GB2119355A

GB2119355A - Modified clays

Info

Publication number: GB2119355A
Application number: GB08310433A
Authority: GB
Inventors: Jean-Claude Plantefeve; Michel Rene
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1982-04-29
Filing date: 1983-04-18
Publication date: 1983-11-16
Also published as: GB2119355B; GB8310433D0

Abstract

A modified clay comprises the product of reaction between 1 part by weight of a sheet-silicate clay and 0.05 - 0.5 part by wt of Mg(OH)2. The modified clay has a plate separation of 1.5 - 1.6 nm reducing to 1.2 - 1.4 nm when heated to 490 DEG C and a cation exchange capacity of 170 - 1700 mEq/100 g. Acid addition products of the modified clay are also included. The modified clays have therapeutic use in anti-acid preparations and compositions containing them are included.

Description

SPECIFICATION Modified Clays The invention relates to modified clays useful as active ingredients in medicaments, to processes for their preparation and to therapeutic compositions containing them.

Clays are used in therapy, notably to bring about a partial neutralization of too high stomach acidity. They have a moderate neutralizing power, which means the patient has to take several grams of product to obtain the desired effect. Other anti-acid products generally have a too rapid speed of neutralization, and do not provide sufficient permanence for the desired effect. This is the case, for example, with magnesium hydroxide.

The invention provides a modified clay comprising the product of reaction between a sheet-silicate clay and from 0.05 to 0.5 part by weight of magnesium hydroxide per part by weight of the sheet-silicate clay, the modified clay having a plate separation of from 1.5 to 1.6 nm reducing to from 1.2 to 1.4 nm when heated to 490"C and a cation exchange capacity of from 170 to 1700 milliequivalents per 100 g; or an acid addition product of such a modified clay with a therapeutically acceptable acid.

Such clays have a high neutralizing power and a good speed of neutralization with residual activity. In fact, the clays have been found active for from some tens of minutes to several hours depending on the proportions of starting material used for its preparation and the time and temperature of the reaction. The modified clay combines neutralizing power with a clay structure in a stable composition.

The modified clay according to the invention is a reaction product of the sheet-silicate clay and the magnesium hydroxide, and not merely a mixture thereof; its action is different from that of a mixture thereof, and it does not exhibit the characteristic X-ray spectrum of the magnesium hydroxide.

The plate separation of the clay is variable as a function of the number of molecules of water, and of the nature and quantity of fixed cations.

The modified clays according to the invention can be prepared from a suitable starting clay by treatment in an aqueous phase, possibly under pressure, with magnesium hydroxide added in an appropriate proportion.

If the materials used are not dry or perfectly pure (apart from impurities which do not affect the process), the quantities used are adjusted so as to put the quantities of the active ingredients within the necessary ranges.

In particular if the clay is in the form of a mud such as can be obtained at the end of the usual purification process, the concentration of the clay in this mud is taken into account. Generally, the clay will be in the form of a mud for the purification of the raw materials if necessary.

This purification is performed as follows: The mineral is roughly crushed in order to eliminate the stones or hard particles and then suspended in water in a rotating tube. The aqueous dispersion thus obtained is treated by a chemically pure and strong inorganic acid, under stirring at room temperature, the addition of the acid being made until the pH of the dispersion is between 2 and 3.

Stirring is maintained for about one hour and then the dispersion is diluted and sent to a series of hydrocyclones in which is separated the portion of clays to be used, i.e. the one passing through sieves with a mesh opening of 0.1 mm.

The separated fraction is either used as such or sent to a thickener for increasing its concentration and dried at a temperature inferior to 200 C. A suitable starting clay is a sheet-silicate clay having a plate separation of from 1.2 to 1.5 nm reducing to from 0.9 to 1 nm when heated to 490"C, and a cation exchange capacity above 80 mEq per 100 g.

