GB2031727A - Pharmaceutical compositions - Google Patents

Abstract

Pharmaceutical compositions for the treatment of hypertonic functional states in the region of the bladder, comprising, as active material, at least one alpha , alpha -diphenyl- alpha -alkoxyacetic acid 1-methyl-4-piperidyl ester derivative and/or at least one salt thereof with a non-toxic and pharmacologically acceptable organic or inorganic acid, in admixture with a solid or liquid pharmaceutical diluent or carrier. The compositions may be administered orally, rectally or parenterally.

Description

SPECIFICATION Pharmaceutical compositions The present invention is concerned with pharmaceutical compositions for the treatment of hypertonic functional states in the region of the bladder.

Cholinergic neuromuscular functional disturbances of the detrusor vesicae in the region of the bladder manifest themselves, for example, in urinary incontinence, very painful bladder cramp and nycturia. Quite apart from psychic stresses, this type of disease leads to social ostracism, prolonged inability to work and a high cost for clinical attention.

Hitherto, the treatment of these disturbances took place polypragmatically with analgesics only symptomatically or with phenothiazine derivatives or other antidepressive drugs in order to treat the psychic components, as well as with cholinolytic drugs, such as atropine and scopolamine butyl bromide, by means of which general spasms of the smooth musculature are relaxed but the action upon the bladder is insufficient and, in addition, considerable side effects occur.

The problems of the therapy of the above-mentioned functional disturbances in the region of the detrusor vesicae depends upon the varying response of the patients to the compositions introduced into the therapy or upon the lack of specificity of the pharmaceuticals employed.

Due to the low degree of specificity, considerable side effects and incompatibilities result in the form of undesired cardiac and circulatory reactions, xerostomia, accomodative distrubances of even central effects extending to excitation states and hallucinations.

Since 1957, emepronium bromide has been used therapeutically but it must be administered in high daily oral dosages of 600 mg., even though the LD50 is of the order to 1000 mg./kg.

(rats per oral).

A comparison with the intravenous dosage (8.35 mg./kg. in rats) points towards a clinically observed and kinetically confirmed low resorption quotient.

The side effects which have been observed in the case of this compound include, for example, an increased pulse rate, xerostomia and ulcerations of the oral cavity and oesophagus.

It is also known that compounds can be derived from diphenylhydroxyacetic acid which possess musculotropicspasmolytic, histaminolytic, analgesic as well as strongly cholinolytic actions in the region of the central nervous system, for which reason they have been used experimentally for treating Parkinson's disease, for reducing ton us of the smooth musculature in the region of the gastrointestinal tract, for example in cases of biliary colic, and for the suppression of reactions caused by histamine in cases of diseases of allergic genesis.

A specific therapeutic use of diphenylhydroxyacetic acid derivatives for selectively influencing hypertonic functional states of the detrusor vesicae in the region of the bladder has, however, not taken place because the known forms of action thereof have not given any indication that the use thereof would give satisfactory results.

It is an object of the present invention to provide novel pharmaceutical compositions which can be used for the treatment of hypertonic functional states of the detrusor vesicae in the region of the bladder.

Surprisingly, we have now found that a,a-diphenyl-a-alkoxyacetic acid 1-methyl-4-piperidyl ester derivatives (i) and the saltls thereof with non-toxic and pharmacologically acceptable inorganic and organic acids and especially the hydrochloride of a,a-diphenyl-a-rkpropoxyacetic acid i-methyl.4-piperidyl ester (II), can be used especially advantageously for increasing the bladder capacity after operations on the bladder and prostate, for lowering internal bladder pressure due to miction in the case of hypertonic bladder inflammation and for reducing painful bladder tenesmus of varying genesis, as well as for the treatment of pollakisuria, nycturia and nocturnal enuresis.

The a-alkoxy radical present in the compounds (I) preferably contains up to 6 carbon atoms and especially 3 carbon atoms. These compounds were first synthesised by J. Klosa.

Thus, according to the present invention, there is provided a pharmaceutical composition comprising at least one a,a-diphenyl-a-alkoxyacetic i-methyl-4-piperidyl ester derivative and/or at least one salt thereof with a non-toxic and pharmacologically acceptable organic or inorganic acid, in admixture with a solid or liquid pharmaceutical diluent or carrier.

The new compositions according to the present invention can be in any of the conventional oral, rectal or parenteral forms of administration, such as tablets, dragees, capsules, suppositories and ampoules. For this purpose, the active material is mixed with solid or liquid carrier materials and subsequently brought into the desired pharmaceutical form.

