NOVEL BILE SEQUESTRANT RESIN AND USES

Abstract: Particular quaternized vinylimidazole-ethylene glycol di­ methacrylate copolymers are useful to sequester non-ab­ sorbed bile acids in the intestinal tract to form a complex which is excreted in the feces. These are of particular interest for lowering blood cholesterol levels. Some of these copolymers have the further useful prop­ erty of being excellent anti-diarrheal agents.

Description: The invention relates to novel resins useful to sequester non-absorbed bile acids from the intestinal tract to form a complex excreted in the feces with the consequent effect of lowering blood cholesterol level. Also, some of these resins are additionally verv useful in inhibiting diarrhea. It is known to use sequesCering agent resins to bind non-absorbed bile acids in the intestinal.tract to form complexes which are excreted in the feces whereby bile acids which would otherwise be reabsorbed and returned to the liver are removed from the system. This interrupts the enterohepatic cycle and leads to increased oxidation of cholesterol to bile acids and reduction in plasma cholesterol level. Such sequestering agent resins have been recognized for use for treatment of hypercholesterolemia,especially primary hypercholesterolemia (i.e. elevated low density lipoproteins). Recently, it has been recognized that reducing serum cholesterol has a beneficial effect on protecting against the occurrence of atherosclerosis including heart disease. Thus, sequestering agent resins for bile acids have recently assumed increased importance. Cholestyramine is one sequestering agent resin currently being used to lower blood cholesterol levels in humans by binding bile acids in the intestinal tract. Since it is orally administered, the fact that it has an undesirable odor and taste requires use in combination with masking excipients. Moreover, while cholestyramine is quite effective in binding bile acids in vitro, binding at between 50 and 809 of its theoretical capacity, in vivo much of the bile acid is stripped off in the ileum so that cholestyramine has a low gram potency. This low gram potency in- combinatwon with bulk added by the need for masking excipients has resulted in need for a daLly rintake t± 27. r54 grarr.s per day which has inhibited widespread use of the drug. Colestipol is another resin orally administered to sequester bile acids to reduce blood cholesterol level. It has a potency about 508 of cholestyramine. Recently sequestering agent resins, including cholestyramine and colestipol, have been considered to protect against or treat diarrhea. Numerous clinical reports during the past 10 years have shown cholestyraiine to be beneficial in treatment of certain chronic infantile diarrheas. This alternative is significant because infantile diarrhea leads to water and essential salt loss with the consequent risk of dehydration and the normal treatment of hydration and administrati of essential salts sometimes is ineffective. Oral administration of cholestyramine has also been beneficial in instances where diarrhea is considered to be caused by the cathartic effect of bile acids reaching the colon in increased amounts, such as occurs in ileal resection and by-pass. There is also some indication thatcholestyramine may be useful in the treatment of bacterial-induced diarrhea by binding bacterial enterotoxins. Summary Of The Invention It has been discovered herein that particular quaternized vinylimidazole-ethylene glycol dimethacrylate copolymers are bile acid sequestering resins which are alternatives for cholestyramine and colestipol. These copolymers contain from about 18 to about 25% of ethylene glycol dsmethacrylate moieties. The term ethylene glycol dimethacrylate moieties is used herein to mean the portions of the copolymer structure derived from ethylene glycol dimethacylate. The percentagPs salt glycol dimethacrylate copolymer moieties herein are weight percentages of the copolymer based on the ethylene glycol dimethacrylate reacting to form the polymer. These