e. (S)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine; the 5-hydroxymethyl metabolite of the (S)-enantiomer, i.e. (S)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine; as well as the corresponding racemate to tolterodine, i.e. (R,S)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine; and prodrug forms thereof.
By the term “active moiety or moities” is meant the sum of free or unbound (i.e. not protein bound) concentrations of (i) tolterodine and active metabolite thereof, when tolterodine (or prodrug form) is administered; or (ii) tolterodine and active metabolite thereof and/or (S)-enantiomer to tolterodine and active metabolite thereof, when the corresponding racemate (or prodrug form) is administered; or (iii) active metabolite, when the (R)-5-hydroxymethyl metabolite of tolterodine (or prodrug form) is administered; or (iv) (S)-enantiomer to tolterodine and active metabolite thereof, when the (S)-enantiomer (or prodrug) is administered; or (v) active (S)-metabolite, when the (S)-5-hydroxymethyl metabolite is administered.
The term “substantially constant” with respect to the serum level of active moiety or moieties means that the release profile of the controlled release formulation should essentially not exhibit any peak values. This may, more sophistically, also be expressed by reference to the “flucuation index” (FI) for the serum
Gren Torkel
Hallen Bengt
Hoeck Ulla
Jacobsen Lene Orup
Kreilgård Bo
Bell Craig M.
Pharmacia AB
Spear James M.
LandOfFree
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