IE46408B1

IE46408B1 - Pharmaceutical compositions

Info

Publication number: IE46408B1
Application number: IE332/78A
Authority: IE
Original assignee: Merck & Co Inc
Priority date: 1977-02-17
Filing date: 1978-02-16
Publication date: 1983-06-01
Also published as: CH636012A5; ZA78913B; ATA87978A; NZ186399A; AU3309978A; IL53978A; FI780296A; DE2806707A1; FI67483B; SE7801242L; PL204642A1; GR66100B; PT67663A; IT7848013A0; SE433170B; FI67483C; DK46578A; NO148838B; FR2381079B1; ES466892A1

Abstract

A pharmacologically acceptable bile acid sequestering agent composition which after the prolonged action of moist air does not stick and is free-flowing, contains an essentially uniform adsorbate of a quaternary ionic polymer on a finely divided, water-insoluble, solid, pharmacologically acceptable aggregate having a large surface-to-mass ratio. The composition is prepared by mixing the component in aqueous solution, evaporating the water and drying the adsorbate thus formed. The composition described can be used for the reduction of cholesterol in the blood.

Description

PATENT APPLICATION BY (71) mercK & CO. inc., A CORPORATION ORGANIZED UNDER THE LAWS OF THE STATE OF NEW JERSEY, UNITED STATES OF AMERICA, OF RAHWAY, NEW JERSEY, UNITED STATES OF AMERICA.

Price 90p Certain ionene polymers, and in particular poly[{methyl-(3-trimethyl-ammoniopr opyl)iminioj trimethylene dichloride], are highly efficient as bile-acid sequestrants. Poly-[£methyl-(3-trimethyl-ammonio5 propyl) iminio ] trimethylene dichloride] is however extremely hygroscopic and, when exposed to air, even at relatively low humidities, rapidly deliquesces to form initially a sticky unworkable product, and finally a solution of the polymer. This hygroscopic charac10 teristic has presented a formidable problem in the formation of poly-[imethyl-(3-trimethylammoniopropyl)iminio} trimethylene dichloride] and, even when such formulation, e.g. by encapsulation or tableting, is conducted under anhydrous conditions, the resulting tablets and capsules rapidly absorb water under normal atmospheric conditions (the coatings of such capsules being permeable to water) to produce unsatisfactory adhesive caking products.

Compositions comprising substantially uniform pulverulent mixtures of poly-[{methyl-(3-trimethylammoniopropyl) iminio] trimethylene dichloride] with various pharmacologically acceptable solid carriers, such as powdered silica, starch, talc, cellulose and kaolin, when prepared by thoroughly dry-mixing the components (as in a ball mill) under substantially anhydrous conditions, are adhesive in character, and ordinarily become sticky and cake after relatively ί - 3 46408 short exposure to air at 25% relative humidity.

A method of preparing substantially non-adhesive, powder ed poly-[£methyl-(3-trimethylammoniopropyl)iminiojtrimethylene dichloride] adsorbate compositions, which remain free-flowing and non-caking, even after prolonged contact with moist air of relative humidity greater than 35% and in some cases up to 76%, has now been discovered and the present invention is based on that discovery. The invention is applicable generally to ionene quaternary polymers of the following formula: Γ3 N+-W (2n+2+V) mYi s CW¥ (ch3)3 Formula I herein called ionene quaternary polymers of Formula I . In Formula I, £ is the number of repeating units in the polymer? Y is a univalent or multivalent pharmacologically acceptable anion; a is the anionic charge on Y? m is the reciprocal of a; W is propyl, hydroxypropyl, allyl, alkoxypropyl (e.g. ethoxypropyl or methoxypropyl), halopropyl (e.g. chloropropyl, bromopropyl or iodopropyl), or primary, secondary, tertiary or quaternary ammoniopropyl, (e.g. unsubstituted ammoniopropyl, alkylammoniopropyl such as methylammoniopropyl, dialkylammoniopropyl such as dimethylammoniopropyl, or trialkylammoniopropyl such as trimethylammoniopropyl); Z is allyl, N-trimethylammoniopropyl-N-methyl-3-aminopropyl, N-trimethylmethyl- 4 ammoniopropyl-Ν, Ν-dimethyl-3-ammoniopropyl, halopropyl (e.g. chloropropyl, bromopropyl or iodopropyl), or primary, secondary, tertiary or quaternary ammoniopropyl, (e.g. unsubstituted ammoniopropyl, alkylammoniopropyl such as methylammoniopropyl, dialkylammoniopropyl such as dimethylammoniopropyl, or trialkylammoniopropyl such as trimethylammoniopropyl) and V is the number of positively charged nitrogens (N+) in the W and Z groupings.

