PSYLLIUM AND CHOLESTYRAMINE COMPOSITIONS WITH IMPROVED PALATABILITY

Abstract: This invention relates to a pharmaceutical composition comprising small particle size (smaller than about 80 mesh U.S. standard) psyllium husk and cholestyramine having improved cholestyramine aesthetics, and a method for treating hypercholesterolemia by administering said pharmaceutical composition.

Description: PSYLLIUM AND CHOLESTYRAMINE COMPOSITIONS WITH IMPROVED PALATABILITY BACKGROUND This invention relates to pharmaceutical compositions comprising small particle size (s aTler than about 80 mesh U.S. standard) psyllium husk and cholestyramine having improved cholestyramine aesthetics, and a method for treating hypercholesterolemia by administering said pharmaceutical composition. High blood cholesterol levels are associated with life threatening cardiac diseases. A drug of choice in the treatment of such disorders is cholestyramine resin, which is known as a basic anion exchange resin. Cholestyramine helps to lower blood cholesterol levels apparently by binding to bile acids in the intestine. It is believed that this in turn causes an increase in hepatic metabolism of cholesterol to replenish the bile acids lost to complexation with the cholestyramine. Cholestyramine is usually dosed using from four to thirty-two grams, given once daily or divided into two, three, or four equal intervals. At the present time a commercial cholestyramine product, Questran ® (manufactured by the Mead Johnson division of Bristol-Myers Company) is sold in a four grams unit dose powder packet or in bulk powder, and as Cholybars (manufactured by Parke Davis) wherein one chewable bar contains four grams of cholestyramine. rPhvsicians Desk Reference. 44th Edition, pages 726-729 and 1595-1597 (1990).] While the benefits of cholestyramine are well known and appreciated, the aesthetics (e.g., outhfeel ; taste; throat sticking) are considered by many users of cholestyramine to be very unpleasant. Obviously, poor aesthetics raise concern about how closely patients comply with any treatment regimen using cholestyramine. The unpleasant mouthfeel of cholestyramine is frequently described as a sandy, gritty texture which tends to stick to the back of the mouth and throat upon ingestion and which leaves an unpleasant fishy taste in the mouth. Several attempts have been made to improve the palatability of cholestyramine. Patents which disclose such attempts include: East German Patent DD 249,634 published September 16, 1987 by V&B Che ukombinat Bitterfeld (discloses grinding a basic anionic exchanger such as cholestyramine in a wet state and spraying on an aqueous solution of pectin during drying); Great Britain Patent Specification Number 1,446,352, published August 18, 1976 by Merck & Co., Inc. (discloses an oral pharmaceutical composition in liquid form comprising a coacervate of a hydrophilic colloid of a cellulose derivative, such as sodium carboxy ethyl cellulose, and cholestyramine); French Medical Patent 6,888 M published June 4, 1964 by Mead Johnson & Company (discloses dry mixing acacia gum w>th cholestyramine resin to aid in making the extreme astringency of cholestyramine disappear); United States Patent 4,895,723, issued to Amer et al. January 23, 1990 (describes orally ingestible compositions for reduction of blood cholesterol levels comprising cholestyramine and a water-soluble carbohydrate syrup such as high fructose corn syrup or a liquid alcohol polyol humectant such as glycerine); United States Patent 4,843,098, issued to Shaw et al. June 27, 1989, United States Patent 4,818,539, issued to Shaw et al. April 4, 1989, and United States Patent 4,790,991, issued to Shaw et al. December 13, 1989, divisions of United States Patent 4,747,881, issued to Shaw et al. May 31, 1988 (relating to preswelled substantially anhydrous hydrocolloid aggregate such as carboxymethyl cellulose with a size range of about 4 to about 70 U.S. mesh, and a substrate comprising dietary fiber and/or drug, such as cholestyramine); United States Patent 4,778,676, issued to Yang et al. October 18, 1988 (discloses a chewable delivery system for actives comprising an active, such as cholestyramine, pre-coated with at least one material selected from the group consisting of lecithin, polyoxyalkenes having chain lengths of about four carbons or less, glycerides having a melting point of 100'C or less, polyalkylene glycols having a molecular weight of 3,700 or less, synthetic and natural waxes and mixtures thereof, and a confectionery matrix comprising a binder system of gelatin and a humectant material); United States Patent 3,974,272, issued to Pol1i et al . August 10, 1976 (discloses a palatable oral coacervate composition containing cholestyramine and a Modified Gum selected from the group consisting of hydrophillic colloid of cellulosive material and charged anionic gum in an aqueous medium); and United States Patent 3,499,960, issued to Macek et al . (discloses coating the cholestyramine particles with an acrylic polymer crosslinked with allylsucrose). Other publications relating to