DE19947747A1 - Treatment of urinary incontinence using (+)-tramadol, O-demethyl-tramadol or O-demethyl-N-mono-desmethyl-tramadol, having strong effect on bladder function without side-effects or analgesic action - Google Patents

Abstract

The use of tramadol compounds (I) is claimed for the production of a medicament for treating increased desire to urinate or urinary incontinence, where (I) is (+)-tramadol (or its salt), O-demethyl-tramadol (or its enantiomer, diastereomer or salt) or O-demethyl-N-mono-desmethyl-tramadol (or its enantiomer, diastereomer or salt). An Independent claim is included for a (I)-containing medicament for use as above.

Description

The invention relates to the use of (+) - tramadol or O-demethyl tramadol, in particular (+) - O-demethyltramadol, as free bases and / or in the form of physiologically acceptable salts for the preparation of a Medicines used to treat increased urge to urinate tinence and related medicinal products and treatment methods increased urge to urinate or urinary incontinence.

Urinary incontinence is the involuntary loss of urine. This occurs uncontrollably loses when the pressure inside the bladder exceeds the pressure which is necessary to close the ureter. Causes can lead to an increased internal bladder pressure (e.g. due to detrusor instability) with the consequence of urge incontinence and on the other hand a decreased Sphincter pressure (e.g. after birth or surgery) with the Be the result of stress incontinence. The detrusor is the roughly bundled one multilayered bladder wall muscles, their contraction to the urinary duct tion, the sphincter is the sphincter of the ureter. Kick it Mixed forms of these types of incontinence as well as the so-called abundance incontinence (e.g. with benign prostatic hyperplasia) or reflex incontinence nence (e.g. after spinal cord damage). Find more about it see Chutka, D.S. and Takahashi, P.Y., 1998, Drugs 560: 587-595.

Urge to urinate is the state aimed at emptying urine (micturition) Increased bladder muscle tension when approaching the bladder capacity (or if they are exceeded). This tension acts as a mic tion charming. An increased urge to urinate means in particular  especially the appearance of premature or heaped sometimes painful urge to urinate That leads to the Follow to a much more frequent micturition. Causes can be urine cystitis and neurogenic bladder disorders as well Be bladder tuberculosis.

Increased urge to urinate as well as urinary incontinence are considered extremely un felt pleasant and there is a clear need for these Indications affected people, a long-term verb as possible to achieve.

Usually there is an increased urge to urinate and especially urine continence medicated with substances that affect the reflexes of the lower urinary tract are involved (Wein, A.J., 1998, Urology 51 (Suppl. 21): 43-47). Most often, these are drugs that have a hem effect on the detrusor muscle, which is responsible for the internal bladder pressure is responsible. These drugs are e.g. B. Parasympatholy tics such as oxybutymine, propiverine or tolterodine, tricyclic antidepressants like imipramine or muscle relaxants like flavoxate. Other drugs, which in particular the resistance of the ureter or bladder neck increase, show affinities for α-adrenoreceptors such as ephedrine, for β- Adrenoreceptors like Clenbutarol or are hormones like Ostradiol. Also certain opioids, diarylmethylpiperazines and piperidines, are for these Indication described in WO 93/15062.

WO 98146216 showed for the first time that in the indications of the increased Urinary urge and urinary incontinence also tramadol can be used can. Tramadol - (1RS, 2RS) -2-dimethylaminomethyl-1- (3-methoxyphenyl) - cyclohexanol - is a racemate and a known central active Analgesic, which is a powerful pain reliever without that for opioids  known side effects (J. Pharmacol. Exptl. Ther. 267, 331 (1993)).

With the indications in question here it should be noted that are generally very long-term drug applications acts and the people concerned, contrary to many situations, in who use analgesics, a very unpleasant one, but not facing unbearable situations. Therefore here is - more than with analgesics - wants to take care to avoid side effects the victim does not exchange one evil for the other.

Tramadol use is also significant, although Tramadol shows fewer side effects than opioids, depending on the dose associated with some, sometimes unpleasant side effects. except this is also analog in the case of permanent urinary incontinence treatment table effects largely undesirable. Accordingly, the Verwen Disadvantages of the racemate tramadol in this indication, because, too if the racemate already affects the doses at lower doses Bladder function shows than are needed for analgesic effects can therapeutic doses - especially at certain Patient circles - already show undesirable side effects.