In accordance with the present invention, a nonadhesive free-flowing pharmacologically acceptable bile acid sequestrant composition comprising a hygroscopic ionene quaternary polymer having the formula I set forth herein, is prepared by forming a substantially uniform suspension of a fumed silica or a silica aerogel in an aqueous solution of the ionene quaternary polymer, evaporating off water from the resulting suspension, and drying the adsorbate thus produced. It is preferred to use approximately equal weights, on a dry basis, of fumed silicon dioxide and the ionene quaternary polymer, which is preferably poly-[{methyl-(3-trimethylammoniopropyl) iminio} trimethylene dichloride] , although substantially non-adhesive adsorbate compositions are prepared when the weight ratio is about 40 parts fumed silica to 60 parts polymer; fumed silicapolymer adsorbates containing up to 75% fumed silica are likewise both non-adhesive and effective as bile-acid sequestrants, but they are not ordinarily used because of their increased proportion of fumed silica material. 6 4 0 8 - 5 It should be noted that fumed silicon dioxides are prepared by burning silicon tetrachloride in a flame of hydrogen and oxygen to produce primary spherical particles which, while still semi-molten, fuse into clusters of such particles called aggregates; these aggregates, during further cooling and collecting, become physically entangled to form agglomerates. The latter, upon dispersion in an aqueous solution, can disentangle to reform aggregates. Fumed silicon dioxides so prepared, are supplied in the form of a light fluffy, amorphous pure white, non-toxic, pharmacologically acceptable powder, approved by FDA for use as a direct food additive, under the trade mark Cab-O-Sil, by Cabot Corporation, 125 High Street, Boston, Massachusetts. A similar non-toxic, FDAapproved, micron-sized synthetic silica is supplied under the trade mark Syloid silica aerogels and xerogels by W. R. Grace and Co., Davison Chemical Division, Charles and Baltimore Streets, Baltimore, Maryland. 2G These aerogels and xerogels are prepared by the reaction of sulfuric acid and sodium silicate. The aerogels are highly porous solids formed by replacement of liquid in a gel by gas so that there is little shrinkage. The xerogels are porous solids formed from a gel by drying with unhindered shrinkage.

The process in accordance with the invention is conveniently conducted by first forming a substantially uniform suspension of fumed silica in approximately ten to fifty times its weight of water, and 3G slowly adding to this suspension, with rapid stirring, an aqueous solution of the ionene quaternary polymer, which preferably contains about 5% of the polymer, e.g. - 6 poly-[{methyl-(3-trimethylammoniopropyl)-iminlo} trimethylene dichloride]. The rate of addition is usually adjusted so as to be complete in from 5 to 15 minutes, and the resulting milky suspension is stirred vigorously for a short time, e.g. 5 to 15 minutes. The suspension is then evaporated to dryness under reduced pressure with stirring at a temperature within the range 25°C to 40°C; the temperature should not exceed 50°C during this evaporation step, since some discoloration of the polymer can occur above this temperature. The residual powdere.d silica-polymer adsorbate composition is then dried in vacuo at a temperature of 25°C to 40°C.

It is a preferred feature of the present invention that it is not necessary to use isolated solid polymer for preparing the aqueous solution. Instead, the aqueous polymerization reaation solution can itself be used in this procedure thereby avoiding the isolation, drying and storage of the ionene quaternary polymer.

This is advantageous when the polymer, like poly[(methyl-(3-trimethylammoniopropyl)iminio] trimethylene dichloride], is highly hygroscopic. This preferred method thus results in the direct product, from the aqueous polymerization reaction solution, of the desired adsorbate composition in a non-adhesive form adapted for pharmaceutical formulation.