therapeutic use of cholestyramine or psyllium include the following. European Patent Application Publication No. 323,666, published July 12, 1989 by The Procter & Gamble Company. This patent describes methods and compositions for reducing blood cholesterol levels by oral administration of psyllium and cholestyramine, optionally in combination with polyol polyesters. It is also stated therein that "cholestyramine resin, administered orally, has sometimes been associated with constipation and preparations containing cholestyramine often have an unpleasant sandy or gritty quality. Advantageously, these problems associated with cholestyramine are alleviated when the psyllium and/or psyllium plus optional polyol polyesters are employed therewith." United States Patent 4,824,672, issued to Day et al. April 25, 1989, discloses an orally utilizable pharmaceutical composition comprising gel-forming fiber (such as guar gum, psyllium seed, pectin, glucomannan, oat and barley) and a mineral salt (such as calcium carbonate, magnesium carbonate, or potassium carbonate) said to be administered to humans to reduce serum cholesterol levels. Management of Hvpercholesterolemia. Approach to Diet and Druo Therapy. Stein, The American Journal of Medicine, Vol. 87(4A) (1989) advises patients who experience constipation from the use of cholestyramine or colestipol (bile acid sequestrants used to decrease blood cholesterol levels) to take a bulk laxative, such as psyllium fiber, with the evening dose of sequestrant if other dietary changes do not alleviate the problem of constipation. The Effect of Psyllium Hvdrocolloid and Cholestyramine on Hepatic Bile Lipid Composition in Man. Behrer et al ., Henry Ford Hospital Medical Journal, Vol. 21(1) (1973), examined the effects of psyllium hydrocolloid and of cholestryramine on the total cholesterol, total phospholipid, total bile salt, cholate, chenodeoxycholate, and deoxycholate concentrations of 6 post-cholecystecto y patients. Although there has been much research devoted to cholestyramine and to improving the aesthetics of cholestyramine, there continues to be a need for improved products containing cholestyramine. In the present invention, it has surprisingly been discovered that small pSrticle size psyllium husk, smaller than that previously commercially available in certain laxative products, when used in combination with cholestyramine, improves the aesthetics of the cholestyramine. The object of the present invention is therefore to provide a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine with improved aesthetics, including palatability and/or mouthfeel. A further object of this invention is to provide a method for improving the palatability and overall mouthfeel of cholestyramine and a method for enhancing compliance and convenience with a treatment regimen for treating hypercholesterolemia by administering to humans a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine. An object of the present invention is also to provide a method for treating hypercho esterolemia by administering to humans a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine. Another object of the present invention is to provide a bowel normalizing benefit to patients being treated for hypercholesterolemia through administration of a pharmaceutical composition comprising small particle size psyllium husk and cholestyramine. These and other objects of the present invention will become readily apparent from the detailed description which follows. All percentages and ratios used herein are by weight and all measurements are made at 25 * C unless otherwise specified. Screen mesh sizes used herein are based on U.S. standards. SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition comprising: (a) cholestyramine; and (b) small particle size psyllium husk (i.e., smaller than about 80 mesh screen) wherein the ratio of small particle size psyllium husk to cholestyramine is from about 3:1 to about 1:2. The present invention further relates to a method for improving the aesthetics of cholestyramine, said method comprising mixing cholestyramine with small particle size psyllium husk in a liquid in a ratio of small particle size psyllium husk to cholestyramine from about 3:1 to about 1:2. Additionally the present invention relates to a method for treating hypercholesterolemia in humans, said method comprising administering to a human in need of such treatment a safe and effective amount of a pharmaceutical composition according to the present invention. DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical Compositions It has been surprisingly discovered that combining small particle size psyllium husk with cholestyramine greatly reduces the unpleasant aesthetics of the cholestyramine resin, even relative to aesthetically improved compositions comprising cholestyramine and the larger particle size psyllium husk (commercially available, e.g., Metamucil ® , sold by The Procter & Gamble Company) taught for use by European Patent Application Publication No. 323,666, published July 12, 1989 by The Procter & Gamble