Use of weak opioids and mixed opioid agonists/antagonists for treating urinary incontinence

The present invention relates to the use of a weak opioid and a mixed opioid agonist / antagonist in the manufacture of a medicament for the treatment of severe urgency or urinary incontinence.

Urinary incontinence is involuntary urination. It occurs uncontrollably when the pressure inside the bladder exceeds the pressure needed to close the urinary tract. Reasons may be, first, increased internal bladder pressure (e.g., by detrusor instability) resulting from urge incontinence, and secondly, decreased sphincter pressure (e.g., after delivery or surgery) resulting from stress incontinence. The detrusor is a coarse tufted, multilayered muscle of the bladder wall, the contraction of which leads to the defecation of urine, the sphincter is the closing muscle of the urethra. There are mixed forms of these types of incontinence and so-called excess incontinence (e.g. in the case of benign prostatic hyperplasia) or reflex incontinence (e.g. after spinal cord injuries). For more information, see the publication of the authors Chutka, DS and Takahashi, P. Y., 1998, Drugs 560: 587-595.

The urge to urinate is a state of increased tension in the bladder muscles when the bladder capacity is close to (or exceeded), which aims to empty the urine (until voiding). The voltage acts as a stimulus for voiding. The term "increased urge to urinate" means in particular the occurrence of premature or frequent, sometimes even painful urge to urinate up to the so-called compulsive urge to urinate. This leads to clearly more frequent micturition. The reasons may be, among others cystitis as well as bladder tuberculosis. However, not all causes are clarified yet.

Increased urge to urinate as well as urinary incontinence are considered to be extremely unpleasant and there is a clear need for those affected by this indication to obtain the longest possible improvement.

Increased urge to urinate, and urinary incontinence in particular, is usually treated medicinally with substances that are involved in the reflexes of the lower urinary tract (Wein, AJ, 1998, Urology 51 (Suppl. 21): 43-47). Usually these are drugs that inhibit the detrusor muscles that are responsible for the internal pressure in the bladder. These drugs are e.g. parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine, or muscle relaxants such as flavoxate. Other drugs that especially increase the resistance of the urethra or bladder neck have affinities for α-adrenoreceptors such as ephedrine, for β-adrenoreceptors such as clenbuterol, or are hormones such as estradiol.

Also certain diarylmethylpiperazines and -piperidines are described in WO 93/15062 for this indication. A positive effect on bladder function has also been found for tramadol in a rat model of rhythmic bladder contraction (Nippon-Shinyaku, WO 98/46216). In addition, there are studies in the literature to characterize the opioid side effect of urinary retention, from which some indications of the influence of bladder function by weak opioids such as diphenoxylate (Fowler et al., 1987 J. Urol 138: 735-738) and pethidine (Doyle and Briscoe, 1976 Br J Urol 48: 329-335), by mixed opioid agonists / antagonists such as buprenorphine (Malinovsky et al., 1998 Anesth Analg 87: 456-461; Drenger and Magora, 1989 Anesth Analg 69: 348-353), pentazocine (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3): 610-616) and nalbuphine (Malinovsky et al., 1998, in the references cited), and by potent opioids such as morphine (Malinovsky et al., 1998 in the references cited; Kontani and Kawabata, (1988); Jpn J Pharmacol. Sep; 48 (1): 31) and fentanyl (Malinovsky et al., 1998 as cited). However, these studies were mostly performed at analgesic effective concentrations.

In the case of the indications involved, however, it should be noted that these are generally very long-term drug uses and that those affected face a very unpleasant but not intolerable situation, unlike many situations in which painkillers are used. Hence, even more so than in the case of painkillers, care must be taken to prevent side effects if the affected person would not exchange one evil for another. The analgesic effects are also highly undesirable in the long-term treatment of urinary incontinence.

PL 204 246 B1

The object of the present invention was therefore the use of substances which would be helpful in the treatment of increased urge to urinate or in the treatment of urinary incontinence and, preferably in effective doses, would simultaneously have little side effects and / or analgesic effects.

It has surprisingly been found that certain weak opioids and mixed opioid agonists / antagonists even at low concentrations have excellent effects on bladder function and are therefore well suited for the treatment of the respective diseases.

Accordingly, an object of the invention is the use of one of the following compounds:

• codeine, • meptinol or • tilidine in free base form and / or in the form of physiologically acceptable salts, for the manufacture of a medicament for the treatment of urgency or urinary incontinence.

It has surprisingly been found that these known compounds have a clearly positive effect on physiological parameters of importance in the case of increased urge to urinate or urinary incontinence, which can be especially recognized in the reduction of the interval in the rhythmic bladder contraction model. This change may mean a clear alleviation in the symptomatic picture of sick patients.

Suitable salts for the purposes of the invention and for each of the claimed applications are the salts of the active compound in question with inorganic or organic acids and / or with a sugar substitute such as saccharin, cyclamate or acesulfame. However, the hydrochloride is particularly preferred.

