IE48886B1 - An oral urolithiasis agent - Google Patents

Description

The present invention is concerned with an oral urolithiasis agent which is especially suitable for the therapy or prophylaxis of ailments due to calcium oxalate and calcium oxalate-containing calculi.

The chemotherapy of ailments due to oxalate calculi gives rise to considerable difficulties which hitherto have not been satisfactorily overcome. Magnesiumcontaining mixtures based on citrate are known frora Federal Republic of Germany Patent Specification No. 22 52 665 but their effectiveness is debatable since the citrate component thereof is metabolised and the effectiveness of the magnesium component present therein is, with regard to the solubility relationships, not clear.

Pharmaceutical compositions containing succinimide as active material are known from Federal Republic of Germany Patent Specification No. 20 30 932 but have not been found to be acceptable in practice and compositions based upon cation exchange resins do not provide a dependable treatment and successful prophylaxis. Consideration has also been given to the use of complex formers for calcium, for example glucuronic acid, or of magnesium compounds, for example magnesium oxide, citrate, adipate and nicotinate, for improving the solubility of calcium oxalate, as well as to the use of various plant extracts which, inter alia, contain ruberythric acid. However, all these various attempts have hitherto not led to the desired success.

We have now, surprisingly, ascertained that alizarin - 3 can be used for the treatment of patients with oxalate calculi since it not only has a marked inhibiting action on calculi formation but is also readily compatible.

Thus, according to the present invention, there is 5 provided an oral urolithiasis composition comprising 5 to 14% by weight alizarin, 10 to 26% by weight magnesium oxide, 22 to 32% by weight disodium hydrogen phosphate and 37 to 53% by weight potassiun dihydrogen phosphate, together with a pharmaceutical diluent or carrier.

The composition according to the present invention is preferably administered in an amount which corresponding to a daily dosage of 140 to 500 mg. alizarin.

As has been ascertained, the administration of alizarin as essential active material for the treatment of urolithiasis results in a distinct success.

The composition according to the present invention preferably contains the potassium dihydrogen phosphate and the disodium hydrogen phosphate in a weight ratio of 5:3.

Mixtures of disodium hydrogen phosphate and potassium dihydrogen phosphate alone have admittedly already been suggested and therapeutically used for the treatment of patients with oxalate calculi. However, the very high phosphate dosages hereby considered to be necessary fox a successful therapy are not entirely satisfactory and con25 siderable disturbing side effects occur, such as diarrhoea and gastrointestinal upsets. Alizarin, on the other hand, as will be shown hereinafter, is very readily compatible and - 4 the above-described active material mixture according to the present invention is also completely compatible and astonishingly effective.

In particular, we have investigated active material 5 combinations in the form of a dosage unit containing 35 mg alizarin, 65 mg magnesium oxide, 150 mg disodium hydrogen phosphate and 250 mg potassium dihydrogen phosphate.

Preferred forms of administration include hard gelatine capsules and dragees, as well as soft gelatine capsules with daily dosages of the preferred active material combination of about 15 to 90 mg./kg. body weight and especially of up to about 60 mg./kg. body weight, good success is achieved. The administration of 3 x 2 dosage units per day of the especially preferred dosage units gives an especially appropriate daily dosage of 43 mg./kg. body weight.

The extraordinarily good compatibility not only of alizarin itself but also of the especially favourable active material combination with the preferred mixture ratio was demonstrated by toxicity tests: The administration of alizarin in amounts of 1 g./kg. body weight (in mice) and of up to 400 mg./kg. body weight (in rats) did not give rise to any undesirable symptoms. The active material mixture administered in -5maximum administrable dosages of up to 10 g./kg. body weight to mice and of up to 5 g./kg. body weight to rats did not give rise to any incompatibilities.