In the adsorbate compositions of the present invention, the polymer, as shown by microscopic examination, forms a thin film on the surface of the fumed silica, in contrast to compositions prepared by dry-mixing the components, in which the polymer component, although intimately associated with the fumed silica, is present in the form of discrete - 7 granules. As might be expected from these observed structures and the necessarily greater surface area possessed by the polymer film in the fumed silicapolymer adsorbate compositions, the hygroscopicity of the adsorbate compositions is appreciably greater than that of the composition prepared by dry-mixing the components. It is indeed surprising that, in spite of their greater hygroscopicity, the adsorbate compositions of the present invention remain completely 1C non-adhesive, non-caking and free-flowing after two days' exposure to moist air at 76% relative humidity, whereas the compositions obtained by dry-mixing the same components become adhesive and cake even after a few hours' exposure to moist air of 35% relative humidity.

Effective lowering of cholesterol blood levels can be obtained by the oral administration of remarkably small dosages of the adsorbate compositions of this invention. This enables a flexibility of formul20 ation previously unavailable. The compositions of the present invention are light fluffy pulverulent powders and are suitably used as such, or admixed with appropriate amounts of conventional pharmaceutically acceptable binders and/or additional solid carrier agents, such as starch, gelatin, sugars, as glucose and lactose, methylcellulose, natural and synthetic, talc or synthetic gums. The compositions are preferably made into unit dosage forms such as tablets or filled gelatin capsules or, if desired, the premeasured dose may be enclosed in a foil or paper envelope which can be readily torn open and added to edible liquids such as fruit juices or other beverages. - 8 The unit dosage may also include supplementary vitamins and minerals. The unit-dose composition may comprise from 10% to 99% by weight of the polymer-silica adsorbate composition, e.g. poly-[£methyl-(3-trimethylammoniopropyl) iminioJ trimethylene dichloride] -fumed-silica adsorbate composition, the remainder being additives such as carriers, flavorings, excipients, and flow agents. In such a unit dose, the active polymer may make up from 100 milligrams to up to 10 grams in powder packets.

For convenience of administration, it is preferred to use tablets or capsules containing 300-600 milligrams of adsorbate compositions comprising equal amounts of fumed silica and the ionene quaternary polymer, e.g. poly-[f methyl-(3-trimethylammoniopropyl)iminioj trimethylene dichloride]. Such unit dosage compositions would thus provide about 150-300 milligrams of the polymer; a capsule or tablet containing 600 milligrams of adsorbent composition taken four times per day would thus provide a daily dosage of 1.2 grams of the polymer. Multiple dosages, e.g., two or three tablets or capsules can of course be taken at one time if desired.

In the case of tablets, a plastic film can be applied, if desired, to seal the tablets from moisture, and to mask the taste of the polymer in well known ways.

An enteric coating such as fats, fatty acids, waxes and mixtures thereof, shellac, ammoniated shellac, and cellulose aaid phthalates, may also be applied by well known and accepted techniques.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes ~ 9 of illustration and not of limitation.

EXAMPLE 1 A mixture of about forty grains of fumed silicon dioxide and 1100 ml of water is stirred vigorously until a thin, lump-free, substantially uniform suspension is obtained. This suspension is stirred while slowly adding to it a solution of forty grams of anhydrous pcly-[£methyl-(3-trimethylammoniopropyl)iminioj trimethylene dichloride] in 300 ml of water.

The resulting suspension is evaporated to dryness under reduced pressure, and the residual adsorbate is dried in vacuo for a period of about 15 hours and milled to give about 85 grams of a white, fluffy, free-flowing, non-caking powder containing about 5% of adsorbed moisture.