The object of the present invention was therefore to find substances which helpful for the treatment of increased urge to urinate or urinary incontinence are and preferably at the same time lower side and analgesic we kungen show as known from the prior art.

Surprisingly, it has now been found that (+) - Tramadol produces one has an excellent effect on the bladder function and therefore good for Treatment of appropriate diseases is suitable and already in doses significantly lower than the racemate.  

Accordingly, the subject of the invention is the use of (+) - Tramadol as a free base and / or in the form of physiologically tolerated Salts for the manufacture of a medicament for the treatment of increased Urge to urinate or urinary incontinence.

Tramadol is a racemate and consists of equal amounts of (+) - and (-) - enantiomers. It is known from analgesia that the Tramadol enantiomers a phar that differs from the racemate have a macological profile. The (+) - enantiomer is characterized by an opiate-like analgesic effect compared to tramadol is increased, while in the (-) enantiomer there is a clear inhibition of the Noradrenaline reuptake is observed. Thereby for (+) - and (-) - Tramadol demonstrated that this changes depending on the model in mutually reinforcing their effect (Raffa, R. et. al., 1993, J. Pharmacol. Exptl. Ther. 267: 331). It is reasonable to assume that the potent analgesic effect of tramadol on this conditional Active amplification is based.

Completely different from these experiences in the field of analgesia was in studies of the separate enantiomers in their effect found a surprisingly different picture on the bladder function. (+) - Tramadol was not only significantly more effective than the racemate but actually considerably more effective than double the dose of the racemate used mixture of (+) - and (-) - Tramadol. From this it can be concluded that (+) - Tramadol is not only the actually effective substance, but that (-) - Tramadol not only to be ineffective, but in contrast to the analog the effect on the bladder function of (+) - tramadol in racemate even seems to inhibit.  

For example, the use of (+) - tramadol compared to the state of the art nik, the use of tramadol as racemate (WO 98/46216), clear Advantages, since the dosage can be significantly lower, significantly less than 50% of the dosage required for Tramadol. They are correspondingly lower Side effects, since (-) - Tramadol to these, especially the analgesic effects. Possibilities to manufacture (+) - Tramadol are in Arzneimittel.Forsch./Drug Res. 28 (I), 114 (1978) and ins particularly preferably described in DE 196 01 745 C1.

When using (+) - Tramadol it is not necessary, but before only uses the (+) - tramadol enantiomer. On compared to the (+) - tramadol, however, is a lower proportion of (-) - tramadol acceptable and may contain when used according to the invention his.

Suitable salts in the sense of this invention and in each of the claimed Uses are salts of the respective active ingredient with inorganic or organic acids and / or a sugar substitute such as Saccharin, cyclamate or acesulfame. However, this is particularly preferred Hydrochloride.

Another object of the present invention is the use of O-demethyltramadol and / or its enantiomers, diastereomers, Bases or salts of physiologically compatible acids for the preparation of a Medicines used to treat increased urge to urinate tinenz. The use of (+) - O- is particularly preferred. Demethyltramadol as a free base and / or in the form of physiologically tolerated licher salts. Tramadol forms the metabolite O-demethyltramadol in vivo, which is also present as a mixture of enantiomers. In terms of analge Studies have shown that both Tramadol enantiomers as well as the two enantiomers of tramadol  metabolites are involved in the analgesic effect (J. Pharmacol. Exptl. Ther. 1992, 260: 275; Pharm. Research 38, 877 (1988)).

Surprisingly, the racemate also had O-demethyltramadol already at low concentrations a significant effect on the Bladder function. Upon closer examination of the enantiomers, it showed found that (-) - O-demethyltramadol had no effect on bladder function had or even had an inhibitory effect in the racemate, while (+) - O-demethyl tramadol is responsible for the overall effect on bladder function and was significantly more effective than the racemate. The production of o Demethyltramadol as racemate or in the form of the enantiomers is from EP 534 628 and WO 93/04675 known. The preparation of the enantiomer (+) - O-demethyltramadol is preferably carried out according to that in DE 196 01 744 C2 described method.

