WO2003101439A1

WO2003101439A1 - Medicament containing 1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol in different formulations for treating urinary incontinence

Info

Publication number: WO2003101439A1
Application number: PCT/EP2003/005489
Authority: WO
Inventors: Johannes BARTHOLOMAÜS; Thomas Christoph
Original assignee: Grünenthal GmbH
Priority date: 2002-05-31
Filing date: 2003-05-26
Publication date: 2003-12-11
Also published as: AU2003237682A1; DE10224556A1

Abstract

The invention relates to the use of 1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol or one of its pharmaceutically acceptable salts in different formulations, for producing medicaments for treating increased urinary urgency or urinary incontinence.

Description

L-DIMETHYLAMINO-3- (3-METHOXY-PHENYL) -2 -ME THYL-PENTAN-3-OI CONTAINING MEDICINE IN VARIOUS FORMULATIONS FOR THE TREATMENT OF URINE INCONTINENCE

The invention relates to the use of 1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol or one of its pharmaceutically acceptable salts in various formulations for the manufacture of medicaments for the treatment of increased urge to urinate or urinary incontinence ,

Urinary incontinence is the involuntary loss of urine. This occurs in an uncontrolled manner when the pressure inside the bladder exceeds the pressure necessary to close the ureter. The causes can be on the one hand an increased internal bladder pressure (e.g. due to detrusor instability) with the consequence of urge incontinence and on the other hand a reduced sphincter pressure (e.g. after birth or surgical interventions) with the result of stress incontinence. The detrusor is the roughly bundled multilayered bladder wall muscles, the contraction of which leads to emptying of the lungs, the sphincter the sphincter of the urethra. There are mixed forms of these types of incontinence as well as so-called excess incontinence (e.g. in benign prostatic hyperplasia) or reflex incontinence (e.g. after spinal cord damage). More on this can be found in Chutka, D.S. and Takahashi, P. Y., 1998, Drugs 560: 587-595. 5

Urge to urinate is the state of increased bladder muscle tension aimed at emptying urine (micturition) when the bladder capacity is approached (or exceeded). This tension acts as a micturition. Increased urge to urinate means in particular the occurrence of premature or sometimes sometimes even painful urge to urinate, up to the so-called urge to urinate. This leads to a significantly more frequent micturition. Causes can include urinary bladder infections and neurogenic bladder disorders as well as bladder tuberculosis. However, not all causes have yet been clarified.

Increased urge to urinate as well as urinary incontinence are perceived as extremely uncomfortable and there is a clear need among those affected by these indications to achieve the longest possible improvement.

Increased urge to urinate and in particular urinary incontinence are usually treated with drugs that are involved in the reflexes of the lower urinary tract (Wein, A.J., 1998, Urology 51 (Suppl. 21): 43-47). Most often, these are drugs that have an inhibitory effect on the detrusor muscle, which is responsible for internal bladder pressure. These drugs are e.g. B. Parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine or muscle relaxants such as flavoxate. Other drugs that in particular increase the resistance of the urethra or bladder neck show affinities for α-adrenoreceptors such as ephedrine, for β-adrenoreceptors such as clenbutarol or are hormones such as estradiol. Certain opioids, diarylmethylpiperazines and piperidines, are also described for this indication in WO 93/15062.

In the case of the indications in question here, it should be noted that, in general, these are very long-term medicinal uses and, in contrast to many situations in which analgesics are used, those affected face a very unpleasant but not unbearable situation. Therefore - even more so than with analgesics - care must be taken to avoid side effects if the person concerned does not want to exchange one evil for the other. Also, with permanent urinary incontinence treatment, analgesic effects are largely undesirable. It was therefore an object of the present invention to find substances or pharmaceutical formulations or medicaments which are helpful for the treatment of increased urge to urinate or urinary incontinence and which in particular release effective doses which show fewer side effects and / or analgesic effects than from the prior art known.

Surprisingly, it has now been found that 1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol and in particular the pharmaceutical formulations according to the invention containing 1-dimethylamino-3- (3-methoxy-phenyl) - 2-methyl-pentan-3-ol have an excellent effect on bladder function and are therefore well suited for the treatment of corresponding diseases.

The invention therefore relates to the use of 1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol for the production of a medicament for the treatment of increased urge to urinate or urinary incontinence, the 1-dimethylamino 3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol in a pharmaceutical formulation selected from:

an oral osmotically driven drug delivery system, a parenteral implant, a multipore tablet, a gel matrix tablet, a transdermal application system, a local application system or a parenteral depot system. The treatment of increased urge to urinate or urinary incontinence includes in particular the treatment of dangincontinence and stress incontinence.

