AU607744B2 - Hypocholesterolaemic gel formulation containing a pharmaceutically acceptable nondigestible anion exchange resin - Google Patents

Description

5) Signsture of Ap1)plicant (s) Se al of Company and Slg.riatures of it, Officers as prescribed by its Articles of Association.

LODGED AT SUB-OFFICE k9 MAR MG8 2V' eXc%> .CIB *A -1G IE *I GY AG by Ian A. Scott ReP6giste-red Patenri &rtto-rcney I Th-..

ElI II II .111 Rt- n,1,qirr 7 7 4(, COMMONV!EALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE

SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: Int. Class Complete Specification Lodged: Accepted: Published: Priority: ,R1tilated Art: 'This document con~tains the amenidm~ents made under secti o n 49 an d is correct f Or pyi'afl1 a 0 Name of Applicant: Atidress of Applicant Actual Inventor: Address for Service CIBA-GEIGY AG Klybeckstrasse 141, 4002 Basle, Switzerland FREDERICK J. DECHOW FBWD-WA+-S-&-SeNSr- 5O-.QUEEN-S-T-REET-MELR.U.RN-E AUSTRALIA, bOOO Compkte Specification for the invention entitled: HYPOCHOLESTEROLAEMIC GEL FORMULATION CONTAINING PHARMACEUTICALLY ACCEPTABLE NONDIGESTIBLE ANI ON

RESIN

A

EXCHANGE

The following statement is a full description of this invention, including the best method of performing it known to us I To: The Commissioner of Patents 12.87 k- 4-16372/16373/-/CGC 1267/1268 Hypocholesterolaemic gel formulation containing a pharmaceutically acceptable non-digestible anicn exchange resin Background of the invention 0 0 0 0 00 0 0 00 0Q 0 0 00 0 00 00 0 Pharmaceutically acceptable particulate sparingly crosslinked non-digestible quaternary ammonium substituted polystyrene anion exchange resins, such as cholestyramine resin powder, are known hypocholesterolaemic agents. See, for example U.S. Patent No. 3,383,281 to Wolf et al. incorporated by reference herein.

Such resins are administered orally, generally in the form of a powder which is admixed with a beverage, such as water, milk, fruit juice or other non-carbonated beverage, or with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple. In the intestinal tract the indigestible resin adsorbs and combines with bile acids to form an insoluble complex which is excreted. The increased loss of bile acids due to resin administration leads to an increased oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or low density lipoprotein plasma levels and a decrease in serum cholesterol levels.

Although the oral administration of such resins results in an increase in hepatic synthesis of cholesterol, plasma cholesterol levels fall.

Accordingly, such resins are useful in the reduction of elevated serum cholesterol levels in patients with hypercholesterolemia and in the relief of pruritis.

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2 -2- Unfortunately such resins in particulate form characteristically exhibit a chalky, gritty texture or taste in the mouth of the patient, even when combined with a beverage, soup or pulpy fruit. In some patients, this undesirable characteristic of the resin may elicit a gagging reflex. As a result, patient compliance to the oral self administration of the resin may be reduced.

It is therefore an object of the present invention to provide a pharmaceutically acceptable semisolid composition containing an effective hypocholesterolaemic amount of a particulate sparingly crosslinked non-digestible quaternary ammonium substituted poly- S" styrene anion exchange resin which possesses a high degree of S° palatability.

e Q e o It is a further object of the present invention to provide a method for treating by oral administration an effective hypocholesterolaemic amount of such semisolid composition.

0 0 0 °a These and other objects of the invention are apparent from the following specification disclosure: i Detailed description of the invention One embodiment of the present invention is a semisolid palatable hypocholesterolaemic formulation for oral administration to a patient comprising an effective hypocholesterolaemic amount of a uniform gelled dispersion of between about 8 and about 20 percent by weight of a particulate sparingly crosslinked non-digestible quaternary ammonium substituted polystyrene anion exchange resin having an average particle size below about 100 microns; between about 1.5 and about 16 percent by weight of a pharmaceutically acceptable gelling agent;

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3 between about 0.015 and about 10 percent by weight of a natural or synthetic pharmaceutically acceptable sweetener; between about 0.05 and about 2 percent by weight of a pharmaceutically acceptable organic acidulent; between about 0.05 and about 5 percent by weight of one or more pharmaceutically acceptable flavouring or coloring agents or mixtures thereof; and S* the remainder water.

o0 0 The particulate resin component belongs to the class of pharmaceutically acceptable particulate anion exchange resin useful in the reduction of cholesterol and triglyceride levels and the relief of pruritis in patients suffering from bile stasis. Such resins possess quaternary ammonium groups attached to a polystyrene containing o backbone. Preferably such quaternary groups are tri-lower alkyl o ammonium groups wherein the nitrogen thereof is attached to the phenyl moiety of the styryl group. The most preferred lower alkyl group is methyl. Further the resin is sparingly crosslinked, e.g.

with a conventional divinyl crosslinking agent, especially divinyl benzene. The amount of crosslinker present in the final resin is generally below about 5 preferably between about 1 and about 4 most preferably about 2 by weight of dry resin. The resin can be prepared, for example, as described in U.S. Patent No. 2,591,573.

