Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-04-05
2003-12-09
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06660774
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the use of (+)-tramadol or 0-demethyltramadol, in particular (+)-O-demethyltramadol, O-desmethyl-N-mono-desmethyltramadol, in particular (+)-O-desmethyl-N-mono-desmethyltramadol as free bases and/or in the form of physiologically compatible salts for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence and to corresponding pharmaceutical preparations and to a method for the treatment of increased urinary urgency or urinary incontinence.
Urinary incontinence is the involuntary release of urine, which occurs in an uncontrolled manner when the pressure within the bladder exceeds the pressure required to seal the ureter. This may be caused, on the one hand, by increased internal bladder pressure (for example due to detrusor instability) resulting in urge incontinence and, on the other hand, by reduced sphincter pressure (for example after giving birth or surgical intervention) resulting in stress incontinence. The detrusor is the coarsely bundled, multilayer bladder wall musculature, contraction of which results in voiding of urine, while the sphincter is the muscle which closes the urethra. Mixed forms of these types of incontinence occur, as do so-called overflow incontinence (for example in cases of benign prostate hyperplasia) or reflex incontinence (for example after spinal cord damage). Further details in this connection may be found in Chutka, D. S. and Takahashi, P. Y., 1998
, Drugs
560: 587-595.
Urinary urgency is the state of increased bladder muscle tension directed towards voiding of urine (micturition) as bladder capacity is approached (or exceeded). This tension acts as the micturition stimulus. Increased urinary urgency is taken in particular to mean the occurrence of premature or more frequent, sometimes even painful urinary urgency, going as far as urinary compulsion. This consequently results in distinctly more frequent micturition. Possible causes are bladder inflammation and neurogenic bladder dysfunction as well as vesical tuberculosis. However, not all causes have yet been explained.
Increased urinary urgency and urinary incontinence are extremely unpleasant and those suffering from these symptoms have a clear need to alleviate them for as long as possible.
Increased urinary urgency and in particular urinary incontinence are conventionally treated somatically with substances which are involved in the reflexes of the lower urinary tract (Wein, A. J., 1998
, Urology
51 (Suppl. 21): 43-47). These are generally medicines which have an inhibitory action on the detrusor muscle, which is responsible for the pressure within the bladder. These medicines are, for example, parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine or muscle relaxants such as flavoxate. Other medicines which in particular increase the strength of the urethra or the neck of the bladder exhibit an affinity to &agr;-adrenergic receptors such as ephedrine, to &bgr;-adrenergic receptors such as clenbuterol or are hormones such as oestradiol. Certain opioids, diarylmethylpiperazines and diarylmethylpiperidines are also described for this indication in WO 93/15062.
WO 98/46216 demonstrated for the first time that tramadol may also be used for the indications of increased urinary urgency and urinary incontinence. Tramadol ((1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol) is a racemate and a known centrally acting analgesic, which strongly inhibits pain without causing the side effects known for opioids (
J. Pharmacol. Exptl. Ther
. 267, 331 (1993)).
It must, however, be born in mind that, for the indications under consideration, drug therapy will generally be of very long duration and, unlike many situations in which analgesics are used, the affected individuals feel themselves to be in a very unpleasant, but not intolerable situation. Care must accordingly be taken in this case, still more than with analgesics, to avoid side effects—the affected individuals will not want to swap one evil for another.
Although tramadol exhibits much fewer side effects than opioids, the use of tramadol is associated with a few, sometimes unpleasant, dose-related side effects. Moreover, analgesic action is largely undesirable in the long-term treatment of urinary incontinence. Using tramadol racemate for this indication thus has disadvantages because, even though the racemate has an effect on bladder function even at relatively low doses, therapeutic dosages may cause unwanted side effects, especially in certain groups of patients.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The object of the present invention was accordingly to identify substances which are helpful in the treatment of increased urinary urgency or urinary incontinence and which preferably simultaneously exhibit reduced side effects and less analgesic action than known from the prior art.
It has surprisingly now been found that (+)-tramadol possesses excellent effect on bladder function and is accordingly suitable for the treatment of such conditions and exhibits this action at considerably lower dosages than the racemate.
The present invention accordingly provides the use of (+)-tramadol as a free base and/or in the form of physiologically compatible salts for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence.
Tramadol is a racemate and consists of equal quantities of (+)- and (−)-enantiomers. It is known from analgesic use that the enantiomers of tramadol have a differing pharmaceutical profile from the racemate. The (+)-enantiomer is distinguished by an opiate-like analgesic action, which is stronger than that of tramadol, while distinct inhibition of noradrenaline reuptake is observed with the (−)-enantiomer. It has been proven for (+)- and (−)-tramadol that, depending upon the model, the two enantiomers mutually reinforce their action (Raffa, R. et al., 1993
, J. Pharmacol. Exptl. Ther
. 267:331). It is obvious to assume that the potent analgesic action of tramadol is based on this mutually dependent reinforcement of action.
Completely at variance with this experience from analgesic use, investigation of the separate enantiomers with regard to their effect on bladder function revealed a surprisingly different picture. (+)-Tramadol was not only distinctly more active than the racemate, but was even considerably more active than twice the dose of the racemate mixture of (+)- and (−)-tramadol used. It may, however, be concluded from this not only that (+)-tramadol is the actual active substance, but also that (−)-tramadol appears not only to be inactive but, in contrast with analgesic use in the racemate, even appears to inhibit the action of (+)-tramadol on bladder function.
Using (+)-tramadol thus has clear advantages over the prior art, namely using tramadol as a racemate (WO 98/46216), as it is possible to use considerably lower dosages of distinctly less than 50% of the dosage required for tramadol. Side effects are correspondingly reduced as (−)-tramadol also makes a contribution to these, in particular also to the analgesic action. Possible methods for producing (+)-tramadol are described in
Arzneim
. -
Forsch./Drug Res
. 28 (I), 114 (1978) and in particular preferably in DE 196 01 745 C1.
When using (+)-tramadol, it is not necessary, but is preferred, to use solely the (+)-tramadol enantiomer. A smaller proportion of (−)-tramadol relative to the (+)-tramadol is, however, acceptable, and may be contained in the use according to the invention.
Suitable salts for the purpose of this invention and in each of the claimed uses are salts of the particular active substance with inorganic or organic acids and/or a sugar substitute such as saccharin, cyclamate or acesulfame. The hydrochloride is, however, particularly preferred.
The present invention also provides
Christoph Thomas
Friderichs Elmar
Crowell & Moring LLP
Gruenethal GmbH
Spivack Phyllis G.
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