1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol is known as an analgesic active ingredient from EP 0 693 475 B1 as well as its preparation. 1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol has two centers of asymmetry so that the compound can exist in the form of four different stereoisomers. In the formulation according to the invention, 1-dimethylamino-3- (3-methoxy-phenyl) -2-methylpentan-3-ol can be used as a mixture of all four diastereomers in any mixing ratio, but also as a mixture of two or three of the four stereoisomers or in stereoisomerically pure form. Preferred stereoisomers here are (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol and (-) - (1 S, 2S) -1 -Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, which can be present in the formulation according to the invention as a mixture, in particular as a 1: 1 mixture (racemate), or particularly preferably in isomerically pure form , For the purposes of the present invention, "active ingredient ^1" is therefore 1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol as a mixture of various of its stereoisomers or as one of its pure stereoisomers, in each case as free Base or in the form of a pharmaceutically acceptable salt, and accordingly the use according to the invention comprises the use of 1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol in the form of its racemates, their pure Stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, especially the enantiomers or diastereomers, in any mixing ratio. However, the use of the optionally pure (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol is particularly preferred.

1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol can be present as a base or in the form of a salt and optionally also a solvate. Accordingly, the use according to the invention comprises the use of 1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol in the form of its base or in the form of a salt, in particular the physiologically tolerable salts, or in the form their solvates, especially hydrates.

The term salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions. In particular, this means (and this is also a preferred embodiment of this invention) physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation ,

The term physiologically compatible salt with anions or acids (a preferred form of the 1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol used according to the invention) is understood to mean at least salts in the sense of this invention one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which are physiologically compatible - in particular when used in humans and / or mammals. For the purposes of this invention, this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Examples of physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2 -dihydro1b6- benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl- benzoic acid, a-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The hydrochloride salt is particularly preferred.

The term of the salt formed with a physiologically compatible acid (a preferred form of the 1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol used according to the invention) is understood in the context of this invention to be salts of respective active ingredient with inorganic or organic acids that are physiologically compatible - especially when used in humans and / or mammals. The hydrochloride is particularly preferred. Examples of physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2-dihydro1λ ⁶ - benzo [ d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid , Acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The term physiologically compatible salt with cations or bases (a preferred form of the 1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol used according to the invention) is understood to mean at least salts in the sense of this invention one of the compounds according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which are physiologically compatible, in particular when used in humans and / or mammals. The salts of the alkali and alkaline earth metals are also particularly preferred, however, with NH ⁺ , but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

The term salt formed with a physiologically compatible cation (a preferred form of the 1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol used according to the invention) is understood to mean at least salts in the sense of this invention one of the respective compounds as an anion with at least one inorganic cation which is physiologically compatible - in particular when used in humans and / or mammals. The salts of the alkali and alkaline earth metals but also NH ₄ ⁺ are particularly preferred, but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

(a) The oral osmotically driven active ingredient delivery system is to be understood in particular as the OROS-SYSTEM from AIza, a system in tablet form with a delivery opening, an osmotic one

Drug core, a semi-permeable membrane and a polymeric part that exerts pressure.

(b) A parenteral implant is understood to mean any form of non-biodegradable implant that slowly releases active substance over a longer period of time. One example is the DUROS SYSTEM from ALZA, as described for example in WO 00/54745 and which consists of an inert tube, a semipermeable membrane, an "osmotic engine", a stamp, a dispensing opening and a depot for receiving the dispensable (Mostly highly concentrated) active ingredient solution Suitable examples are described in the patents US4612008, US4765989, US4783337, US5264446, US4519801, US4612008, US4783337 and US5082668. Another example is based on non-biodegradable polymers based on ethylene-vinyl acetate copolymers, as described for example for contraceptives by De Nijs et al (US4,957,119, US5,088,505)

(c) Examples of a multipore tablet are the products developed by Gacell, Andrx, Elan (for example under Modas, Sodas). Suitable examples can be found in EP 122077 A2, EP360562 B1, EP 320097 A1 and US 499276.

(d) Examples of a gel matrix tablet are the products developed by Penwest Pharmaceuticals (for example under TimeRX). Suitable examples can be found in US 5,330,761, US 5,399,362, US 5,472,711 and US 5,455,046.

(e) A transdermal application system is understood to be systems which - if appropriate using penetration aids such as plasticizers and penetration accelerators - are applied to the skin and release the active ingredient through the skin into the body. Examples that can all be used here include described in DE 10033853, US 5,411,740, EP 767659, AT185694E, DE 69326848T2. Further examples transferred directly in the formulation are the suitable plasters from EP 0 430 019 B1, WO 98/36728 or WO96 / 19975.