copolymers (referred to hereinafter as copolymer I) have polyvinylimidazolium moieties having the structural formula EMI3.1 wherein n, on average, ranges from 3 to about 40 and wherein R is selected from the group consisting of alkyl and alkenyl groups having from 1 to p carbon atoms and -CH2R1 wherein is selected from the group consisting of phenyl, -CR2OS, -CH2NHCOC6H5, and -CE2NR2R3 wherein R2 and are each selected from the group consisting of methyl and ethyl and wherein X is an anion. The term "polyvinylimidazolium moiety is used herein to refer to each portion of the copolymer with the structural formula as depicted above, and n is given on the basis of average values because a plurality of such moieties can be found in a copolymer structure. The average value for n is readily obtained by considering the amount of ethylene glycol dimethacrylate inthe copolymer and the number of Vinyl groups in the copolymer structure. Preferred resins referred to hereinafter as copolymers II, which possess about 130 to 160% of the potency of ground cholestyramine in respect to sequestering bile acids in the intestinal tract of rats to form complexes which are excreted in the feces, arebthe copolymers I which contain from about 15% to about 20t of ethylene glycol dimethacrylate moieties and wherein in the above set forth structural formula n averages from about 3 to about 10 wherein R is alkenyl having from three to four carbon atoms As indicated above, the copolymers I and II have utility as sequestrants for bile acids in mammals and are orally administered to said mammals in an amount effective to increase the amount of bile acids in the feces. The copolymers function by binding non-absorbed bile acids in the intestinal tract to form complexes which are excreted in the feces. It is well recognized that removal of bile acids from the intestinal tract in this way lowers blood cholesterol level. It has been discovered herein that particular copolymers I, referred to hereinafter as copolymers III, are useful to inhibit diarrhea in mammals, i.e. as a prophylactic against the occurrence of diarrhea or as treatment for diarrhea. The copolymers III contain from about 1' to about 19% of ethylene glycol dimethacrylate and have polysinylimidazolium :noieties with the above set forth structural formula where n averages from about 25 to about 35 and wherein R is alkyl having from 1 to 3 carbon atoms. The copolymers III are orally administered in an amount effective to inhibit diarrhea. The copolymers I, II and III herein, as indicated in more detail hereinafter are reaction products wherein one reactant is ethylene glycol dimethacrylate. The ethylene glycol dimethacrylate can be considered a cross-linking agent with potential sites depicted below: EMI5.1 In view of this, the ethylene glycol dimethacrylate (EGD) is sometimes referred to hereinafter as a cross-linking agent. Turning now to the variables in the resin structure guaternization is critical because resin which is the same as that of the invention except unquaternized has very low bile acid binding activity. Furthermore, the selection of R in the copolymer structure set forth above is a variable in respect to bile acid binding activity. rurthermore, it has been found herein that selection of particular R and n in the copolymer structure set forth above and particular percentage EGD cross-linker provides a very high order of bile acid binding activity. Moreover, it has also been found that selection of particular R and n and of ethylene glycol dimethacrylate in place of other reactant/constituent and of the percentage thereof determines anti-diarrheal activity So far as X is concerned ln thein the above structural formula used m conjuction witn describing copolymer I, a wide variety of anions are useful herein, a criterion being the pharmaceutically acceptable nature of such. Suitable anions include, for example, halides, acetate, propionate and phosphate. Chloride is preferred. As indicated above, the copolymers I have bile acid binding activity. The copolymers