NO148838B - PROCEDURE FOR THE PREPARATION OF A NON-ADHESIVE, MULTIPLE, PHARMACOLOGICAL PROPERTY BALLIC ACID COMPLEXING ADSORABLE PREPARATION - Google Patents

Description

The present invention relates to a method for the production of a non-sticky, free-flowing, pharmacologically acceptable bile acid complex-forming adsorbate preparation by combining poly-[{methyl-(3-trimethylammoniumpropyl)-iminoj-trimethylene chloridej and burnt silicon oxide and drying the product obtained .

Poly-[{methyl-(3-trimethyl.ammoniumpropyl)-imino J-trimethylene dichloride is very effective: as a bile acid complex former. Poly-[[methyl-(3-trimethyl-amttoniumpropyl)-imine oj-trimethylene dichloride, however, is extremely hygroscopic, and when exposed to air even at relatively low humidity levels, it rapidly flows to form a sticky, unworkable product, and to finally a solution of the polymer.

This hygroscopic property has been a major problem in the production of preparations of poly-[^methyl-(3-trimethylammonium propy]> imino j-trimethylene dichloride] , and even when the preparation, e.g.

in the case of encapsulation or tableting, carried out under anhydrous conditions, the manufactured tablets and capsules rapidly absorb water under normal atmospheric conditions' (since the coatings of such capsules are permeable to water) and form unsatisfactory sticky, caking products.

Preparations comprising substantially uniform powdery mixtures of poly-[|_methyl-(3-trimethyl:ammoniumpropyl)-imino J-trimethylene dichloride] with various pharmacologically acceptable solid carriers, such as powdered silicon oxide, starch,

talc, cellulose and kaolin, when prepared by careful dry mixing of the ingredients (as in a ball mill) under essentially anhydrous conditions, are sticky in nature, and usually become sticky and caking after a relatively short exposure to air at 25% relative humidity .

It has now been found that substantially non-sticky, powdered poly-[^methyl-(3-trimethy]ammoniumpropyl)-imino j-trimethylene dichloride] adsorbate preparations, which remain free-flowing and non-caking, even after prolonged contact with moist air of 76% relative humidity, can be produced.

The method according to the invention is thus characterized

in that an essentially uniform suspension of burnt silicon oxide is formed in 10 to 50 times its weight of water, that a dilute aqueous solution of poly-££methyl-(3-trimethylammoniumpropyl)- iminoj-trimethylene dichloridej, and that the water is evaporated from the formed suspension under reduced pressure while stirring and maintaining the temperature of the mixture at 25 - 40°C. It is generally preferred to use approximately equal amounts by weight, on a dry basis,

of fumed silica and poly-[^methyl-(3-trimethylammoniumpropyl)-imino J-trimethylene dichloride, although substantially non-adhesive adsorbate preparations are prepared using a weight ratio of 40 parts fumed silica to 60 parts polymer. Fumed silica polymeric adsorbates containing up to 75% fumed silica are likewise non-sticky, and effective as bile acid complexing agents, but are generally not used because of their increased amount of fumed silica material.

Fused silicon dioxide is produced by burning silicon tetrachloride in a flame of hydrogen and oxygen to form essentially spherical particles which, while still semi-molten, sinter into druses of such particles called aggregates; these aggregates are filtered during further cooling and physically collected into agglomerates. The latter can be separated into aggregates by dispersion in an aqueous solution. The calcined silicon dioxide thus produced is supplied in the form of a light, voluminous, pure white, non-toxic, pharmacologically acceptable powder, approved by the FDA

for use as a direct food additive, under the trade name Cab-O-S i l''0 . A similar non-toxic, FDA-approved micronized synthetic silicon oxide is promised under the trade name Syloid<®.>

The process for producing the adsorbate preparations according to the invention is carried out by first preparing an essentially uniform suspension of burnt silicon oxide in 10 to 50 times its weight of water, and slowly adding to this suspension, with rapid stirring, a dilute (preferably 5%) aqueous solution of poly- [{methyl-(3-trimethyl ammonium propyl)-imino J-trimethylene dichloride]. The rate of addition is usually adjusted so that it is completed within 5 to 15 minutes, and the resulting milky suspension is vigorously stirred for a short time, e.g. 5 to 15 minutes. The suspension is then evaporated to dryness under reduced pressure, while stirring and maintaining the temperature in the range from 25°C to 40°C. The temperature should not exceed 50°C during the evaporation steps, as some discoloration of the polymer may occur above this temperature. The remaining powdered silicon oxide polymer adsorbate preparation is then dried in vacuum at a temperature of from 25° to 40°C.