(f) A local application system is understood to mean, in particular in the urogenital tract, for example pharmaceutical forms to be applied to mucous membranes, with the active ingredient being released more slowly in most cases. An example is the vaginal ring from Enhance Pharmaceuticals as well as the system (vaginal ring) described in WO 01/70154.

(g) A parenteral depot system means in particular depot systems based on slowly disintegrating or biodegradable polymers. Examples are polylactide polymers or

Polyglycolide polymers or in particular polylactide / polyglycolide copolymers (PLGA). Examples well known to those skilled in the art of manufacture are manufactured by Alkermes or Medisorb, and in particular for Takeda enantones and trenantones. This term also includes sprayable gels, especially those that solidify in situ and slowly release the active ingredient dissolved in them. Examples are the Atrigel technology and other systems from Atrix (US5,278,201, US5,739,176, US6,143,314), in which PLGA polymers and active ingredients are mixed with pharmaceutically acceptable solvents which, after being introduced into the body, form an implant solidify, and the SABER technology from DURECT, which uses a three to four component system with sucrose acteate Isobutyrate (SAIB), a pharmaceutically acceptable solvent such as ethanol and one or more additives, and of course the active ingredient. ALZA's ALZAMER technology, in which stabilized particles are injected in a thick polymer solution made of PLGA, is also included. Another example can be found in EP729357.

All of the objects according to the invention are produced analogously to the known products described above under a) to g), so that the production process, structure and composition of these known products which are accessible to the person skilled in the art are readily part of the disclosure of these known products from product information or web sites or patent applications and documents Registration is. Likewise, part of the disclosure is the content of each of the patents or published documents mentioned above under a) to g) and AU 1256399 and AU 9052298.

Examples

The examples serve to illustrate the present invention and preferred embodiments, but are not intended to limit the scope thereof.

Example 1: List of substances tested:

The following is a list of the compounds tested for effectiveness:

Example 8: Test system cystometry on the awake naive rat

Cystometric studies 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, the animals were examined while awake, free to move. The urinary catheter was connected to a pressure transducer and an injection pump. The animals were placed in metabolic cages, which made it possible to measure urine volume. Physiological saline was infused into the emptied bladder (10 ml / hour) and bladder pressure and micturition volume were recorded continuously. After a stabilization phase, a 20-minute phase was recorded, which was characterized by normal, reproducible micturition cycles. Among other things, the following parameters were determined:

^■ threshold pressure (threshold pressure TP, bladder pressure immediately before micturition),

^■ bladder capacity (bladder capacity BC, residual volume after prior micturition plus volume of infused solution during the filling phase)

^■ Inter-contraction interval (ICI), the time interval between micturition.

An increase in the threshold pressure (TP) indicates an important therapeutic effect in one of the indications according to the invention. The inter-contraction interval (ICI) is also an important parameter for measuring the physiological effectiveness of a substance in the treatment of urinary incontinence, as is the bladder capacity (BC). It is for effectiveness due to the very heterogeneous causes for the

Symptoms of these symptoms are not necessary to positively influence all three parameters. It is therefore entirely sufficient if only in one of these A positive effect is to be determined in order to be usable in urinary incontinence or increased urination.

After recording three reproducible micturition cycles as a pre-value, the test substances 1 (1.0 mg / kg), 2 (0.1, 0.3 and 0.5 mg / kg) and 21 (0.5 mg / kg) in vehicle = 0.9% NaCI iv applied and the effect on the cystometric parameters recorded 90 to 120 minutes. The mean of 3 micturition cycles was determined at the effective maximum and presented as a percentage change compared to the previous value (Table 1).

Table 1: Influence of the cystometric parameters by the test substances (change from previous value [%]); n corresponds to the number of test animals; Significance (Student T-Test): * p <0.05; ** p <0.01; *** p <0.001.

The investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence. Among other things, it is shown that of the enantiomers of racemic compound 1, the (+) enantiomer (compound 2) is very effective (and is therefore a particularly preferred compound of this invention), while the (-) enantiomer (compound 21) is not contributed so much to the effect.

Claims

Expectations

1. Use of 1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol for the manufacture of a medicament for the treatment of increased urge to urinate or urinary incontinence, characterized in that the 1-dimethylamino-3 - (3-methoxy-phenyl) -2-methyl-pentan-3-ol in a pharmaceutical formulation selected from:

■ an oral osmotically driven

Wirkstoffreisetzungssystem,

^■ a parenteral implant, ^■ a multipore tablet,

^■ a gel-matrix tablet,

A transdermal application system,

■ a local application system or

^■ a parenteral depot system is included.

2. Use according to claim 1, characterized in that (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-pentan-3-ol or a pharmaceutically acceptable salt thereof is used.