II and III herein are species of copolymers I. The copolymers II are very superior bile acid binders and even significantly surpass cholestyramine in this regard. The copolymers III, in addition to having bile acid binding capacity, are excellent anti-diarrheal agents. Examples of copolymers I which are not copolymers II or III are listed below. These have the structure set forth for copolymers I above and variations in R and n in said structure and the percentage ethylene glycol dimethacrylate moieties (% EGD) are set forth below: Copolymer R n % EGD IA -CE3 5 17 13 CR2CR2CR3 5 17 IC -(CE2)7CR3 5 17 ID -(CH2)15CH3 5 17 IE -CR2C6E5 5 17 IF -CH2CR2OH 5 17 IG -CH2CH2NRCOC6H5 4 17 IS -CH2CH2N (C2H5)2 4 20 Examples of copolymer II are listed below. These have structures as set forth for copolymers II above and the variations in R and n in said structures and the percentage ethylene glycol dimethacrylata moieties (@ EGD) are set0 forth below: Copolymer R n % EGD -CH2CH=CH2 lIB -CH2CH=CH2 8 16 IIC -CH2CH2CH=CH2 3 19 Copolymer IIA is preferred for bile acid binding/anticholesterol activity. Examples of copolymers III are listed below. These have structures as set forth for copolymers III above and the variations in Rand n in said structures and the percentage ethylene glycol dimethacrylate moities (% EGD) are set forth below Copolymer R n % EGD IIIA -CH3 30 3 IIIB -CR3 25 3 IIIC -CH3 35 3 IIID -CE3 28 7 IIIE -CE 2 3 25 9 IIIF -CR2CH2CE3 . 33 2 Copolymer IIIA is preferred for anti-diarrheal activity. In the above, IA-IS, IIA-IIC and lIA-IlIF, the resins have structure as set forth for copolymer I with X as chloride. Useful resins are also provided when the X in these exemplary resins is another resin anion as indicated above. The copolymers I (including species copolymers II and III) are readily prepared, for example, by reacting l-vinylimidazole and ethylene glycol dimethacrylate and then quaternizing. The reaction of l-vinylimidazole and ethylene glycol dimethacrylate is readily carried out at, for example, 55 C-80 C, in the presence of benzoyl peroxide catalyst. For copolymers where the ethylene glycol dimethacrylate moiety content is 10% or more a mixture of aqueous sodium sulfate and ethyl acetate is suitable as a reaction medium. Where such content is less than 10t, benzene is suitable as a reaction medi a such cont@n@ is less than @@@, benzens is suitable @@ @ reaction medium Quaternization is carried out by refluxing, for example, in ethanol with quaternizing agent. Chloride formation is advantageously carried out by quaternizing with iodide and then exchanging utilizing silver chloride. For bile acid binding capacity a dosage of 2 to 5 grams three or four times per day is preferred and with the preferred copolymer for this, namely IIA, 2-3 grams three or four times a day. For anti-diarrheal activity, a dosage of copolymer III of 1-2 grams twice a day for adults and0.5-l grams twice a day for pediatric diarrhea is preferred. The following examples are illustrative of the discoveries herein. Example I Preparation of Copolymer IIA A freshly prepared solution of l-vinylimidazole (400 ml, 4.44 moles), ethylene glycol dimethacrylate (40 ml, 0.21 moles), and benzoyl peroxide (36.0 g, 0.16 moles) in ethyl acetate (400 ml) was added to an aqueous solution of sodium sulfate (2.0 1, saturated at 60 C) kept at 600C. The mixture was stirred well for 16 hours under nitrogen. The resulting ba6letswere collected on a filter and washed four times with water. This material was dried two days in a vacuum oven at 80 C to give 142.4 g consisting essentially of vinylimidazole-ethylene glycol dimethacrylate copolymer containing 178 ethylene glycol dimethacrylate moiety and having structural formula set forth above for. copolymer I with n equal to 5 except that the resin was unquaternized. 