As to the magnesium hydroxide, the dry material can have a less satisfactory purity than certain pastes or suspensions, so it is preferred to use these latter forms of the material and calculate the equivalent quantity which is necessary.

The reaction temperature should be at least 50"C, and depending on the quality of the clay initially used, could be up to 1 200C or even more, the limit being in practice defined by industrial operating conditions and the start of the transformation of the clay. Ther period of the reaction is a function of the temperature and pressure. The progress of the reaction is tested by the disappearance of the spectrum lines of magnesium hydroxide (Brucite) on a sample of the mixture.

In the following examples, modified clays according to the invention are prepared in autoclaves from samples each weighing 14 g, containing 2.5 g of clay (smectite but variable quantities of neutralizing agent, the said 14 g being reached by the addition of water. The quantities of magnesium hydroxide are always given for one part of clay. After placing the sample in the autoclave and closing, the treatment is as follows: Example 1 Magnesium hydroxide paste : 0,606 g corresponding to 0,200 g of pure product (0.08 part). Reaction temperature 900C. Reaction time 24 hours. Mg(OH)2 rate : 6.45%.

Example 2 Magnesium hydroxide paste: 1.819 9 g corresponding to 0.600 g of pure product (0.24 part). Reaction temperature 90"C. Reaction time 24 hours.

Substantially the same product is obtained by treating the same starting material for 2 hours at 1 200C.

Mg(OH)2rate: 19,35%.

Example 3 Magnesium hydroxide paste : 2.019 g corresponding to 0.606 g of pure product (0.265 parts). Reaction temperature 90"C. Reaction time 24 hours. Mg(OH)2 rate 21.04%.

Example 4 Magnesium hydroxide paste: 2.273 g corresponding to 0.750 g of pure product (0.30 part). Reaction temperature 1200C. Reaction time 3 hours. Mg(OH)2 rate : 23.07%.

Example 5 Magnesium hydroxide paste : 2.278 g corresponding to 0.900 g of pure product (0.36 part). Reaction temperature 120"C. Reaction time 4 hours. Mg(OH)2 rate : 26.47%.

Example 6 Magnesium hydroxide paste: 3.183 g corresponding to 1.050 g of pure product (0.42 part). Reaction temperature 1250C. Reaction time 4 hours. Mg (OH)2 rate : 29.58%.

Example 7 Magnesium hydroxide paste : 3.638 g corresponding to 1.200 g of pure product (0.48 part). Reaction temperature 142"C. Reaction time 4 hours. Mg(OH)2 rate : 32.43%.

After the end of the reaction in each case, the autociave is cooled and the product recovered in the form of a mud. In order to use the product as such, after washing and drying it is ground to powder. It can then be placed in capsules for oral administration. However, as the product is very basic, it is generally preferred to treat it with carbon dioxide or a therapeutically acceptable acid in order to lower the pH to form 7.5 to 9, after which the product is washed and dried, and can be used either in the form of a powder for putting in suspension or pressed to make tablets. Citric, tartaric, phosphoric and silicic acids are therapeutically acceptable and examples of acids which can be used in this way.

Various determinations and experimentations have been conducted to show the interest of the composition of the invention ; toxicity has been determined on rats and experimentation on anti-acid activity and coating power are also reported.

Toxicity The toxicity of the composition of the invention has been determined on Wistar rats, both male and female, for 5 days at the oral daily dose of 15 g/kg (average weight of the rats : 200 g).

Tests were conducted on 4 batches, each of 20 rats: - a first batch of control female rats receiving 3 times a day, at 8, 12 and 16 hours, a dose of 1 ml of physiological serum only; - a second batch of female rats receiving 3 times a day, at 8, 12 and 16 hours, an oral dose of 5 g/kg, suspended in 1 ml of water and administered by intragastric route; - a third batch of control male rats treated as the first batch above, and - a fourth batch of male rats treated as the second batch above.

All the animals were weighed before the test and at the end of the test; the average weight of the female rats increased by 2.67% compared to the control females, whereas the average weight of the male rats decreased by 2.93% compared with the control males.