Codeine ((5a, 6a) -7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-morphinan-6-ol) is an active substance with antitussive, narcotic and analgesic properties. It is described in the German Reichs Patent (DRP) No. 247 189 for CH Boehringer v. 1912.

Meptinol (3- (3-ethyl-hexahydro-1-methyl-1H-azepin-3-yl) -phenol), a narcotic and analgesic agent, is described in DE-OS 1 941 534 or GB 1 285 025.

Tilidine (trans-2- (dimethylamino) -1-phenyl-3-cyclohexene-1-ethyl carboxylate) is described in DE 1 518 959 or US 3 557 126 and is a known analgesic and narcotic agent.

The use of codeine, meptinol or tilidine in particular for the manufacture of a medicament is preferred.

In an embodiment according to the invention and in a preferred embodiment, codeine is used, preferably in the form of the free base, HBr salt or HI salt or in the form of codeine phosphate.

In a preferred and preferred embodiment according to the invention, tilidine is used, preferably in the free base or HCl salt form, and also in the form of its racemates, enantiomers, diastereoisomers, especially mixtures of enantiomers or diastereoisomers, or of a single enantiomer or diastereoisomer.

In a preferred and preferred embodiment according to the invention, meptinol is used, preferably in the free base or HCl salt form, and also in the form of its racemates, enantiomers, diastereoisomers, especially mixtures of enantiomers or diastereoisomers, or of a single enantiomer or diastereoisomer.

Even if the uses according to the invention show little side effects, for example to avoid certain forms of addiction, it may also be advantageous to use morphinan antagonists in addition to these compounds, in particular the use of naloxone, naltrexone and / or levalorphan. Preferred examples would be tilidine and naloxone.

Agents for the treatment of urgency or urinary incontinence may contain as the active ingredient at least one of the compounds selected from • codeine, • meptinol or • tilidine as a free base and / or in the form of physiologically acceptable salts, and optionally contain additives and / or auxiliary.

Suitable salts for each of the claimed uses are the salts of the active ingredient with inorganic or organic acids and / or with a sugar substitute such as saccharin, cyclamate or acesulfame. However, the hydrochloride is particularly preferred.

Suitable additives and / or auxiliaries are all substances known from the state of the art for obtaining galenic preparations. Selection of these auxiliary substances 4

The treatment and the amounts used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically. Preparations in the form of tablets, chewable tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, solutions, suspensions, easily reconstitutable dry preparations and aerosols are suitable for parenteral, topical and inhalation administration. A further possibility is suppositories for use in the rectum. Use in a cartridge, in dissolved form, in a carrier film or in a patch, optionally with the addition of skin penetration enhancers, are examples of suitable forms for percutaneous administration. Examples of adjuvants and additives for oral dosage forms are grinding agents, lubricants, binders, fillers, mold release agents, optionally solvents, flavor improving agents, sugars, especially carrier agents, diluents, dyes, antioxidants, etc. . fatty acid waxes or esters, and for parenteral application agents, carriers, preservatives, suspending aids, etc. can be used. The amounts of active ingredient administered to the patient will vary depending on the weight of the patient, the mode of administration and the severity of the disease. When used orally, rectally or percutaneously, the compounds used according to the invention may be released with a delay. For the indication according to the invention, the corresponding sustained-release formulations are particularly preferred, in particular in the form of a "once-daily" formulation which only needs to be taken once a day.

Medicinal products containing from 0.05 to 90.0% of the active ingredient are further preferred, especially at low doses effective to avoid side or analgesic effects.

In the case of the use of these substances according to the invention, for a medicament for incontinence or for a medicament containing these active ingredients, it is advantageous to use a dose which is lower than that required for the analgesic effect, i.e. a dosage below the analgesic effect is used. Typically the dosages will be between the lower limit of the dose used in analgesic therapy and 10% of this dose, preferably between 80% and 20% of this dose, especially between 50% and 30% of this dose.

For the opioids claimed for use in the treatment of urinary incontinence according to the invention, this means that the following specific doses are usually used per dose:

<td rowspan="2">Substance</td><td colspan="3">Human dose [mg]</td><td colspan="3">Dose [mg / kg]</td>

<td>normal</td><td>beneficial</td><td>special</td><td>normal</td><td>beneficial</td><td>special</td>

<td>Codeine</td><td> 4-40</td><td> 8-32</td><td> 12-20</td><td> 62-616</td><td> 123-493</td><td> 185-308</td>

<td>Meptinol</td><td> 5-50</td><td> 10-40</td><td> 15-25</td><td> 77-770</td><td> 154-616</td><td> 231-385</td>

<td>Tilidine</td><td> 5-50</td><td> 10-40</td><td> 15-25</td><td> 77-770</td><td> 154-616</td><td> 231-385</td>

Auxiliary substances can be, for example: water, ethanol, 2-propanol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositide, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, cooking oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene fatty acid esters, esters with fatty acid, esters sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, magnesium sulfate, zinc sulfate, calcium sulfate, potassium, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, cross-linked polyvinylpyrrolidone, agar and bentonite.

