Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-11-09
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S459000, C424S461000, C424S462000, C424S468000, C424S469000, C424S490000, C424S493000, C424S494000, C424S495000
Reexamination Certificate
active
06630162
ABSTRACT:
The present invention relates to a pharmaceutical formulation for administering tolterodine or a tolterodine-related compound, and to the medical use of such a formulation.
A substantial part (5-10%) of the adult population suffers from overactive or unstable urinary bladder, often also referred to as urinary incontinence. The symptoms of an unstable or overactive bladder comprise urge incontinence, urgency and urinary frequency. The prevalence of overactive bladder, particularly of so-called urge incontinence, increases with age. 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.
Recently, however, 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.
Our co-pending international application PCT/SE99/01463 relates to the administration of tolterodine and tolterodine-related compounds through a controlled release formulation and is based on the finding 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.
Our above-mentioned PCT/SE99/01463 discloses treatment of overactive bladder by the administration of a controlled release formulation that delivers tolterodine, a tolterodine-related compound, or a pharmacologically acceptable salt thereof such that a substantially constant serum level of the active moiety or moieties is maintained for at least 24 hours.
The present invention is based on the unexpected observation that a substantially constant serum level of the active moiety or moieties for 24 hours may be obtained through oral administration of a controlled release pharmaceutical formulation that releases the major content of active compound in less than about 18 hours, and more particularly that the formulation has an in vitro release of not less than about 80% after 18 hours at the conditions specified below.
In one aspect, the present invention therefore provides a pharmaceutical formulation containing tolterodine or a tolterodine-related compound, or a pharmacologically acceptable salt thereof, as active ingredient, in which the formulation exhibits a controlled in vitro release of the active ingredient in phosphate buffer at pH 6.8 of not less than about 80% after 18 hours, and after oral administration to a patient is capable of maintaining a substantially constant serum level of the active moiety or moieties for 24 hours.
A second aspect of the invention relates to the use of the pharmaceutical formulation for treating a disorder or disease selected from overactive bladder (including i.a. urinary incontinence and nocturia) and gastrointestinal disorders.
A third aspect of the invention relates to the use of tolterodine or a tolterodine-related compound, or a pharmacologically acceptable salt thereof, for the preparation of the pharmaceutical formulation of the above first aspect of the invention.
Preferably, the fraction of tolterodine, tolterodine-related compound or salt thereof that is released is not less than about 80% after 15 hours, especially not less than about 80% after 12 hours.
On the other hand, the fraction of tolterodine, tolterodine-related compound or salt thereof that is released in vitro after 1 hour is preferably not more than about 50%, especially not more than about 30%.
The fraction of tolterodine, tolterodine-related compound or salt thereof that is released in vitro after three hours is preferably from about 30 to 95%, especially from about 40 to about 85%.
It may be preferred that after 7 hours, the fraction of tolterodine, tolterodine-related compound or salt thereof that is released in vitro is not less than about 50%, especially not less than about 80%.
In an exemplary in vitro release profile for the pharmacutical formulation, the fraction of tolterodine, tolterodine-related compound or salt thereof that is released in vitro is less than about 50% after 1 hour, from about 30 to about 95% after 3 hours, and more than about 50% after 7 hours.
The in vitro release measurement conditions referred to above are those for a drug release test that utilizes the United States Pharmacopea (USP) Apparatus 1 (rotating basket) at 100 rpm with 900 ml of deareated phosphate buffer at pH 6.8 and 37° C., where the phosphate buffer solution is prepared as described on pages 2049-2050 in USP 23. The phosphate buffer nominally contains 0.05 M phosphate.
By the term “active moiety or moities” it is meant, in the case of tolterodine and its related compounds, 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 serum profile after administration of the control
Gren Torkek
Hallen Bengt
Nilvebrant Lisbeth
Olsson Birgitta
Ringberg Anders
Bell Craig M.
Pharmacia AB
Ware Todd D
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