50 g of the resulting product and a solution of allyl chloride (100 ml) in ethanol (400 ml) were combined and refluxed with stirring fog 4 days. The mixture was cooled, collected by filtration on crepe paper, and washed thrice with ethanol. The resulting product was dried 18 hours at 600C in a vacuum oven to 62.30 grams of light brown solid consisting essentially of copolymer lIA as defined hereinbefore. Example TI Preparation of Copolymer IIIA Benzene (500 ml) was heated to reflux under nitrogen in a flask. Benzoyl peroxide (27.2-g) was-dissolved in another 500 ml of benzene and to this was added 300 ml of l-vinyl imidazole and ethylene glycol dimethacrylate (3 ml) to form a solution. This solution was added to the refluxing benzene and washed in with 200 more ml of benzene. The resulting mix was stirred under nitrogen with refluxing for 5 hours. After slight cooling and filtering, the resulting mix was dried under vacuum for 16 hours at 600C and then dried further under vacuum at 600C to yield 147.8 g of a viscous liquid including vinylimidazole-ethylene glycol dimethacrylate containing 3t ethylene glycol dimethacryiate moiety and having structure formula as set forth above for copolymer I with n equal to 30 except that the resin was unguaternized. This liquid was admixed with ethanol (1 liter) and iodomethane (90 ml, 1.44 moles), and stirring at room temperature was carried out for 16 hours. The resulting mix was filtered and washed three times with absolute ethanol to provide a light tan powder with a skin on top. The skin was removed and the powder was dried under vacuum at 60C for 23 hours to yield 127.1 g of light brown powder. To 123.4 g of this was added 40 ml of iodomethane and 500 ml of absolute ethanol, and this mix was ref fluxed for 19 hours, cooled, filtered, washed three times with absolute ethanol and dried at 60*C under vacuum for 44 hours to yield 137.2 g of poly-3-methyl-l- vinylimidazolium iodide resin./ Chloride was then exchanged with iodide as follows: Silver nitrate (144.2 g) was dissolved in water. Sodium chloride (50.8 g) was dissolved in water. The solutions were combined. The resulting silver chloride precipitate was filtered and washed. The washed silver chloride precipitate was combined with the 137.2 g of the resin and 1 1 of water. The mixture was stirred well and reluxed for 18 hours. The reaction mixture was centrifuged and the solid'was washed with water and fentrlfuged again. The combined supernatants were concentrated under vacuum at approximately 900C. Then ethanol was added and concentration under vacuum carried out. This was repeated twice more. Then acetone was added and solid was scraped off the sides of the flask, filtered, dried 17 hours at 72iC under vacuum and sieved through a t9 screen to. yield 96.1 g of copolymer IIIA. Example III Testing for Bile Acid Binding Activity compositions tested herein were copolymers IA, TB, IC, ID, TE, IF, IG, IB, ITA and IIIA as described hexeinbefore as well as copolymer IVA (the unquaternized precursor of copolymer IA). The compositions were tested in vitro as well as in vivo. The in vitro testing consisted of incubating 20 mg amounts of dry resin in 5 ml of 0.15 M NaCl containing 100 ambles of sodium cholate for 16 hours of continuous shaking at 370C. After centrifugation, unbound bile salt remaining in the supernatant was measured by the-hydroxysteroid dehydrogenase assay. Results are reported in terms of percentage of the activity/of cholestryramine beadlets. The in vivo testing was carried out in rats as follows: Male weanling rats (Wistar strain) were individually housed and fed a basal diet (20.0% casein, 62.55 Amidex, 10.0% corn oil, 4% non-nutritive fiber, 2.458 mineral mixture and 1.0t vitamin mixture) for a 10 day period. On the basis of body weight and the 10-day weight gain, the animals were selected into groups of 10 animals each and fed the basal diet plus the test resins at 0.25 to 1.08 by weight of the diet.for a.14-day test period. During the last four days of the test period feces were collected, freeze-dried, ground and analyzed for bile acids by the hydroxysteroid dehydrogenase enzyme method. Results are reported as a percentage of the activity of cholestyrarnine fed in the diet at the same percentage value as the test resin. Test Results for Example III Copolymer In Vitro In Vivo IA MJ 12577 93 113ê , 126Ú IB MJ 12577 97 92Ú IB MJ 12826 97 92Ú IC MJ 12976 94 911, 782,88 1 2 ID MJ 12845 . 