The medicaments and pharmaceutical preparations used according to the invention are prepared by means, devices, methods and methods well known in the pharmaceutical preparation art, as for example described in "Remington's Pharmaceutical Science", Hrsg. AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), especially in part 8, chapters 76-93.

For example, for a solid preparation such as a tablet, the active ingredient of the medicament, i.e. the said compound or a pharmaceutically acceptable salt thereof, can be granulated with a pharmaceutical carrier, e.g. with traditional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or a pharmaceutically acceptable gum, and with pharmaceutical diluents such as e.g. water to form a solid composition that contains the compound used according to the invention or a pharmacologically acceptable salt when dispersed uniformly. By homogeneous dispersion is meant here that the active ingredient is evenly dispersed throughout the composition so that it can be distributed without difficulty in equally effective unit dose forms, such as tablets, pills or capsules. The fixed kit is then divided into unit dose forms. The tablets or pills of the medicament according to the invention or of the formulations used according to the invention can also be coated or mixed by other means to prepare a delayed release dosage form. Suitable coating agents are, inter alia, polymeric acids and mixtures of polymeric acids with materials such as, for example, shellac, cetyl alcohol and / or cellulose acetate.

Medicinal products which especially contain codeine, meptinol or tilidine are particularly preferred.

Even if the medicaments used according to the invention show little side effects, it may be advantageous, for example to avoid certain forms of addiction, to use morphinan antagonists in addition to these compounds, in particular the use of naloxone, naltrexone and / or levalorphan. Preferred examples would be tilidine and naloxone.

The examples below illustrate the invention without, however, limiting the subject matter of the invention.

Examples

Example 1

Test system of cystometry on anesthetized rats not coming into contact with a given stimulus so far

A cystometric study on stimulus naïve female rats was performed by the method of Kimura et al. (Kimura et al., 1996, Int. J. Urol. 3: 218-227). In anesthetized, ventilated rats, the abdomen is opened and the ureter is ligated. Urine is drained from the kidneys. A catheter is inserted into the bladder and fixed. Saline is poured into the bladder through the catheter by means of an infusion pump until the bladder exhibits rhythmic spontaneous activity in the form of contractions that can be recorded by an attached pressure sensor. After a stable starting value has been obtained, the test substance is administered intravenously in a cumulative manner. Bladder function is influenced by the suppression of spontaneous contractions. As a parameter for this damping, the absence of contractions for 10 minutes is valid.

For all the substances listed below, there was a measurable constant of spontaneous contractions, with Table 1 giving the mean value of 3 independent experiments in which for the first time there were no contractions for 10 minutes.

Table 1

<td>Relationship</td><td>Lowest dose (mg / kg)</td>

<td>Tilidine</td><td>0.5 (n = 3)</td>

<td>Meptinol</td><td>1.0 (n = 3)</td>

<td>Codeine (phosphate)</td><td>4.7 (n = 3)</td>

(n corresponds to the number of trials included in the value)

The tested substances have a positive effect on the regulation of the bladder and are therefore suitable for the treatment of urinary incontinence.

Example 2

Parenteral application forms

38.5 g of meptazinol hydrochloride are dissolved in 1 liter of water for injection at room temperature, and then made isotonic by adding anhydrous glucose for injection.

In the case of an average patient of about 65 kg body weight, for example, 0.5 ml or 19.25 mg or = 300 μg / kg is administered. This administration may be approximately 3 times daily.

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Example 3

Liquid, oral dosage form as a mixture with naloxone

23.82 g of tilidine hydrochloride hemihydrate and 2.04 g of naloxone hydrochloride dihydrate are dissolved at room temperature in 874 ml of purified water, 124 ml of ethanol (96%) and 2 ml of HCl.

Of these, the average patient with a body weight of about 65 kg will ingest, for example, 20 drops (= 0.72 ml), i.e. 17.15 mg of active ingredient (about 16.7 mg of tilidine hydrochloride, respectively) or 264 μg / kg. This may be up to 4 times a day in total.

Example 4

Long-acting solid oral dosage form (prolonged-release tablets) For 1 prolonged-release tablet:

mg of codeine phosphate hemihydrate

143 mg of microcrystalline cellulose 94 mg of methylhydroxypropyl cellulose (100,000 mPa ^ s) mg of highly dispersed silica 3 mg of magnesium stearate

260 mg in total.

The excipients and the active ingredient are homogeneously mixed in a mixer, and then tablets with a diameter of 9 mm are pressed in a tablet press.

Dosage example: 1 tablet, i.e. for a body weight of 65 kg, respectively = 262 μg / kg. Usually 2 capsules are taken daily.