For testing the chronic toxicity in the case of 5 rats, two groups of experimental animals were given differing daily dosages for a long period of time according to the following protocol: time daily dosage for Group 1 (mg. Ag.) daily dosage for Group 2 (mg./kg.) 1st - 4th week 200 600 5th - 8th week 250 750 9th - 29th week 300 1000 In the case of Group 1, an increase in kidney weight was ascertained in the case of female animals (absolute and relative to body weight).

In the case of animals in Group 2, the kidney weight of the male animals increased relatively and the kidney weight of the female animals was significantly increased absolutely and relatively to the body weight and to the weight of the brain. However, a histological investigation of the kidneys did not give any indication of any reason for this increase in weight. It is assumed that it is to be attributed to a general hypertrophy of the kidney parenchymatous tissue. A histological investigation of the lumbar vertebrae showed no deviations in comparison -6with non-treated control animals.

A testing of the chronic toxicity in dogs, with the maintenance of a dosage programme which was the same as in the case of rats, gave the following results: in the case of Group 1, the 24 hour urine volume was slightly increased and the magnesium and calcium concentrations in the urine were somewhat lower than in the case of the control animals. In the case of Group 2, the magnesium and calcium concentrations in the urine were lower but the excretion of these ions in the increased 24 hour urine volume was increased. The kidney weights in the case of dogs were also remarkably high.

Histological investigation of the lumbar vertebrae showed no deviations in comparison with the control animals. The same applied to the electrocardiogram investigations carried out.

In the case of general pharmacological investigations of the active material combination according to the present invention in the preferred amount ratio (i.e. with 7% by weight alizarin, 13% magnesium oxide, 30% disodium hydrogen phosphate and 50% by weight potassium dihydrogen phosphate, which is hereinafter briefly referred to as AMDP), tests were made on the action on the central nervous system, the smooth musculature, the heart-circulation function, respiration and blood gases, choleresis and the kidney activity, as well as the antiinflammatory action. -71. Action on the central nervous system. a) Pentetrazole cramp.

Groups of female mice with a body weight of 20 to 24 g. were given 600 or 1200 mg./kg. body weight AMD)? orally and, after 30 minutes, pentetrazole was administered intraperitoneally. Instead of AMDP, the control group were given the solvent used therefor. The appearance of cramps within 10 minutes of pentetrazole administration was noted. The results obtained are given in the following Table 1: 1° Table 1 Influence on cramps produced by pentetrazole by AMDP in mice N dosage (mg/kg) p.o. cramps pentetrazole action W yes N no N AMDP 20 600 14 6 70 9 1200 8 1 88 controls 20 - 16 4 80 9 - 7 2 77 As can be seen, the stimulation of the central nervous system by AMDP is not displaced upwardly or downwardly. b) Extensive investigations of the influence of AMDP (600 mg./kg. body weight orally) on hexobarbital sedation (100 mg./kg. body weight) in mice gave practically no indication of a sedative action of AMDP. -8c) In the case of the analgesia test by the burning ray method in mice, with 600 and 1200 mg./kg. body weight of AMDP, neither noteworthy changes in comparison with the control animals nor accompanying phenomena were observed. 2. Action on the gastrointestinal activity.

For the ascertainment of possible gastrointestinal actions, the stomach-intestine passage time was tested in mice. No influence was ascertained in the case of 600 or 1200 mg./kg. body weight AMDP on the speed of the stomach intestine passage in comparison with the controls.

Intestinal motility was also tested in mice: fasting experimental animals were given subcutaneously, 30 minutes after the oral administration of 600 mg./kg. body weight AMDP or of 25 ml./kg. body weight tragacanth (animals of the control group), lOO/ig./kg. body weight (2-hydroxyethyl)-trimethyl ammonium chloride carbamate (also known by the Trade Mark Doryl) as a motility-stimulating agent, followed immediately by a tragacanth-carmine red mixture (50 ml./kg. body weight orally). After a further 25 minutes, the animals were sacrificed and the intestinal length from the pylorus to the anus or the carmine red-coloured length of intestine then measured. The following Table 2 shows the results obtained: it can be seen that AMDP has practically no 25 influence on intestinal motility. -9Table 2 Intestinal motility in male mice (Percentage of the length of passage of the dyestuff to the total intestinal length) substance n dosage effect (%) action compared with control (%) AMDP 10 600 mg./kg. 66.63 + 12.82 + 19.61 tragacanth 10 25 ml./kg. 63.12 + 8.7 3. Action on the heart-circulation function, respiration and blood gases.