The quaternary ammonium resin is in the form of a pharmaceutically acceptable salt thereof, such as the chloride, acetate, sulfate or the like. Generally, useful resins are those having a water content greater than about 65 by weight after equilibration with air at 100 relative humidity at about 20 0 C. Most preferably, the resin employed is cholestyramine resin The resin should be milled such that the average particle size is less than about 100 microns.

Preferably, at least about 80 percent of the resin particles have a particle size betweeen about 20 and about 100 microns, with less i o 09 It oI I ft -4than about 0.5 of the particles having a particle size greater than about 200 microns. Preferably, the amount of resin in the composition is between about 12 and about 18 percent by weight.

Component consists of a pharmaceutically acceptable gelling agent, such as gelatin USP, which is soluble in hot water, e.g.

above about 35 0 C, and, in the preferred amount of 4 to 16 by weight employed, forms a stable elastic shape retaining colloidal solution within which the resin component is substantially uniformly dispersed upon cooling to room temperature, e.g. about 20°C. The most preferred amount of gelatin employed is between about 5 to about 10 percent by weight of the formulation. The preferred gelatin is gelatin USP, type A. The gelatin component in the amounts specified also assists in masking the chalky taste characteristics of the resin.

The gelling agent present in component also consist of a pharmaceutically acceptable water compatable gum, to provide smooth spreadability and masking of the resin by coating and suspending the same, preferably acacia, carrageenan, xanthan or tragacanth gums or mixtures thereof. Most preferred is tragacanth gum. Preferably, the gum is present in the composition in an amount between about 2 and about 3 percent by weight, in order to assist in masking the chalky taste characteristics of the resin and to provide spreadability.

The pharmaceutically acceptable organic acidulent is present in combination with the sweetener and the gelling agent for the purpose of further masking the unpleasant mouth feel of the active agent resin, and include, for example adipic acid, ascorbic acid, citric acid, malic acid and tartaric acid or mixtures thereof. Again the optimum amount will, in part, depend upon the particular acidulent chosen. Preferably, the amount of acidulent is between about 0.1 and about 0.5 percent by weight. The most preferred acidulent is adipic acid.

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5 The pharmaceutically acceptable flavouring and coloring agents (e) may be selected from any of a wide variety of known agents and include pharmaceutically acceptable colors as well as artificial and natural flavors, including lime, cherry, orange, banana, spearmint, lemon, raspberry, blueberry, vanilla, strawberry, cinnamon, peppermint and the like, as well as mixtures thereof.

t o 0 4 00 o Q 4 o 0 0 O 0 00 0 04 0 O 0 0 #0 o o 0 I 0l 0 0 6 00 0 00 00 0 Also, if desired, minor amounts, preferably between about 0.01 to about 1.0 percent of pharmaceutically acceptable preservatives, stabilizers or anti-binding agents and the like may be present in the composition. Suitable preservatives include potassium sorbate and sodium propionate. As an anti-binding agent, to reduce the potential of constipation in some patients, methyl cellulose is preferred.

The present invention also relates to a process for the preparation of the above-mentioned pharmaceutical compositions which comprises micronizing the anion exchange resin to an average particle size below about 100 microns, preparing an aqueous solution of the pharmaceutically acceptable gelling agent at temperatures above 35°C and adding components and at lower or elevated temperatures to the suspension and allowing the suspension to cool to temperatures below 35 0

C.

When gelatin is used, prior to cooling and consequent gelatinization, the dispersed liquid, containing uniformly suspended resin can be poured into individual containers or molds of desired shape and size where the liquid sol hardens to the desired elastic shape retaining colloidal solution containing the uniformly dispersed particulate resin. As an alternate embodiment, the gelatinization can be performed in trays, or the like, and unit dose forms can be obtained by, for example, cutting portions therefrom.

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i 1- -1 6 When gum is used, the spreadable composition can then be placed into an ointment or toothpaste type tube or the like, for multiple dosing, or in unit dose containers. The active agent containing spreadable composition may be orally administered as is or may be spread on a cereal wafer, biscuit, or bread or the like.