75 61 , 49 TE MJ 12675 102 1134, 1375 IF MJ 12682 107 1035 IG MJ 12814 82 781, 802 IH MJ 12766 139 79Ú, 762 IIA (Lot 1) MJ 12678 119, 111 110 , 1355 IIA (Lot 2) 117 98Ú, 1162, 1213, 1314, 1434, IIIA MJ 12650 101 521, 51 IVA (reference- 3 19Ú unquaternized) Footnotes: 1. Compared to cholestyramine beadlets at 1% of diet. 2. Compared to cholestyramine beaalets at 0.5% of diet. 3. Compared to cholestyramine beadlets at 0.25% of diet. 4. Compared to ground cholestyramine at 1% of diet. 5. Compared to ground cholestyramine at 0.5% of diet. As indicated above, the copolymers herein contain at least about 50% of the activity of cholestyramine and preferred copolymer herein (IIA) is from 98% to 161% as effective as cholestyramine. Note also the data for reference resin IVA which indicates unquaternized copolymer has very low activity. Example IV Testing for Anti-Diarrhea Activity Compositions tested herein were the same as tested in Example III. The compositions were tested in viva in rats as follows: Male Sprague-Dawley rats (150-290 g) were dosed orally with test material 1 hour before receiving a standard dose of castor oil orally (3 ml/rat). The rats were individually caged and examined for the presence of diarrhea at hourly intervals. Control animals had a 100% incidence of diarrhea 1 hour after castor oil administration. With a dosage of 100 mg of resin per kilogram of body weight, test results were as follows: Copolymers IA, IB, ID, IE, IF, IR, IIA and IVA did not protect against diarrhea in any rats as of 1 hour after castor oil challenge. Copolymers IC and IG protected 17t of rats against diarrhea as of 1 hour after castor oil challenge but failed to protect any rats two hours after castor oil challenge. On the other hand, copolymer IIIA protected 100% of rats against diarrhea 1 hour after castor oil challenge and 17% of rats even two hours after castor oil challenge. Copolymer IIIA was tested against cholestyramine and colestipol with results as set forth in the following table: Table - Example IV Percentage of Rats Protected Against Diarrhea EMI14.1 <tb> <SEP> No. <SEP> Dose <tb> <SEP> Test <SEP> of <SEP> mg/kg <SEP> <tb> Compound <SEP> Rats <SEP> (p.o.) <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6 <SEP> irs <SEP> <tb> Copolymer <SEP> 6 <SEP> 512 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> <tb> <SEP> IIIA <SEP> <tb> <SEP> 12 <SEP> 256 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 58 <SEP> 17 <tb> <SEP> 12 <SEP> 128 <SEP> 100 <SEP> 58 <SEP> 50 <SEP> 33 <SEP> 0 <SEP> <tb> <SEP> 12 <SEP> 64 <SEP> 67 <SEP> 25 <SEP> 8 <SEP> 8 <SEP> 0 <tb> <SEP> 6 <SEP> 16 <SEP> 0 <tb> <SEP> 6 <SEP> 16 <SEP> 0 <tb> Cholestyramine <SEP> 6 <SEP> 512 <SEP> 100 <SEP> 17 <SEP> 0 <tb> <SEP> 12 <SEP> 256 <SEP> 67 <SEP> 8 <SEP> 0 <tb> <SEP> 12 <SEP> 128 <SEP> 50 <SEP> 0 <tb> <SEP> 18 <SEP> 64 <SEP> 33 <SEP> 0 <SEP> <tb> <SEP> 18 <SEP> 32 <SEP> 28 <SEP> 0 <tb> <SEP> 12 <SEP> 12 <SEP> 16 <SEP> 0 <tb> Colestipol <SEP> 6 <SEP> 512 <SEP> 83 <SEP> 0 <tb> <SEP> 6 <SEP> 256 <SEP> 50 <SEP> 0 <tb> <SEP> 6 <SEP> 128 <SEP> 17 <SEP> 17 <SEP> 17 <SEP> 17 <SEP> 17 <SEP> 17 <tb> <SEP> 6 <SEP> 64 <SEP> 33 <SEP> 0 <tb> <SEP> 6 <SEP> 32 <SEP> 0 <tb> <SEP> 6 <SEP> 16 <SEP> 0 <tb> The above results indicate that copolymer IIIA at higher dosages protects up to at least 6 hours, and that it is significantly more potent than either cholestyramine or colestipol. The data indicates an ED50 for copolymer IIIA of 50.8 (38.5-69.3) compared to ED50's for cholestyramine of 107. (68-194) and for colestipol of 213 (118-530). While the foregoing describes preferred embodiments, modifications within the scope of the invention will be readily evident to those skilled in the art. For example, the resins herein are readily combined with a pharmaceutically acceptable carrier or excipient. Thus, the scope of the invention is intended to be defined by the claims.