The behaviour of the heart-circulation functions, as well as of the blood gases, were analysed in dogs and rats. The measured parameters were the pulse frequency, pressure behaviour in the left ventrical, pressure behaviour in the right atrium, pressure behaviour in the femoral artery, respiratory frequency, respiratory volume, blood gases and pH. The AMDP dosage was 600 mg./kg. body weight in dogs and 300 and 600 mg./kg. body weight in rats.

Neither in the rat nor in the dog were significant changes of the measured parameters found so that there is no reason to suppose side effects of the active material mixture according to the present invention on the heart25 circulation and respiratory systems. -104. Action on choleresis.

In order to obtain information regarding the excretion behaviour of the active material mixture according to the present invention, there was investigated the 5 influence of AMDP on the bile secretion of Hie liver in rats at dosages of 600 mg./kg. body weight of AMDP. The results are given in the following Table 3: the bile secretion is practically unchanged.

Table 3 Influence of 600 mg,/kg, body weight AMDP intraduodenally on the bile flow of narcotised rats n bile flow ml./100 g. /30 min. AMDP 10 0.22 + 0.014 * 15 control (tragacanth) 10 0.23 + 0.012 ★ * average error . Action on the kidneys. a) Testing of the influence of AMDP on urine flow, as well , j. a. _ as on the concentration and excretion of Na , K , Cl and creatinine on awake rats.

After the oral administration of AMDP, fasting animals were placed overnight for 16 hours in diuresis cages and the urine collected via a funnel. During this time, the animals remained in an air-conditioned room at a tenperature of 26°C. and an atmospheric humidity of 60%. -11At the end of the experiment, the following parameters were determined in the collected urines of all the animals: urine flow (calculated on 1 hour and kg. of Ψ J. body weight), Na and K concentration (flame photometric5 ally) and Cl- concentration (coulometrically). The determination of creatinine was carried out with the Biochemica test combination of Boehringer Mannheim GmbH NO.15S43. The excreted amounts were calculated from the measured concentrations and urine volumes (see the following Table 4). b) Determination of urine flow, GFR and fractional fluid resorption, as well as of the fractional resorption and of the clearances for Na+, K+, Cl-, urea, paminohippuric acid (PAH) and glucose.

These determinations were carried out in mannitol diuresis on narcotised male rats (fasting) within the course of about 3 hours.

After the experimental animals had achieved a sufficient depth of narcosis, both ureters were canulated. intravenous injections and infusions were made into a jugular vein and blood was sampled from a carotid artery.

A pre-injection of inulin (50 mg./kg. body weight) and of PAH (20 mg./kg. body weight) took place 20 minutes before tbe commencement of infusion. The AMDP (800 mg./kg. body weight) was administered directly after pylorus into the duodenum at the time of commencement of the infusion.

The control animals received an aqueous suspension of -12tragacanth intraduodenally in the same manner. The infusion volume was 0.2 ml./minute per animal. Inulin was diffused in at a rate of 5 mg./kg. body weight per minute and PAH at a rate of 0.2 mg./kg. body weight per minute. The infusion medium was a 5% mannitol-Ringer solution. 1 Hour and 2 hours after the commencement of infusion, urine was collected for 7 minutes and, at the same time, about 1 ml. of blood was taken from the carotid artery. 14C-Inulin (1 mC/392 mg.), mixed with inactive inulin in a weight ratio of 1:100 was added as a 2% solution to the amount of pre-injection or infusion solution needed in each case. The radioactivity was 4* + measured in a liquid scintillation counter. Na and K were determined flame photometrically and Cl coulometrically. The urea determination was carried out by the urea method (Biochemica Boehringer Mannheim GmbH No.15945), PAH was determined by the method of A.C. Bratton and E.K. Marshall jr. (J. Biol. Chem. (Am.), 128, 537/1939).