It is a preferred feature of the present invention

that it is not necessary to use isolated solid polymer in the preparation of the diluted aqueous solution of poly-[^methyl-(3-trimethylammoniumpropyl)-imino j-trimethylene dichloride] used in the above-mentioned method for the preparation of burnt silicon oxide polymer adsorbate preparation. Instead, the aqueous polymerization reaction solution itself can be used in this method, thereby avoiding isolation, drying and storage of the highly hygroscopic poly-[{methyl-(3-trimethylammoniumpropyl)-imino J-trimethylene dichloride]. This preferred method thus leads to the direct production, from the aqueous polymerization reaction solution, of the desired poly-[{methy1-(3-tri-methy]ammoniumpropyl)-imino}-trimethylenedichloride]burnt silicon oxide adsorbate preparation in a non-sticky form suitable for pharmaceutical preparations.

These poly-[{methyl-(3-trimethylammoniupro<p>yl)-imino J-trimethylene dichloride]-burnt silicon oxide adsorbate preparations are characterized in that the polymer, as shown by microscopic examination, forms a thin film on the surface of the burned silicon oxide, in contrast to preparations made by dry mixing of the components, where poly- [{methyl-(3-trimethyl. ammonium propyl)-

imino J-trimethylene dichloride] component, although intimately associated with the burnt silica, is present in the form of separate grains. As could be expected from these observed structures

and the necessarily larger surface area of the polymer film in the burnt silicon oxide polymer adsorbate preparations, the hygroscopicity of the adsorbate preparations is considerably greater than that of the preparation prepared by dry mixing of the components, where the polymer is present in the form of single grains. It is truly astonishing that, despite their greater hygroscopicity, the burnt silica poly-[{methyl-(3-trimethyl ammonium prcpyD-imino J-trimethylene dichloride]-adsorbate<p>repairs remain completely non-sticky, non-caking and free-flowing after several days of exposure to moist air of 76% relative humidity, while the preparations obtained by dry-mixing the same ingredients become sticky and caking even after a few hours of exposure to moist air of 35% relative humidity.

To illustrate the differences achieved in product properties by a wet-mixing process versus a dry-mixing process, two formulations were prepared (1) approximately equal parts by weight of polymer and Cab-O-Sil ® prepared by the wet-mixing process (sample A) and (2)

approximately equal parts by weight of polymer and Cab-O-Sil<®> prepared by the dry-mix process (Sample B).

The samples were exposed to atmospheres of different relative humidities at room temperature, the amount of weight gain due to the humidity was measured at different times while the flow properties of the samples were observed.

The results were as follows:

Sample B was caking at all the indicated relative humidities and times.

* Negligible caking of sample A was observed only at 76% relative humidity after 24 and 48 hours. At all other times and relative humidities, this sample was free-flowing.

These observations show that although sample B is markedly less hygroscopic than sample / A, its flow properties are significantly less favorable after it has been exposed to moisture.

Effective lowering of cholesterol blood levels is achieved by oral administration of remarkably small doses of poly-[{methyl-(3-trimethylammoniumpropyl)-imino }-trimethylenedichloride]-burnt-silicon-oxide-adsorbate preparations.. This possible-

enables a flexibility in processing that was previously unattainable. These poly-[(,methyl-(3-trimethylammoniumpropyl)-imino-trimethylenedichloride]-fused silica preparations are light, fluffy, fine powders, and are conveniently used as such, or mixed with suitable amounts of conventional pharmaceutically acceptable binders and/or additional solid carrier materials, such as starch, gelatin, sugar, such as glucose and lactose, methyl-cellulose, natural and synthetic talc and synthetic gums. The preparations are preferably produced in unit dose forms such as tablets or filled gelatin capsules, or optionally the pre-measured dose can be enclosed in a foil or paper envelope which can be easily torn up and added to potable liquids such as fruit juices and other drinks. The unit dose may also include additional vitamins and minerals. The unit dose preparation may contain from 10% to 99% by weight of poly-[[methyl-(3-trimethyl ammonium propyl) - imino '-trimethylene dichloride] burnt silicon oxide adsorbate preparation, the remainder being carriers, flavorings, excipients and r j r-.lingn~.idl is. in such a unit dose, the active polymer can amount from 100 mg up to 10 g in powder packets.