When using (+) - O-demethyltramadol it is not necessary but preferably, only the (+) - O-demethyltramadol enantiomer to use. One less than the (+) - O-demethyltramadol Percentage of (-) - O-demethyltramadol is acceptable and may not inventive use may be included.

Even if the uses according to the invention are only minor Show side effects, for example, to avoid be certain forms of dependency may be beneficial, in addition to (+) - tramadol, O-Demethyltramadol or (+) - O-Demethyltramadol also Morphinantago nest, especially naloxone, naltrexone and / or levallorphan, to ver turn.

The invention further relates to medicaments for the treatment of increased Urge to urinate or urinary incontinence, which are at least (+) - trama as active ingredient dol as a free base and / or in the form of physiologically acceptable salts  and optionally contain additives and / or auxiliaries. In the ent talking drugs it is not necessary, but preferred to finally to use the (+) - tramadol enantiomer. One opposite the (+) - tramadol lower proportion of (-) - tramadol is acceptable and may be contained in pharmaceuticals according to the invention.

The invention also encompasses drugs for the treatment of more tem urge to urinate or urinary incontinence, the O-Demethyltramadol and / or its enantiomers, diasteroisomers, bases or salts of physiolo gisch compatible acids, especially (+) - O-demethyltramadol as free Base and / or in the form of physiologically acceptable salts. In the corresponding drugs with (+) - O-demethyltramadol are not necessary agile but preferred, only the (+) - O-demethyltramadol To use enantiomers. One versus the (+) - O-demethyltramadol however, a lower proportion of (-) - O-demethyltramadol is acceptable and may be in Medicaments according to the invention may be included.

Suitable salts in the sense of this invention and in each of the claimed Uses are salts of the respective active ingredient with inorganic or organic acids and / or a sugar substitute such as Saccharin, cyclamate or acesulfame. However, this is particularly preferred Hydrochloride.

Suitable additives and / or auxiliary substances in the sense of this invention are all substances known to the person skilled in the art from the prior art submission of galenic formulations. The selection of these excipients as well the amounts to be used depend on whether the Medicinal products orally, intravenously, intraperitoneally, intradermally, intramuscularly, to be applied intranasally, buccally or locally. For oral applications preparations in the form of tablets, chewable tablets, Dragees, capsules, granules, drops, juices or syrups for which  parenteral, topical and inhalation application solutions, suspensions, easily reconstitutable dry preparations and sprays. Another Suppositories for use in the rectum are possible. The users in a depot in dissolved form, a carrier film or a Plasters, if necessary with the addition of skin penetration promoting Agents are examples of suitable percutaneous forms of administration. at games for aids and additives for oral administration forms Disintegrants, lubricants, binders, fillers, mold release agents, given if solvents, flavors, sugar, in particular carriers, Diluents, dyes, antioxidants etc. For suppositories can nen u. a. Waxes or fatty acid esters and for parenteral applications medium carriers, preservatives, suspension aids etc. ver be applied. The amount of drug to be administered to patients vary depending on the weight of the patient Type of application and the severity of the disease. From oral, rectal or percutaneously applicable forms of preparation can the invention according to the connections are released with a delay. In the invention according to the indication are corresponding slow release formulations, ins special in the form of a "once-daily" preparation that is used only once a day must be taken, particularly preferred.

Further preferred are drugs that contain at least 0.05 to 90.0% of the Contain active ingredient, in particular low effective doses to Avoid side effects or analgesic effects.

Even if the medicinal products according to the invention have only minor additions show effects, it can be used, for example, to avoid certain Forms of dependency may be beneficial in addition to (+) - tramadol, O- Demethyltramadol or (+) - O-demethyltramadol also morphine antago nest, especially naloxone, naltrexone and / or levallorphan, to ver turn.  

The invention also relates to a method for treating ver increased urge to urinate or urinary incontinence, where (+) - tramadol is free Base and / or in the form of physiologically acceptable salts, or corresponding processes in which O-demethyltramadol and / or its enantiomers, diasteroisomers, bases or salts of, physiolo gisch compatible acids, especially (+) - O-demethyltramadol as free Base and / or in farm physiologically acceptable salts used will be.