Glucose was determined by the GOD-peride method (Biochemica Boehringer Mannheim GmbH No.15755). The values of the fractional resorption, as well as of the clearances, are average values from both urine collecting periods and the related blood samplings. The results obtained are summarised in the following Table 5. -13Table 4 Diuresis experiment with female rats (n = 10) body weight 200 - 250 g., after oral administration of 600 mg. AMDP/kg. body weight. i AMDP Control 5 urine flow 2.03 + 0.38 2.26 + 0.48 (g,urine/h. x kg.) 4- Na concentration 76.5 + 9.52 * 26.4 + 8.3 (mMol/1.) 10 excretion 155.9 + 39.1 * 59,5 + 20.1 ( Mol/h x kg) K+ concentration 176.4 + 40.9 * 101.6 + 22.4 (mMol/1.) 15 excretion 348.6 + 47.6 * 234.6 + 93.7 ( Mol/h x kg) Cl concentration 47.7 + 12.5 41.6 + 6.4 (mMol/1.) 20 excretion 95.6 + 26.4 95.2 + 28.9 ( Mol/h x kg) creatinine concentration 122.3 + 40.7 * 72.9 + 10.0 (mg/100 ml.) 25 excretion 2.43 + 0.29 * 1.64 + 0.31 (mg/h x kg) significant difference (a = 0.01) * -14Table 5 Clearance experiment with male rats of 250 - 370 kg.body weight (n = 20, control n = 20) after oral administration of 800 mg. AMDP/kg. body weight.

AMDP Control , urine flow : (ml/min x kg.) 0.604 + 0.124 0.760 + 0.142 i GFR ! (ml/min x kg) 9.39 + 1.98 10.23 + 1.96 resorbed fluid (% GFR) 93.38 + 1.64 92.48 + 1.28 Na+ resorbed (% d.filtr.Fl.) 95.02 + 2.12 93.83 + 1.37 clearance (ml/min x kg) 0.456 + 0.187 0.632 + 0.137 resorbed (% d.filtr.Fl.) 39.35 + 15.24 53.44 + 6.21 K clearance (ml/min x kg) 5.97 + 1.63 4.77 + 0.98 Cl- resorbed (% d.filtr.Fl.) 92.75 + 2.46 91.48 + 1.75 clearance (ml/min x kg) 0.664 + 0.212 0.872 + 0.226 urea clearance (ml/min x kg) 7.12 + 1.36 9.12 +1.58 PAH removed ( g/min x kg, 95.08 + 23.73 84.45 + 47.88 clearance (ml/min x kg) 27.49 + 5.58 24.73 + 7.57 -15Results of the excretion tests: a) The experimental animals excreted a urine, the amount of which was not increased, which, with regard to the + + · concentration and excretion of Na , K and creatinine, 4* + was above that of the controls. The higher Na and K concentrations or excretions are easily understood: it is the result of the fact that, with the test substance, considerable amounts of Na+ and K+ are administered.

The higher creatinine concentration in the urine of the experimental animals is the result of the higher total concentration of the urine. Although this was not 4* + measured, the fact of a higher Na and K concentration with unchanged Cl” concentration indicated a higher total concentration. This is also expressed in the higher creatinine concentration. b) In the case of none of the measured parameters is there a significant difference between the experimental and the control groups. As a result of the unequally higher urine flow, caused by the mannitol infusion, in contradistinction to experimental series (a), the administered amount of Na or K does not change the urine concentration. From this and from the fact that there is no difference between the experimental and control groups, it follows that the effects observed in experimental series (a) are exclusively the result of the administration of AMDP. -16This means that, in the case of a single enteral administration, AMDP does not influence the kidney function. Changes of the concentration and excretions A A of Na and K under the conditions of the diuresis 5 experiment on awake rats are the result of the high rate of administration of these ions. They cannot be due to an influencing of the kidney function. 6. Anti-inflammatory action.