Solid carrier materials which can be used include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly-dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol). Compositions suitable for oral administration can, if desired, contain flavouring and/or sweetening materials.

As injection medium, it is preferred to use water which contains conventional additives for injection solutions, such as stabilising agents, solubilising agents and/or buffers. Additives of this type include, for example, acetate and tartrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as polyethylene oxide) for viscosity regulation.

In the case of humans, the active material can be administered orally at a daily dosage of 1 5 to 60 mg., rectally at a daily dosage of 25 to 100 mg. and parenterally at a daily dosage of 10 to 30 mg.

The advantages provided by the use of the compounds (I) and especially of compound (11) is that, in the case of hypertonic functional states of the detrusor vesicae and the bladder distrubances resulting therefrom, a specific therapy is now possible, with simultaneously high compatibility.

Even in the case of comparatively high dosages, only insignificant side effects occur and there are no changes of the blood picture, pulse frequency, plasma protein, residual nitrogen and blood glucose values.

Furthermore, the possibility of administering the active materials intravenously is also an especially favourable characteristic.

In the above-mentioned dosage ranges, good to very good therapeutic results have been achieved with patients after bladder and prostate operations with the object of a post-operative increase of the bladder capacity.

The active materials are outstandingly useful for reducing the internal pressure of the bladder caused by miction in the case of a hypertonic inflamed bladder, in the case of urge incontinence and for the reduction of painful bladder tenesmus of differing genesis, as well as for the treatment of pollakisuria, nycturia and nocturnal enuresis, provided that these are caused by hypertonic states of the detrusor vesicae.

The advantageous properties of the active compounds used according to the present invention in comparison with those previously employed is demonstrated by the following experimental results: 1. Neutrotropic-spasmolytic action.

The investigation took place with the use of a conventional protocoll: the inhibition of the intestinal contraction of the isolated guinea pig ileum, initiated by acetylcholine (bath concentration 10-7 g./ml.), was tested.

4 to 6 different concentrations of the test substances were used and the dosage with a 50% inhibitory effect (ED50) was determined by graphic interpolation. The following results were obtained: ED50 towards acetylcholine contractions on the isolated substance guinea pig ileum atropine 7X10-9 a,a,-diphenyl-a-n- propoxyacetic acid 9 x 10-7 1 -methyl-4-piperidyl ester hydrochloride The neurotropic-spasmolytic effectiveness of (II) on the isolated guinea pig ileum is clearly smaller than that of atropine used as comparison substance. This could be the explanation for the substantial absence of disturbing side effects in the region of the gastrointestinal tract, for example constipation.

2. Clinical effectiveness.

The action of (II) on the tonus of the detrusor vesicae of the bladder was investigated in the case of various urological diseases on the basis of the influencing of the bladder capacity. The capacity measurement of the bladder and the masurement of the pressure values were carried out by means of cystosphinctero-tonometry, the investigations being carried out with constant parameters, such as rate of inflow, water column height and catheter size.

The bladder capacity present before the administration of (II) was determined from the average value of three individual measurements and used as the reference or initial value. 30 Minutes after the intravenous administration of 10 mg. of (II) per patient, the bladder capacity was again determined. It was thereby found that the action of the compound manifested itself especially clearly in the case of bladders with reduced initial volume and hypertonic functional states in the region of the detrusor vesicae. In the group of patients in question, the average increase of the bladder capacity was 67%.

A comparison with the action of atropine clearly indicates the elective action of (II).

Corresponding investigations on one and the same group of patients shows, in the case of the intramuscular administration of 0.5 mg. atropine per patient, in comparison with the intramuscular action of 1 5 mg. of (II) per patient, 45 minutes after injection, an average bladder capacity increase due to atropine of 12% and due to (II) of 60%.

An especial advantage which was ascertained was that, in the case of (II), no incompatibility phenomena occurred, whereas the above-mentioned dosage of atropine gave rise to xerostomia, mydriasis and accommodation disturbances.

In the case of the oral administration of (II), all the results of the acute experiments with intravenous administration could, in principle, be confirmed. The investigations were carried out in the form of single oral administration at a dosage of 1 5 to 30 mg. and, in a long-term study of, on average, 1 80 days at a dosage of 3 X 1 5 mg. or 4 X 15 mg. of active material on a total of 75 patients. In the case of one long-term study, the miction frequency prior to the therapeutic experiment was, on average, 14 mictions per day. After the use of the active material, the miction frequency decreased to an average of 5 per day. No clear effects could be observed in a placebo group.