The following example is intended to illustrate the invention without the opposite the invention would be limited to this.

example

Cystometric examinations were carried out on naive, female Sprague-Dawley rats using the method of Ishizuka et. al. ((1997) Naunyn-Schmiedeberg's Arch. Pharmacol. 355: 787-793). Three days after the implantation of bladder and venous catheters were the animals are awake, examined freely. The bladder cat ter was attached to a pressure transducer and an injection pump closed. The animals were placed in metabolic cages, which the Measurement of urine volume enabled. Physiological saline was infused into the emptied bladder (10 ml / hour) and bladder pressure and Micturition volume recorded continuously. After stabilization a 20-minute phase was recorded, which was defined by nor male, reproducible micturition cycles was characterized. In detail the following parameters were determined:

Micturition pressure MP, maximum pressure during the Micturition), basal pressure BP, lowest pressure during the  Filling phase), threshold pressure (TP), bladder pressure immediately before micturition), bladder capacity BC, residual volume men after previous micturition plus volume of the infused solution during the filling phase), micturition volume MV, Volume of urine deposited) and residual volume (residual volume RV, Bladder capacity minus micturition volume). Special attention is to be directed to the threshold pressure, since an increase gave way term therapeutic effect in the indications according to the invention displays, as well as on residual volume and micturition volume.

After recording three reproducible micturition cycles as a pre-value, the test substances (tramadol, 10 mg / kg iv; (+) - tramadol, 5 mg / kg iv; (-) - tramadol, 5 mg / kg iv; vehicle = 0 , 9% NaCl) and the effect on the cystometric parameters was recorded for 90 to 120 minutes. The mean of 3 micturition cycles was determined at the effective maximum and shown as a percentage change compared to the previous value (Table 1).

Tramadol (10 mg / kg IV) showed the expected effect here. It was a significant increase in threshold pressure and basal pressure below Bei maintaining micturition pressure. The bladder capacity was not changed while the micturition volume increases and the residual volume was significantly reduced. All of this speaks for a positive we tramadol racemate on the bladder function, as already from the WO 98/46216 was known. When examining the two enantiomers (5 mg / kg IV in each case), on the other hand, it turned out that only the (+) - Enantiomer but not the (-) - enantiomer has an effect on the bubble para meter exercises. The effect of 5 mg / kg tramadol exceeds the effect of 10 mg / kg racemic tramadol clearly. In the area of sleepers pressure is even double the effect. It can be said conclude that (+) - tramadol is a vehicle for the activity of the racemate and that (-) - Tramadol in racemate is probably not only ineffective, but probably even has an inhibitory effect.

It is therefore proven here that (+) - tramadol is a much better we bladder function than racemic tramadol.

Claims (8)

1. Use of (+) - Tramadol as free base and / or in form physiologically acceptable salts for the manufacture of a medicinal product for the treatment of increased urge to urinate or urinary incontinence. 2. Use of O-demethyltramadol and / or its enantiomers, Diastereomers, bases or salts are more physiologically tolerated Acids for the manufacture of a medicament for the treatment of ver increased urge to urinate or urinary incontinence. 3. Use of (+) - O-demethyltramadol as the free base and / or in Form of physiologically acceptable salts for the manufacture of a drug for the treatment of increased urge to urinate or urinary incontinence incontinence. 4. Use according to one of claims 1 to 3 characterized thereby records that the salt is a hydrochloride. 5. Medicines to treat increased urination or Urinary incontinence containing at least (+) - tramadol as active ingredient free base and / or in the form of physiologically acceptable salts and optionally additives and / or auxiliary substances. 6. Medicines to treat increased urge to urinate or Urinary incontinence containing at least O-demethyl as an active ingredient tramadol and / or its enantiomers, diastereomers, bases or Salts of physiologically compatible acids and optionally Zu Substitute and / or auxiliary substances.   7. Medicines to treat increased urination or Urinary incontinence containing at least (+) - O- Demethyltramadol as a free base and / or in the form physiologically ver inert salts and optionally additives and / or auxiliaries. 8. Medicament according to one of claims 5 to 7, characterized records that the salt is a hydrochloride.