Company. Combination of the small particle size psyllium husk with the cholestyramine may be accomplished through simple admixture (e.g., by a dry blending process), by preferably forming a dry drink mix composition or by admixing in a liquid (e.g., water) a composition comprising small particle size psyllium husk and a composition comprising cholestyramine, as described in greater detail hereinafter. A. Small Particle Size Psyllium Husk The .small particle size psyllium husk used in the present invention is from psyllium seeds, from plants of the Plantago genus. Various species such as Plantago lanceolate. P^. rugelii, and J . ma.ior are known. Commercial psyllium husk include the French (black; Plantago indicah Spanish (P. psyllium) and Indian (blonde; J\_ ovata). Indian (blonde) psyllium husk is preferred for use herein. Also preferred is psyllium husk which is at least about 85% pure, more preferably at least about 90% pure, and most preferably at least about 95% pure. The psyllium husk is obtained from the seed coat of psyllium seed. It is typical to remove the seed coat from the rest of the seed by, for example, slight mechanical pressure, and then to use only the seed coat. The seed coat is preferably removed and sanitized by methods known in the art (e.g., ethylene oxide sanitization or superheated steam sanitization as taught in European Patent Application Publication No. 308,003, published March 22, 1989 by The Procter & Gamble Company the disclosures of which are incorporated herein by reference in their entirety) prior to reducing the particle size to that described herein. Methods for reducing psyllium particle size to those of the present invention are known in the art, preferably may be reduced by the use of a stud mill (also known as "pin mills") under conditions which selectively reduce the psyllium husk size relative to non-husk impurity, thereby allowing for further purification if so desired, as described in more detail in European Patent Application Number 362,926, published April 11, 1990 by The Procter & Gamble Company. "Small particle size psyllium husk", as used herein, means that essentially all of the psyllium husk is smaller than about 80 mesh screen. The preferred particle size comprises small particle psyllium husk wherein more than about 97% are smaller than about 100 mesh and less than about 40% are smaller than about 200 mesh. Particle sizes may be readily determined by one of ordinary skill in the art, for example by sieving using an Alpine Laboratory Air Jet Sieve. Type 200 LS (sold by Alpine American Corporation, Natick, Mass.). While not essential, it is preferred that the small particle size psyllium used in the present invention be agglomerated and more preferably these agglomerates also comprise the cholestyramine. Agglomerated psyllium is well known. Agglomerating psyllium husk appears to improve the mixability and suspendability of the small size particle psyllium husk in liquids, especially water. Agglomeration processes may be chosen by one of ordinary skill in the art as appropriate for the small particle size psyllium husk, in the present invention. An example of a fluid bed agglomerating equipment useful in the agglomeration process is the Fluid Air, Inc., Model 0300 Granulator-Dryer. The small particle size psyllium husk in the present invention comprises from about 1% to about 75% by weight of the pharmaceutical composition of the present invention and more preferably from about 10% to about 65%. Most preferred is that the small size psyllium husk comprises from about 30% to about 65% by weight of the pharmaceutical composition of the present invention. The ratio of small particle size psyllium husk to cholestyramine is from about 3:1 to about 1:2, preferably from about 2:1 to about 1:1. B. Cholestyramine The cholestyramine resin used in the present invention is a strongly basic anion exchange resin which contains quaternary ammonium functional groups attached to a styrene-divinylbenzene copolymer. .The Merck Index. 10th Edition, published by Merck & Co., No. 2182 (1983)]. Cholestyramine resin-containing compositions are available commercially in powder form under the tradenames Cuemid ® (Merck, Sharp & Dome) and Questran ® (Bristol Myers division of Mead Johnson). Cholestyramine is commercially available as Duolite AP-143 resin (Rohm & Haas Co.). The cholestyramine resin in the present invention comprises from about 1% to about 65% by weight of the pharmaceutical composition of the present invention, and more preferably from about 10% to about 50%. Most preferred is that the cholestyramine resin in the present invention comprises from about 25% to about 50% by weight of the pharmaceutical composition of the present invention. C. Optional Components: The compositions of the present invention also optionally comprise food grade carrier materials suitable for human consumption. The carrier materials useful in the present invention include the group consisting of flavoring agents, sweetening agents, agglomerating agents (such as maltodextrin) and/or coloring agents. Flavoring