A possible influencing of inflammatory reactions 10 was tested on the viscarin-carrageenin oedema on the rat paw (groups each of 10 animals). The AMDP dosage was 600 mg./kg. body weight, administered orally. The administration of the AMDP took place 2 hours before the oedema provocation. The measurement of the oedema development was carried out 3, 5, 7 and 24 hours after the oedema provocation. The results were tested in the F test and in the t test for the uniformity of the variance from experimental and control groups or for significant differences of the average values of both groups. In the case of non-uniformity of the variants of experimental and control groups, the intensified t test (according to Snedecor) was used for the assessment. The following Table 6 summarises the results obtained: -17Table 6 controls n = 10 oedema volume x (ml.) 79.4 80.7 76.5 25.2 % s 12.9 12.7 13.1 10.6 AMDP n = 10 oedema volume x (ml.) 71.5 71.9 68.9 24.2 % s 15.3 13.5 12.4 10.1 inhibition (%) 9.95 10.9 9.93 3.97 sodium aescinate n = 10 oedema volume x 46.5 50.7 46.6 14.9 % s 11.5 10.8 12.9 8.5 inhibition (%) 41.4 37.2 39.1 40.9 A slight inhibition of the development of oedema due to the presence of AMDP can be observed.

The above-given results show, in particular, that the active material combination according to the present 5 invention of alizarin, magnesium oxide, disodium hydrogen phosphate and potassium dihydrogen phosphate exerts no disadvantageous actions on the gastrointestinal tract and is predominantly excreted via the kidneys where, with a combined influencing of the urinary system, it manifests a surprisingly favourable and hitherto not achieved action, the previous inhibiting action with regard to inflammatory processes in the scope of a treatment of urolithiasis being promoted. -18Summarising, it can thus be said that the mixture according to the present invention and especially the component alizarin shows a good compatibility not only in acute but also in chronic toxicity experiments. In none of the tests carried out was there any indication whatsoever of the possibility of expecting incompatibilities or side effects. The sole slight side effect which was ascertained, namely a slight bronchspasm, should be of no practical importance, having regard to the enormous difference between the selected human daily dosage and the dosage employed in the animal experiments.

The above results clearly demonstrate that the composition according to the present invention can, without misgivings, also be administered for comparatively long periods of time.

For the testing of possible therapeutic effects, the individual components were first tested in vitro; there was thereby ascertained: 1) an inhibiting action of alizarin on the crystallisation 20 of calcium oxalate; 2) the presence of magnesium salts brings about a distinct increase of the solubility of calcium oxalate; and 3) the phosphate mixture stabilises, on the one hand, the pH value having regard to an increased excretion of citrate, which favours calcium chelate formation in the urine and, on the other hand, acts as a growth -19inhibitor with regard to the calcium oxalate crystallisation.

Clinical results.

Patients (oxalate calculi formers) were subjected for 1 to 6 years to a therapy to prevent the formation of calculi with, on average, 3x2 capsules according to the following Example 2 per day. 18 of the patients belonged to the so-called rapidly recidivating oxalate calculi formers (new formation of at least 4 calculi per year), whereas the remaining 4 patients displayed a recidivating oxalate calculi formation of less than 4 calculi per year.

In all cases, the new formation of calculi were certainly prevented, independently of whether hypercalciuria was present or not. The compatibility was generally very good. A supervision of the patients by conventional laboratory controls (blood picture etc.) showed no deviations from normal.

As stated above, the oral urolithiasis agent according to the present invention comprises a pharmaceutical diluent or carrier.

The agent can be in the form of capsules, dragees, tablets, pills, dispersible powders and granules. In such compositions, the inert diluent can be, for exanple, calcium carbonate, starch, alginic acid or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, for example, lubricating agents, such as magnesium stearate. -20Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents, such compositions may also comprise adjuvants, such as wetting and suspension agents, and sweetening and flavouring agents.