The unit dose may vary widely, depending on the condition treated, but is preferably between about 2 and 16 grams of active agent resin, most preferably about 4 grams of active agent resin.

e °The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. All parts are by weight.

Example 1: 2.0 parts by weight gelatin USP, type A is dissolved in 24.0 parts by weight water at 60 0 C with stirring. After stirring the solution for 3 minutes, 4.0 parts by weight of dry cholestyramine, "Dowex 1x2" made by Dow Chemical Co., Midland, Mich. and containing about 2 of divinyl benzene crosslinking agent, which has been milled and screened to obtain an average particle size less than about 100 microns, with about 80 percent having a particle size between about 20 to about 100 microns, and 0.07 parts by weight I aspartame are added to the solution with stirring at 60 0 C. After stirring for an additional 3 minutes, there is then added to the liquid mixture maintained at 60 0 C, 0.10 parts by weight adipic acid 4 and 0.10 parts by weight of a mixture of artificial strawberry flavor and FD&C Red dissolved in ethanol. After stirring the mixture for an additional 5 minutes, the uniformly distributed suspension of resin in the resulting solution is placed in rectangular molds where, upon allowing the mixture to cool to room temperature for a period of two hours, the stable elastic shape retaining colloidal solution, or gel, containing the resin uniformly dispersed therein, is obtained. i i i. _i i. i i Ij I W -I 7 Example 2: 4.0 parts by weight of dry cholestyramine, "DOWEX 1x2" made by Dow Chemical Co., Midland, Mich. and containing about 2 of divinyl benzene crosslinking agent, is milled and screened to obtain an average particle size less than about 100 microns, with about percent having a particle size between about 20 to about 100 microns, and dry blended with 0.07 parts by weight tragacanth gum and 0.07 parts by weight aspartame. The resulting blend is then added with mixing to 24.0 parts by weight water and mixed thoroughly for 5 minutes at 40 0 C. To this mixture there is then added 0.10 parts by weight adipic acid, and 0.1 parts artificial banana I flavor admixsd with FD&C Yellow dissolved in ethanol. The resultant S. composition is then thoroughly mixed for another 5 minutes until a smooth, palatable, easily spreadable blend is obtained.

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Example 3: A composition identical in composition components to those of Examples 1 and 2 prepared, except that 0.2 parts of methyl cellulose is added to the solution with aspartame and resin. Due to the additional presence of methyl cellulose, the incidence of a c, possible constipation is minimized.

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Claims (8)

1. A hypocholesterolaemic semisolid formulation for oral administration comprising an effective hypocholesterolaemic amount of a semisolid dispersion of: between 8 and 20 percent by weight of a particulate, crosslinked, non-digestible, pharmaceutically acceptable quaternary ammonium substituted polystyrene anion exchange resin crosslinked with less than 5% by weight of dry resin crosslinking agent and which resin is having an average particle size below about 100 microns; between 1.5 and 16 percent by weight of a water compatible pharmaceutically acceptable gelling agent; between 0.015 and 10 percent by weight of a natural or synthetic pharmaceutically acceptable sweetener; between 0.05 and 2 percent by weight of a pharmaceutically acceptable organic acidulent; between 0.05 and 5 percent by weight of one or more pharmaceutically acceptable flavouring or coloring agents or mixtures thereof; and the remainder water.

2. A formulation according to claim 1 wherein the amount said resin in the formulation is between 12 and 18 percent b weight.

3. A formulation according to claim 1 wherein the resin i; cholestyramine.

4. A formulation according to claim 1 wherein said gellin agent is gelatin USP, type A. A formulation according to claim 1 wherein said gellin agent is tragacanth gum. of Y s g g i 1 1! I 8 0281e/GHG

6. A formulation according to claim 1 wherein the sweetening agent is aspartame and the acidulent is adipic acid.

7. A formulation according to claim 1 wherein the resin is cholestyramine, the sweetening agent is aspartame, and the acidulent is adipic acid.

8. A hypocholesterolaemic semisolid formulation for oral administration substantially as herein described with reference to any one of the Examples.

9. A method of treating hypocholesterolaemia in a patient comprising orally administering to said patient in need of the same, an effective hypocholesterolaemic amount of the formulation according to any one of claims 1 to 8. o a o o oo a 0 0 00 0 o O o O 0 0 DATED this 20th day of November, 1990. CIBA-GEIGY AG o600 By Its Patent Attorneys ARTHUR S. CAVE CO. o LS; 0 t 9