EXAMPLE 2 A mixture of 122.61 mg of fumed silicon dioxide is suspended in 5 ml of water using a high-speed stirrer. A solution containing 121.1 mg anhydrous weight of poly-[imethyl-(3-trimethylammoniopropyl)iminloj trimethylene dichloride] in 3 ml of water is added slowly while agitation is continued. The resulting milky suspension is evaporated to dryness in vacuo, and the residue adsorbate is further 2S dried in vacuo to give a fumed silica-poly-[{methyl(3-trimethylammoniopropyl)iminio]trimethylene dichloride] composition in the form of a fluffy white free-flowing non-caking powdery adsorbate which, upon exposure to laboratory atmosphere (relative 3C humidity approximately 35%) for a period of 15 hours, fully retains its free-flowing and non-caking character i stic s. - 10 EXAMPLE 3 A mixture of 1.34 g of fumed silicon dioxide is suspended in 60 ml of water using a high-speed stirrer.

A solution containing 1.34 g anhydrous weight of poly[[methyl-(3-trimethylammoniopropyl)iminio) trimethylene dichloride] in 30 ml of water is added slowly while agitation is continued. The resulting milky suspension is stirred vigorously for approximately half an hour, and then evaporated to dryness in vacuo, and the residual adsorbate is further dried in vacuo to give approximately 2.5 g. of a fumed silica-poly-[{methyl(3 -trimethylammoniopropyl) iminloStrimsthylene dichloride] composition in the form of a fluffy, white, freeflowing, non-caking powdery adsorbate. This material remains free-flowing and non-caking after prolonged exposure to air at 76% relative humidity.

The poly-[{methyl-(3-tr imethylammoniopropyl) iminioj trimsthylene dichloride] , utilized as the bile acid sequestrant polymer component of the adsorbate compositions prepared as described in foregoing examples, as well as other ionene quaternary polymers and pharmacologically acceptable salts which may also be used as the polymer component in such adsorbate compositions, may be synthesized in accordance with various procedures described in Patent Specifications Nos. 39795, 44097 and 44098.

Claims

1. A method of preparing a non-adhesive freeflowing pharmacologically acceptable bile acid sequestrant composition comprising a hygroscopic ionene quaternary polymer, having the formula I set forth herein, that comprises forming a substantially uniform suspension of a fumed silica or a silica aerogel in an aqueous solution of the ionene quaternary polymer, evaporating off water from the resulting suspension, and drying the adsorbate thus produced.

2. A method as claimed in Claim 1, in which the ionene polymer is poly[{methyl-(3-trimethylammoniopropyl) iminio j trimethylene diehloride] and the solid aggregate is fumed silica.

3. A method as claimed in Claim 2, in which there is initially formed a substantially uniform suspension of fumed silica in approximately 10 to 50 times its weight of water, an aqueous solution of poly[(methyl(3-trimethylaramoniopropyl)iminto} trimethylene dichloride] is slowly added to this suspension with rapid stirring, and the water is evaporated from the resulting suspension under reduced pressure while stirring and maintaining the temperature of the mixture at 25-4O°C to produce a composition comprising approximately equal weights of poly-[(methyl-(3-trimethylammoniopropyl ) imimio J trimethylene dichloride] and fumed silica.

4. A method as claimed in Claim 3, in which the initial suspension contains one part by weight of fumed silica in approximately 25 parts by weight of water and the dilute solution of poly-[(methyl-(3trimethylammoniopropyl) iminio ) trimethylene dichloride] contains one part of it in about eight parts by - 12 weight of water.

5. A method as claimed in any one of Claims 1 to 4, including the further step of milling the resulting adsorbate after drying it.

6. A bile acid sequestrant composition that is non-adhesive and free-flowing after prolonged exposure to moist air and that comprises a substantially uniform adsorbate of an ionene quaternary polymer, having the formula I set forth herein, on a fumed silica or silica aerogel.

7. A sequestrant composition as claimed in Claim 6 comprising a substantially uniform adsorbate film of poly[{methyl-(3-trimethylammoniopropyl)iminioj trimethylene dichloride] on fumed silica.

8. A composition as claimed in Claim 7 containing approximately equal weights of poly-[{methyl-(3trimethylammoniopropyl) iminioj trimathylene dichloride] and fumed silica.

9. A tablet or capsule comprising a composition as claimed in Claim 7 or 8 in amount such that it contains from 150 to 300 milligrams of poly-[jmethyl(3-trimethylammoniopropyl)iminioj trimethylene dichloride].

10. A composition as claimed in Claim 6 substantially as hereinbefore described.