For convenient administration, it is preferred to use tablets or capsules containing 300-600 mg of the adsorbate preparations containing equal amounts of burnt silicon oxide and poly-[{methyl-(3-trimethyl.ammoniumpropyl)-imino j-trimethylenedichloride]. Such unit-dose preparations will thus provide 150-300 mg of the bile acid-complexing polymer, poly-[(meth<y>l-(3-trimeth<y>lamKoniumpropyl)-imino-j-trimethylenedichloride]. A capsule or tablet containing 600 mg of the adsorbate preparation taken four times a day would thus give a daily dose of 1.2 g poly-[[_methyl-(3-trimethylammoniumpropyl)-imino }-trimethylene dichloride]. Multiple doses, e.g. two or three

tablets or capsules, can of course be taken at once if desired.

In the case of tablets, a plastic film may optionally be applied to

to seal the tablets against moisture, and to mask the taste of poly-[[methyl-(3-trimethylammoniunpropyl)-imino)-trimethylene dichloride], in a manner known per se. An enteric coating such as fat, fatty acids, waxes and mixtures thereof, shellac, ammoniated shellac, and acid cellulose phthalates can also be applied in a manner known per se.

The following examples illustrate methods of carrying out the present invention.

Example 1

A mixture of 40 g of burnt silicon dioxide and 1100 ml of water is stirred vigorously until a thin, lump-free, essentially uniform suspension is obtained. This suspension is stirred while slowly adding a solution of 40 g of anhydrous poly-[[methyl-(3-trimethylammoniumpropyl)-imino '-trimethylene dichloride]

in 300 ml of water. The resulting suspension is evaporated to dryness under reduced pressure, and the remaining adsorbate is dried in vacuum in

15 hours and milled, whereby 85 g of a white,

fluffy, free-flowing, non-caking powder containing 5% adsorbed moisture. This adsorbate remains free-flowing and non-caking when exposed for three days to moist air of 76% relative humidity.

Example pel 2

A mixture of 122.61 mq of burnt silicon dioxide is suspended

in 5 ml of water using a high speed stirrer. A solution containing 121.1 mg anhydrous weight of poly-[(methy1-(3-trimethylammoniunpropyl)-imino}-trimethylene dichloride| in 300 ml of water is added slowly while stirring is continued. This milky suspension formed is evaporated to dryness in vacuo, and the remaining adsorbate is further dried in vacuum to obtain a

calcined silica-poly [methyl-(3-trimethylammoniumpropyl)-imino trimethylene dichloride] preparation in the form of a fluffy, white, free-flowing, non-caking powdery adsorbate, which, on exposure to laboratory atmosphere (35% relative humidity) for 15 hours, completely retains its free-flowing and non-caking properties.

Example 3

A mixture of 1.34 g of burnt silicon dioxide is suspended in

60 ml of water using a high speed mixer. A solution containing 1.34 g anhydrous weight of poly-[{methyl-(3-trimethyl ammonium propyl)-imino j-trimethylene dichloride] in 30 ml of water is added slowly with continued stirring. The formed milky suspension is stirred vigorously for approx. half an hour, and then evaporated to dryness in vacuum, and the remaining adsorbate is further dried in vacuum, whereby 2.5 g of a burnt silicon oxide-poly-[{methyl-(3-trimethyl ammonium propyl)-imino J-trimethylene dichloride] is obtained -preparation in the form of a fluffy, white, free-flowing, non-caking powdery adsorbate. This material remains free-flowing and non-caking after prolonged exposure to air of 76% relative humidity.

Poly-[{methyl-(3-trimethyl ammonium propyl)-imino j-trimethylene dichloride] used as the bile acid-complexed polymer component of the adsorbate preparations prepared as described in the preceding examples can be prepared according to various methods described in US patent applications No. 570,910 filed April 23, 1975 , a ert: has fast to U.S. patent no, 4U±b^c9. It has the following formula:

where n is the number of repeating units of the polymer.

Claims (2)

1. Process for the production of a non-sticky, free-flowing, pharmacologically acceptable bile acid-complexing adsorbate preparation by combining poly-[fmethyl-(3-trimethylammoniumpropyl)-imino}-trimethylene dichloride] and burnt silicon oxide and drying the product obtained, characterized in that an essentially uniform suspension of burnt silicon oxide is formed in 10 to 50 times its weight of water, that a dilute aqueous solution of poly-[(methyl-(3- trimethylammoniumpropyl)-iminoj-trimethylene dichloridej , and that the water is evaporated from the formed suspension under reduced pressure while stirring and maintaining the temperature of the mixture at 25 - 40°C. 2. Method according to claim 1, characterized in that the suspension is formed from one part by weight of burnt silicon oxide in 25 parts by weight of water, and that a solution containing 1 part by weight of poly-{methyl-(3-trimethylammoniumpropyl)-imino)-trimethylene dichloride} in 8 parts by weight of water is added to the suspension.