CH644016A5 - MEDICINES FOR TREATING HYPERTONE FUNCTIONAL STATES OF THE URBAN BLADDER. - Google Patents

Description

The invention relates to a medicament for the treatment of hypertensive functional states in the urinary bladder and the manufacture of this medicament.

Cholinergic neuromuscular dysfunction of the detrusor vesicae in the urinary bladder are expressed e.g. in urinary incontinence, very painful bladder cramps and nocturia. Apart from psychological stress, these clinical pictures lead to social outsiderity, long-term incapacity to work and high clinical care expenditure.

So far, these disorders have been treated polypragmatically: only symptomatically with analgesics, with phe-nothiazine derivatives or other antidepressants to treat the psychological component, as well as with cholinolytics such as atropine and scopolamine butyl bromide, which generally resolves spasms of the smooth muscles Effect on the bladder is insufficient and there are also considerable side effects.

The problem of the therapy of the functional disorders mentioned at the outset in the area of the detrusor vesicae is based on the different responsiveness of the patients to the preparations introduced in the therapy or the lack of specificity of the drugs used.

The lack of specificity results in considerable side effects and intolerance in terms of undesirable cardiac and circulatory reactions, dry mouth, accommodation disorders or even central effects up to excitement and hallucinations.

Emepronium bromide has been introduced into therapy since 1957, but this requires high oral daily doses of 600 mg at an LDS0 of 1000 mg / kg (rat orally).

The comparison with the intravenous dose - 8.35 mg / kg rat - indicates the clinically observed and kinetically confirmed low absorption rate.

The side effects are e.g. described: pulse rate increases and dry mouth or ulcerations of the oral cavity and esophagus.

It is also known that compounds derived from diphenylhydroxy-acetic acid have musculotropic-spasmolytic, histaminolytic, analgesic and strongly cholinolytic effects in the area of the CNS, which is why they are tentatively used to influence Parkinson's syndrome, to reduce the tone of smooth muscular organ systems in the area of the area Gastrointestinal tract (eg with biliary colic) and to suppress histamine-related reactions in diseases of allergic origin.

In contrast, no specific therapeutic use of diphenylhydroxyacetic acid derivatives for selectively influencing hypertensive functional states of the detrusor vesicae in the area of the bladder has taken place, because the known qualities of action have given no indication for this.

The purpose of the invention is to be able to effectively treat hypertonic functional states in the urinary bladder.

The object of the invention is to develop a medicament with which hypertonic functional states of the detrusor vesicae in the area of the bladder can be effectively treated.

Surprisingly, it was found that a, a-di-phenyl-a-alkoxyacetic acid-1-methylpiperidyl-4-ester (I) and its salts with inorganic and organic acids, in particular the hydrochloride of a, a, -diphenyl-an prop-oxyacetic acid-l-methyl-piperidyl-4-ester (II), are particularly advantageous for increasing the bladder capacity after bladder and prostate surgery, but also for lowering the vesicle-related bladder pressure in the case of hypertonic irritable bladder or for reducing painful bladder doses of different origins and for Have treatment of pollakiuria, nocturia and nocturnal enuresis started. The substance was first synthesized by J. Klosa. All conventional oral and parenteral administration forms such as tablets, dragées, capsules, drops, suppositories, infusion solutions and ampoules can be used as the preparation of this substance according to the invention. For this purpose, the active ingredient is mixed with solid or liquid carriers and then brought into the desired pharmaceutical form. The active substance can be administered orally in humans in a daily dose of 15-60 mg, rectally 25-100 mg and parenterally 10-30 mg.

The invention has the advantage that when I, in particular II, is used, in the case of hypertonic functional states of the detrusor vesicae and the resulting bladder disorders, specific therapy with excellent tolerability has become possible.

Even at higher doses, there are only minor side effects and no changes in the blood count, pulse rate, plasma protein, residual N and blood sugar levels.

The option of i.v. Application of the active ingredient can be viewed.

In the specified dose range, good to very good therapeutic results were achieved in patients after bladder and prostate surgery with the aim of increasing the bladder capacity postoperatively.

The active ingredient has proven itself excellently for lowering the urinary bladder pressure in hypertonic irritable bladder, for urge incontinence or for reducing painful bladder tesmen of different origins as well as for the treatment of pollakiuria, nocturia and nocturnal enuresis if this was caused by hypertonic functional states of the vesica detrusor.

The advantageousness of the pharmaceuticals according to the invention compared to the prior art is to be demonstrated with some test results.

1. Neurotropic spasmolytic effect

The examination was carried out in the usual order. The inhibibility of the then contractions triggered by acetylcholine (bath concentration 10 ~ 7 g / ml) on the isolated guinea pig ileum was tested.

4-6 different concentrations of the substances examined were tested and the dose with a 50% inhibitory effect (ED50) was determined by graphic interpolation.

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644 016

substance

EDS0 versus acetylcholine

contractions at the ileum

Atropine

7 x 10 ~ 9

a, a-diphenyl-a-n-propoxy-

9x10 "7

acetic acid-1-methyl-piperidyl-

4-ester • HCl

The neurotropic-spasmolytic effectiveness of II on the guinea pig ileum is significantly lower than that of the reference substance. This could be the explanation for the largely lack of disturbing side effects in the area of the gastrointestinal tract (e.g. constipation).