Accordingly, no significant variation of weight could be noticed during the test. Moreover, no death occurred during the test.

It can be concluded that the composition of the invention is devoid of any noticeable toxicity.

Determination of anti-acid activity The anti-acid activity has been determined by two methods: 1J In vitro This test was conducted comparatively with a known substance presently on the market and which is a mixture of aluminium and magnesium hydroxides; comparable doses of both compositions were used, i.e. 2 bags containing 31.2 mEq of ion exchange capacity for the modified clay according to the invention and 1 dose of the reference compound, containing 41.6 mEq of ion exchange capacity.

It should be noticed that the reference compounds contained about 25% more of ion exchange capacity than the modified clay of the invention; however, the comparison has been conducted in that way in order to compare the effectively used therapeutical doses.

This test was performed according to the technique of Fordtran JS (Reduction of acidity by diet, antacids, and anticholinergic agents; In Gastro-intestinal disease; Pathophysiology, diagnosis, management; Sleisenger MH and Fordtran JS, Saunders, Phiiadelphia, 1973, p 718-742). Each sample of product was maintained at pH 3 by automatic addition of 0.1 N hydrochloric acid and the graph representing the acid demand plotted against the time is recorded continuously and automatically. From the amounts of acid are determined the used amounts of mEq of each product, the corresponding percentage and the available amounts of mEq at various times.

The results are reported in the following Table.

TABLE Reference Composition Tested Composition Time Used mEq Available Used mEq Available h mn mEq % mEq mEq % mEq 0 5.8 14 35.8 5.9 19 25.3 2 16.3 39 25.3 - - 3 19.3 46 22.3 - - 5 31.6 76 10.0 10.8 35 20.4 6 39.5 95 2.1 - - 7 40.5 97 1.1 - - 10 - - - 14.2 46 17.0 20 - - - 18.8 60 12.4 30 41.3 99 0.3 21.8 70 9.4 1 00 - - - 26.7 86 4.5 30 41.6 100 0 29.0 93 2.2 2 00 - - - 30.8 99 0.4 2 30 - - - 31.1 100 0.1 2 45 - - - 31.2 100 0 From these results, it will be seen that, at about 7 minutes, the reference composition is almost completely neutralized, whereas the composition of the invention requires about 2 h 45 for neutralization.The compound of the invention has a far longer action and a very progressive pace of neutralization compared to the reference composition.

2) In vivo This test was conducted on 12 people and consisted in the intra gastric pH determination at various times after the administration of either the same reference composition of the composition according to the invention.

Ail patients received both compositions, one on the first day after a standard meal, and a second one the day after, after the same standard meal; administration was effected in double blind.

In both cases, the time after administration during which the pH value in the stomach was greater than or equal to 5 was determined. The tested compound gave longer times for 7 patients, equal times for 3, and shortertimes for 2. The time after administration during which the pH value in the stomach was greater than or equal to 3.5 was also determined. The tested compound gave longer times for 9 patients, equal times for 2 and a shorter time for 1.

The results in vivo have the same orientation as in vitro but appears a little less favourable. It should be however noticed that the tested composition contained a lower amount of mEq than the reference composition.

The comparative results would surely have been more favourable for the tested composition, if same amounts of mEq of both compositions were used.

Coating power The coating power or covering power has been determined on rats' gastric mucous (male Wistar rats, weight about 250 g).

This test was conducted comparatively on the composition of the invention, on the starting clay used as raw material for the preparation of the same and with a commercialized reference compound consisting of a gel of magnesium and aluminium hydroxides.

For the composition of the invention, the dose used was 10 ml of the suspension prepared for the composition of Example 3; for the treatment with the clay used as starting material, the suspension has been prepared containing the same amount of clay as the composition of the invention and for the gel of magnesium and aluminium hydroxide, the dose was of 10 ml per kilo which is equivalent to the dose used for the composition of the invention.