agents if optionally chosen may include certain volatile oils, liquids or dry agents which are pharmaceutically acceptable for internal ingestion by humans. Examples of such flavoring agents include citrus flavors (such as orange and grapefruit), strawberry, and cherry flavors. Another optional component of the present invention, as noted above, is a sweetening agent. Examples of suitable sweetening agents include but are not limited to, saccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch, or corn syrup solids and sugar alcohols. Additionally low caloric sweetening agents may be used in the present invention, including, but not limited to, aspartame, saccharin, cycla ate, acesulfame (American Hoechst), gem sweet (Cumberland Packing Corp.), L-sugars (Lev-0-Cal Biospherics), Hernandulcin (University of Illinois), Alitame (Pfizer), Thaumatins, trichloro sucrose, Rebaudioside A, aspartyl-D-valine isopropyl ester, aspartyl amino alonates, dialkyl aspartyl aspartatesr, stevio side, glycyrrhizin, p-phenetylurea, 5-nitro-2-propoxy aniline and neohesperidin dihydrochalcone. Preferred artificial sweetners are saccharin, cyclamate, ausulfame K, and especially aspartame, sold as Nutrasweet® by G. D. Searle. The food grade carrier materials comprise from about 0% to about 98% by weight of the pharmaceutical composition of the present invention, and more preferably from about 5% to about 80%. Most preferred is that the food grade carrier materials comprise from about 10% to about 50% by weight of the pharmaceutical composition of the present invention. The combination in the present invention of small particle size psyllium husk and cholestyramine may be achieved by dry blending these materials by any means known to one skilled in the art, and preferably by a method which will achieve a uniform mix of the small particle size psyllium husk and cholestyramine. Examples of apparatuses which may be helpful in obtaining such uniformity are the Hobart mixer (model number N-50), the Glen mixer, and the Patterson-Kelly twin-shell blender. Compositions of the present invention may also be formed into liquid suspensions (typically by the consumer just prior to ingestion) by mixing a composition comprising the small particle size psyllium husk with a composition comprising cholestyramine into a liquid, typically water. The present invention therefore also relates to methods for improving the aesthetics of cholestyramine by a method comprising mixing cholestyramine with small particle size psyllium husk in a liquid in a ratio of small particle size psyllium to cholestyramine from about 3:1 to about 1:2. Preferably, the pharmaceutical composition comprising the small particle size psyllium husk and cholestyramine or each component separately are dispersed in at least an eight ounce glass of water or fruit juices and drunk. Method of Treatment The method of treatment herein comprises orally administering to a patient in need of having a lowered blood cholesterol level a safe and effective amount of a mixture of small particle size psyllium husk and cholestyramine. The ratio of small particle size psyllium husk to cholestyramine should be from about 3:1 to about 1:2, and preferably from about 2:1 to about 1:1, wherein a patient in need of such treatment receives from lg to 30g of the small particle size psyllium husk and from about 4g to about 30g of the cholestyramine daily. However, this can vary with size and condition of the patient and the patient's blood cholesterol levels. Such matters will, of course, be apparent to the attending physician. Furthermore, since the psyllium materials and cholestyramine are non-toxic, even higher ingestion levels can be used without undue side effects. Treatment of the patient comprises continuous administration of small particle size psyllium husk and cholestyramine in order to lower and maintain low cholesterol levels. As used herein "continuous administration" means ingestion by a human in need of said treatment one or more doses a day of small particle size psyllium and cholestyramine for two or more days. Daily ingestion of the present compositions preferably comprises from about 5g to about 15g of small particle size psyllium husk and from about 4g to about 24g of cholestyramine taken orally, with said ingestion being once daily or at two, three, or four regularly spaced intervals throughout the day. It may also be beneficial to administer said dose in relati-onship to meals, preferably prior to a meal, and at bedtime. It is essential to the present invention that the small particle size psyllium husk and cholestyramine be combined prior to administration. Preferably said materials, in powder form, are combined prior to use by a dry blending process, described in detail hereinabove, and then admixed with a liquid drink, preferably eight ounces, such as fruit juices and water, and drunk. The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope. Example I Component Small particle size psyllium mucilloid a ) Citric acid Potassium citrate Aspartame^) FD&C Yellow 6 D&C Yellow 10 Artificial