The compositions according to the present invention for oral administration, include capsules of absorbable material, such as gelatine, containing the active material, with or without the addition of diluents or excipients.

The following Examples are given for the purpose of illustrating the present invention:15 Example 1.

Preparation of hard gelatine capsules.

The following components were weighed out for the production of a batch of 1000 size 0 capsules: alizarin 35.0 g· 20 magnesium oxide 65.0 g· disodium hydrogen phosphate (anhydrous) 150.0 g- potassium dihydrogen phosphate (anhydrous) 250.0 g. carboxymethylcellulose 2.0 g- 25 magnesium stearate 3.0 g.

Method of production: The carboxymethylcellulose was dissolved, with stirring, in a mixture of methanol and methylene chloride -2110 This solution was used in an amount sufficient for pasting the mixed active materials, which had previously been separately and thoroughly ground. The moist mass was forced through a V2* sieve of 2 mm. mesh size and then dried at 40 to 50°C. The dried granulate thus obtained was comminuted by forcing through a VjA sieve of 0.8 mm. mesh size and then mixed with the magnesium stearate. The finished mass was filled, with the use of a capsule filling device, in 505 mg. amounts into size 0 hard gelatine capsules.

Example 2.

Production of soft gelatine capsules.

The following conponents were weighed out for the production of a batch of 1000 capsules of format 11 minims oblong: alizarin 35.0 g. magnesium oxide 65.0 g. disodium hydrogen phosphate 150.0 g. (anhydrous) potassium dihydrogen phosphate 250.0 g. (anhydrous) Method of production: The active materials were finely ground in a ball mill. The ground material was stirred up with a sufficient amount of an inert oil, for example paraffin oil of low viscosity, to give a paste. The paste was subsequently filled, with an appropriate capsulating device, into soft gelatine capsules of format 11 minims oblongj -22Example 3.

Production of dragees.

The following components were weighed out for the production of a batch of 1000 dragees: alizarin 35.0 g. magnesium oxide 65.0 g. disodium hydrogen phosphate 150.0 g. (anhydrous) potassium dihydrogen phosphate 250.0 g. 10 (anhydrous) microcrystalline cellulose 40.0 g. carboxymethylcellulose 5.0 g. wheat starch 20.0 g. highly-dispersed silicon dioxide 5.0 g. 15 magnesium stearate 5.0 g. Method of production: The active materials were finely ground in a ball mill and subsequently mixed with the microcrystalline cellulose. The binding agent (carboxymethylcellulose) was dissolved, with stirring, in a mixture of methanol and methylene chloride. Subsequently, the above powder mixture was pasted with this solution and pre-granulated through a sieve with 2 mm. mesh size. After drying at 40 to 50°C., the coarse granulate was comminuted through a sieve of 1.0 mm. mesh size. Thereafter, the adjuvants, i.e. wheat starch, silicon dioxide and magnesium stearate, were admixed. The mass thus obtained was pressed in a tabletting press to give domed dragee -23cores of 11 mm. diameter and with an individual weight of 575 mg. The dragee cores were worked up in the usual manner with a sugar solution in which conventional adjuvants, for exanple calcium carbonate, titanium dioxide and talc, were suspended, to give dragees, each of which had a weight of 950 mg.

Claims (3)

CLAIMS:

1. to oral urolithiasis composition, comprising 5 to 14% by weight alizarin, 10 to 26% by weight magnesium oxide, 22 to 32% by weight disodium hydrogen phos5 phate and 37 to 53% by weight potassium dihydrogen phosphate , together with a pharmaceutical diluent or carrier

2. A composition according to claim 1 in the form of a dosage unit containing 35 mg. alizarin, 65 mg. magnesium oxide, 150 mg. disodium hydrogen phosphate and 10 250 mg. potassium dihydrogen phosphate.

3. to oral urolithiasis composition according to claim 1, substantially as hereinbefore described and exemplified.