The rats were divided in three batches, each of eight rats, and treated as follows: The appropriate dose of each product was administered intragastrically to each rat of each batch and ten minutes later, the rats were killed by diethyl ether. The stomachs were taken, opened along their large curve, placed in recipients containing physiologic serum and smoothly rinsed.

The amount of protective coat was estimated by number from 0 to 4 in relationship with the coated area and the amount of product (0: no coating at all).

Average values for these three batches were as follows: compound of the invention: 2.5 clay used as starting material: 1.9 gel of magnesium and aluminium hydroxide : 0.5.

Accordingly it should be remarked that the commercialized compound is of poor value for the coating of the rats' gastric mucous; the composition of the invention affords it better protection than the clay used as starting material, however the amount of mineral is the same in both cases.

Presentation - posology The compound according to this invention may be presented in any suitable form for therapeutic administration, such as powder, tablets, gel or suspension.

In human therapy, a unit dose may contain from 1 to 5 g of dry substance.

As examples of suspension, for instance, may be given: 1) Composition of the invention (Example 3) 1.900 g Citric acid 0.008g Methyl Parahydroxybenzoate 0.008g Propyl Parahydroxybenzoate 0.0049 Ethyl alcohol at 95" 0.065 g Saccharose 1.30 g CO2 (sufficient amount for pH 9 + 0.5) about 0.040 g Purified water, sufficient amount for 9 ml This suspension is contained in an individual bag.

2) Composition of the invention (Example 6) 1.900 g Tart ric acid 0.070g Methyl Parahydroxybenzoate 0.010g Ethyl alcohol at 95 0.0709 Saccharose 1.0009 Purified water, sufficient amount for 9 ml This suspension is contained in an individual bag.

3) Composition ofthe invention (Example 4) 1.900 g Methyl Parahydroxybenzoate 0.010 g Menthol 0.001 9 Ethyl alcohol at 950 0.065 g Saccharose 0.050g CO2 (sufficient amount for pH 8.5 ~ 0.5) about 0.025 g Purified water, sufficient amount for 8 ml This suspension is contained in an individual bag.

As example of powder form, may be given: 4) Composition of the invention (Example 2) 1.400g Phosphoric acid 0.1009 Sorbitol 0.250 g Pectin 0.0509 1.800 g This dose is contained in an individual bag.

As example of tablets, may be given: 5) Composition of the invention (Example 5) 1.400 g Mannitol 0.250 g Starch 0.100 g Magnesium Stearate 0.030 g Talc 0.100 g Silicic acid 0.020 g Menthol 0.0005g Saccharose : sufficient amount for a tablet of 2 g In human therapy, there may be administered from 1 to 12 bags or tablets per day.

Claims

1. A modified clay comprising the product of reaction between a sheet-silicate clay and from 0.05 to 0.5 part by weight of magnesium hydroxide per part by weight of the sheet-silicate clay, the modified clay having a plate separation of from 1.5 to 1.6 nm reducing to from 1.2 to 1.4 nm when heated to 490"C and a cation exchange capacity of from 170 to 1700 milliequivalents per 100 g; or an acid addition product of such a modified clay with a therapeutically acceptable acid.

2. A process for the preparation of a modified clay according to claim 1, the process comprising reacting, at a temperature of from 50"C to 1400C for a period of from 3 to 24 hours, a purified sheet-silicate clay having a plate separation of from 1.2 to 1.5 nm reducing to from 0.9 to 1 nm when heated to 490"C and a cation exchange capacity at least 80 milliequivalents per 100 g with 0.05 to 0.5 part by weight of magnesium hydroxide per part by weight of the sheet-silicate clay.

3. A process for the preparation of a modified clay according to claim 1, the process being substantially as described herein with reference to any of the Examples.

4. A therapeutic composition of matter comprising as an essential ingredient therein, a sufficient amount of a modified clay of claim 1.