Grapefruit Flavor F57364/AP0551 C ) Naringind) Cholestyramine resin e ) a) The small particle size psyllium mucilloid is prepared and agglomerated by the following process: A psyllium-containing dry blend (85.42 parts by weight) comprising 62.96 parts by weight superheated steam sanitized psyllium husks (particle size of 98% minimum through 100 mesh screen) and 24.28 parts by weight Maltrin M100 (maltodextrin having a D.E. of about 10; sold by Grain Processing Corporation; Muscatine, Iowa) is agglomerated by spraying the dry blend with a citric acid solution (11.83 parts by weight) comprising 3.64 parts by weight citric acid, and 8.19 parts by weight water using a Bepex Turboflex Model No. TFX-4 (sold by Bepex Corporation; Minneapolis, Minnesota) and then drying using a six square foot bed stationary fluid bed dryer (sold by Bepex Corporation; Minneapolis, Minnesota). b) Nutrasweet ® (G.D. Searle) c) Firmenich, Inc. (Princeton, N.J.) d) flavoring agent manufactured by Baromatic Corporation (Great Neck, NY). e) Duolite AP-143 resin (Rohm & Haas Co., Philadelphia, PA). The process for manufacturing is as follows: (1) Place the citric acid, potassium citrate, aspartame, FD&C yellow #6, D&C yellow #10, Artificial flavor F57364/AP0551, and Naringin in the bowl of a Hobart mixer (model number N-50). (2) Mix for 5 minutes using speed #1. (3) Add the small particle size psyllium mucilloid and mix for 5 minutes using speed #1. (4) Add the cholestyramine resin and mix on speed #1 for 5 minutes or until a homogeneous mixture is obtained. A flavored small particle size psyllium/cholestyramine-containing drink, according to the present invention, is prepared by dispersing 7.143 grams of the above pharmaceutical composition according to the present invention, in 8 ounces of water which may then be drunk by a human in need of such treatment for hypercholesterole ia. %w/w 49.367 50.633 a) sold by The Procter & Gamble Co. (Cincinnati, Ohio) wherein 8.775g of powder mix provides 5.1g of small particle size psyllium 100% through 80 mesh screen. b) sold by The Bristol Myers division of Mead Johnson (Evansville, Indiana), wherein 9g of powder mix provides 4.0g of cholestyramine resin. A patient in need of a cholesterol lowering agent may disperse 8.775g of the Sugar Free Sunrise Smooth Metamucil ® , orange flavor, and 9.0g of Questran ® into an eight ounce glass of water, stir the mixture to provide uniformity, and drink once every day or more according to their physician's orders. A patient in need of 8g of cholestyramine per day may combine 18.Og of Questran ® with 8.775 of Sugar Free Sunrise Smooth Metamucil ® , orange flavor divided equally between two eight ounce glasses of water. WHAT WE CLAIM IS:

Claims: CLAIMS - CASE 4318 1. A pharmaceutical composition comprising: (a) small particle size psyllium husk; and (b) cholestyramine; and wherein the ratio of small particle size psyllium husk to cholestyramine is from 3:1 to 1:2. 2. A pharmaceutical composition according to Claim 1, wherein more than 97% of the small particle size psyllium husk is smaller than 100 mesh screen. 3. A pharmaceutical composition according to Claims 1 or 2, wherein the small particle size psyllium husk is agglomerated. 4. A pharmaceutical composition according to any of Claims 1-3 wherein the ratio of small particle size psyllium husk to cholestyramine is from 2:1 to 1:1. 5. A pharmaceutical composition according to any of Claims 1-4 further comprising food grade carrier materials suitable for human consumption selected from the group consisting of flavoring agents, sweetners, preservatives, coloring agents, binders, and combinations thereof. 6. A pharmaceutical composition comprising: (a) from 1% to 75% small particle size psyllium having more than 97% of the small particle size psyllium husk smaller than 100 mesh screen; (b) from 1% to 65% cholestyramine; and (c) from.0% to 98% food grade carrier materials suitable for human ingestion; and wherein the ratio of small particle size psyllium husk to cholestyramine is from 3:1 to 1:2. U A pharmaceutical composition according to Claim 6, comprising: (a) from 10% to 65% small particle size psyllium having more than 97% of the small particle size psyllium husk smaller than 100 mesh screen; (b) from 10% to 50% cholestyramine; and (c) from 5% to 80% food grade carrier materials suitable for human ingestion; and wherein the ratio of small particle size husk to cholestyramine is from 2:1 to 1:1. A method for improving the aesthetics of cholestyramine, said method comprising mixing cholestyramine with small particle size psyllium husk in a liquid in a ratio of small particle size psyllium to cholestyramine from 3:1 to 1:2. A method for improving the aesthetics of cholestyramine, said method comprising mixing cholestyramine with small particle size psyllium husk according to any of Claims 1-8.

Inventors: COLLIOPOULOS JOHN ANDREW, KARDOUCHE NABIL GEORGE, COLLIOPOULOS, JOHN, ANDREW, KARDOUCHE, NABIL, GEORGE
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1991
Main classification: A61K35
IPC codes: A61K31, A61K36, A61P3