The effectiveness of (II) was impressive in the case of nycturia. The average nocturnal miction frequency before the therapeutic experiment was 5 times a night, whereas after the administration of the active material, the rate of nocturnal miction frequency was only 0 to 1. The administration of a placebo had no effect.

In the case of long-term therapy, capacity changes of the bladder were also especially strongly marked. In the case of a prolonged administration of the active material, in the case of patients with an initial bladder capacity of 50 to 80 ml., an average increase of 200% was recorded.

Patients with an initial volume of 80 to 1 50 ml. showed an average increase of the bladder capacity of 130%. The administration of a placebo showed no detectable action.

The compatibility of the active material was excellent, not only in the case of patients with short-term administration but also during the course of long-term therapy. All investigated clinical and paraclinical parameters, such as blood picture, urine status, blood glucose level and liver function tests, were satisfactory. Even patients with increased creatinine serum values did not suffer from any deterioration and no increase of the urine nitrogen compounds took place.

3. Pharmacokinetic behaviour The tissue distribution of (II) in rats 72 hours after oral administration showed a relatively high concentration in the adipose tissue (indicative of the lipophilic properties of the compound) with minimal amounts in the liver, uterus and musculature. 80% of the administered dose was detected in the urine.

The course of renal elimination was as follows: 6 hours after oral administration, 30% was excreted renally and was detectable in the urine and 24 hours after administration more than 50% was excreted renally.

This specific kinetic behaviour explains the low or absent cholinolytic activity in the region of the central nervous system and the elective action in the region of the bladder or detrusor vesicae.

Furthermore, because of the lipophilic properties of the substances, there must be assumed a strong local action of (II) in the region of the bladder wall due to reabsorption.

4. Toxicological behaviour.

The average oral daily dose for adults is only 3 x 1 5 mg. = 45 mg. per day.

The oral LD50 (rat) is 2250 mg./kg. and the intravenous LD50 (rat) is 29 mg./kg., the toxicity being substantially smaller than that of emepronium bromide. A favourable therapeutic spectrum is achieved.

In the case of the therapeutically administered dosages of (II), the side effects which are characteristic for anticholinolytic drugs, as well as other side effects, do not occur.

Testing of the chronic toxicity for half a year (rats) with 5% of the LD50 did not result in any macroscopic or histological changes of the organs nor in any influencing of the fertility.

The following examples are given for the purpose of illustrating the present invention: Example 1.

A mixture of (II) with solid carrier materials can be prepared with, for example, lactone, starch, talc, methyl cellulose, magnesium stearate and gelatine. An example of a tablet formulation for a 100 mg tablet is as follows: 15 mg. (11) 45 mg. potato starch 30 mg. lactose 10 mg. talc.

For the production of tablets, the active material is mixed with 75% of the potato starch and all of the lactose and an about 10% aqueous gelatine solution and granulated with the use of an appropriate device. After drying at a temperature of not more than 30'C., the granulate is mixed with the talc and the remainder of the starch and pressed to give tablets.

Example 2.

A typical ampoule solution contains the following: 1.0 9. (11) 50.0 ml. propylene glycol 2.6 ml. N hydrochloric acid ad 200.0 ml. injectable water.

Example 3.

A typical example of a suppository composition is the following: 2.5 g. (Il) ad 100.0 g. "Lasupol".

("Lasupol" is a synthetic ointment or suppository base prepared from phthalic acid and high molecular weight fatty alcohols, such as cetyl alcohol; see Pharm. Zentralk., 89, 369/1950 and Pharmazie, 8, 211/1953).

Claims (5)

1. Pharmaceutical composition for the treatment of hypertonic functional states in the region of the bladder, comprising, as active material, at least one a,a-diphenyl-a-alkoxyacetic acid 1methyl-4-piperidyl ester derivative and/or at least one salt thereof with a non-toxic and pharmacologically acceptable organic or inorganic acid, in admixture with a solid or liquid pharmaceutical diluent or carrier.

2. Pharmaceutical composition according to claim 1, wherein the active material is a,a diphenyl-a-n-propoxyacetic acid 1 -methyl-4-piperidyl ester hydrochloride.

3. Pharmaceutical composition according to claim 1 or 2, in a form suitable for oral, rectal or parenteral administration.

4. Pharmaceutical composition according to any of the preceding claims, whenever in the form of a tablet, dragee, capsule, suppository or ampoule.

5. Pharmaceutical compositions according to claim 1, substantially as hereinbefore described and exemplified.