2. Clinical effectiveness

The effect of II on the tone of the detrusor vesicae of the bladder in various urological diseases was examined by influencing the bladder capacity. The measurement of the capacity of the bladder and the measurement of the pressure values were carried out with the help of cysto-sphinctero-tonometry, whereby the examinations were carried out with constant parameters such as inlet speed, water column height and catheter strength.

The bubble capacity before the application of II was determined by averaging three individual measurements and recorded as a reference or starting value. 30 min after i.v. Administration of 10 mg II per patient again determined the bladder capacity.

It was found that the effect of the substance was particularly pronounced in blisters with a reduced initial volume or hypertonic functional states in the area of the detrusor vesicae. The average increase in bladder capacity was 67% in the patient group mentioned.

The comparative effects of atropine speak in particular for the elective effect of the II.

Corresponding examinations in one and the same patient group showed at i.m. Application of 0.5 mg atropine per patient compared to i.m. Effect of 15 mg II per patient 45 min after the injection, an average bladder capacity increase of 12% with atropine and 60% with II.

It was also found to be particularly advantageous that no intolerance symptoms occurred under II, while the atropine dose mentioned already caused dry mouth, mydriasis and accommodation disorders.

When the II was used orally, all results of the acute trials with i.v. Application can be confirmed in principle. The investigations were carried out in the form of a single oral application in a dosage of 15 or 30 mg and in a long-term study of 180 days on average in a dosage of 3 x 15 mg or 4 x 15 mg of active ingredient in a total of 75 patients. In a long-term study, the micturition frequency before the therapy attempt averaged 14 micturition / days. The frequency of micturition was reduced to an average of 5 / days when the active ingredient was used. No clear effects were detectable in the placebo group.

The effectiveness of the II in nocturia was impressively documented. The average nightly frequency of micturition before the therapy attempt was 5 / night. Under the drug application, the micturition rate was only 0-1. The placebo medication was unsuccessful.

In long-term therapy, changes in the capacity of the bladder were also extraordinarily pronounced. With the long-term administration of active substances, an increase of an average of 200% was registered in the patients with a primary bladder capacity of 50-80 ml. Patients with an initial volume of 80-150 ml had an average increase in bladder capacity of 130%. The placebo medication had no demonstrable effect here.

The tolerability of the active ingredient was excellent both in the patients with short-term application and during long-term therapy. All the clinical and paraclinic parameters examined, such as blood count, urine status, BSG and liver function samples, were normal. Even patients with increased creatinine serum levels did not experience any deterioration or there was no increase in urinary nitrogen compounds.

3. Pharmacokinetic behavior

The tissue distribution of the II in rats resulted in a relatively high concentration in adipose tissue (reflection of the lipophilic properties of the substance), minimal amounts in the liver, uterus and muscles, 72 hours after oral administration. 80% of the applied dose was found in the urine.

The course of renal elimination was as follows:

6 hours after oral administration, 30% and 24 hours after application over 50% were already excreted in the urine and detectable in the urine.

This specific kinetic behavior explains the low or no cholinolytic activity in the area of the CNS and the elective effect in the area of the urinary bladder or detrusor vesicae.

Due to the lipophilicity of the substance, a strong local effect of the II in the area of the bladder wall by reabsorption must also be assumed.

4. Toxicological behavior

The average daily oral dose for adults is only 3 x 15 = 45 mg / d.

The LDS0 (rat orally) is 2250 mg / kg, the intravenous LD50 (rat) 29 mg / kg. The toxicity is therefore significantly lower than that of emepronium bromide. A favorable therapeutic range is achieved.

The side effects characteristic of anticholinolytics or other side effects do not occur with the therapeutically used doses of II.

The examination of the chronic toxicity over half a year (rat) with 5% of the LD50 brought neither macriscopic nor histological organ changes nor an influence on fertility.

The invention will be explained in more detail below using an exemplary embodiment:

The active ingredient can be mixed with solid carriers with milk sugar, starch, talc, methyl cellulose, magnesium stearate and gelatin.

The tablet formulation for a 100 mg tablet is, for example, the following:

15 mg II

45 mg potato starch 30 mg lactose 10 mg talc

For the preparation of the tablet, the active ingredient is mixed together with 75% of the potato starch and the entire lactose and about 10% gelatin solution and granulated with a suitable device.

After drying at a maximum of 30 ° C, the granulate is mixed with talc and the remaining starch and compressed into tablets.

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644016

Example of an ampoule solution:

ad

1.0 g II

50.0 ml propylene glycol

2.6 ml of hydrochloric acid

200.0 ml aqua ad injectionem

Example for the production of suppositories: Contain 100 g suppositories

2.5 g ad 200.0 g

II

Lasupol®

s

Claims (3)

644016 PATENT CLAIMS 1. Medicament for the treatment of hypertonic functional states in the urinary bladder, characterized in that it contains a, a-di-phenyl-a-alkoxyacetic acid-l-methylpiperidyl-4-ester and its salts with organic and inorganic acids as the active ingredient. 2. Medicament according to claim 1, characterized in that it contains as active ingredient a, a-diphenyl-oc-n-propoxyacetic acid 1-methylpiperidyl-4-ester hydrochloride. 3. A process for the manufacture of medicaments according to claim 1, characterized in that the active ingredient is mixed with solid and liquid carriers and is brought into the form of tablets, dragées, capsules, drops, suppositories and ampoules and infusion solutions which are suitable for oral and parenteral use Application are suitable.