Claims: Patent Claims 1. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymers I containing from about 1t to about 25% of ethylene glycol dimethacrylate moieties and having polyvinylimidazolium moieties having the structural formula EMI16.1 wherein n, on average, ranges from 3 to about 40 and wherein R is selected from the group consisting of alkyl and alkenyl groups having from 1 to 18 carbon atoms and -CH2R1 wherein R1 is selected from the croup consisting of phenyl, -CH2OH, -CH2NHCOC6H5, and -CH2NR2R3 wherein R2 and R3 are each selected from the group consisting of methyl and ethyl and wherein X is an anion. 2. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 1, said copolymer containing from about 15% to about 20% of ethylene glycol dimethacrylate moieties and wherein the polyvinylimidazolium moieties have n averaging from about 3 to about 10 and wherein R is alkenyl having from two to four carbon atoms. 3. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 2, said copolymer containing about 17 & of ethylene glycol dimethacrylate moieties and wherein the polyvinylimidazolium moieties have n averaging about 5 and wherein R is prop-2-en-1-yl, and X is chloride. 4. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 1, said copolymer containing from about 1% to about 10% of ethylene glycol dimethacrylate moieties and wherein the polyvinylimidazolium moieties have n averaging from about 25 to about 35 and wherein R is alkyl having from 1 to 3 carbon atoms. 5. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 1, said copolymer containing from about 2% to about 5% of ethylene glycol dimethacrylate moieties. 6. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer is recited in Claim 5 wherein R is methyl. 7. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 6 wherein the polyvinylimidazolium moieties have n averaging from about 28 to about 32. 8. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 7 wherein X is halide. 9. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 8 wherein the polyvinylimidazolium moieties have n averaging about 30. 10. Quaternized vinylimidazole-ethylene glycol dimethacrylate copolymer as recited in Claim 9 wherein X is chloride. 11. A process for preparing the copolymer I of claims 1 - 10, which is quaternized vinylimidazoleethylene glycol dimethacrylate copolymer containing from about 1% to about 25% of ethylene glycol dimethacrylate moieties and having polyvinylimidazolium moieties having the structural formula EMI18.1 wherein n, on average, ranges from 3 to about 40 and wherein R is selected from the group consisting of alkyl and alkenyl groups having from 1 to 18 carbon atoms and -CH2R1 wherein R1 is selected from the group consisting of phenyl, -CH2OH, -CH2NHCOC6H5, and -CH2NêR wherein Rê and R are each selected from the group consisting of methyl and ethyl and wherein X is an anion, said process comprising (a) reacting 1-vinylimidazole monomer and ethylene glycol dimethacrylate monomer in the presence of a suitable polymerization catalyst under polymerization conditions so as to form a first polymerization product; and then (b) quaternizing said first polymerization product so as to form said copolymer I. 12. A process according to Claim 11, wherein said polymerization catalyst is benzoyl peroxide. 13. A process according to Claim 12, wherein the proportion of 1-vinylimidazole monomer to ethylene glycol dimethacrylate monomer used to produce said copolymer is such as to result in a copolymer containing from about 15% to about 20% of ethylene glycol dimethacrylate moieties. 14. A process according to Claim 13, wherein the proportion of 1-vinylimidazole monomer to ethylene glycol dimethacrylate monomer used to produce said copolymer is such as to result in a copolymer containing about 17% of ethylene glycol dimethacrylate moieties. 15. A process according to Claim 11 or 12, wherein the proportion of 1-vinylimidazole monomer to ethylene glycol dimethacrylate monomer used to produce said copolymer is such as to result in a copolymer containing from about 1% to about 10% of ethylene glycol dimethacrylate moieties. 16. A process according to Claim 15, wherein the proportions of monomers are such as to result in a copolymer containing from about 2% to about 5% of ethylene glycol dimethacrylate moieties. 17. A compound according to anyone of Claims 1 - 10 for use as a drug for sequestering bile acids in a mammal for lowering blood cholesterol in a mammal or for treating diarrhea in a mammal. 18. A pharmaceutical compound according to Claim 17 for use as a drug for sequestering bsse acids or for lowering blood cholesterol, wherein said copolymer I contains from about 15% to about 20% of ethylene glycol dirrethacrylate moieties. 19. A compound according to Claim 18, wherein said copolymer I contains about 178 of ethylene glycol dimethacrylate moieties. 20. A pharmaceutical composition comprising at least one of the compounds of Claims 1 - 10, optionally together with pharmaceutical carriers and/or adjuvants. 21. The pharmaceutical composition of Claim 20 in unit dosage form for sequestering bile acids in a mammal, said composition comprising a dosage of about 2 to about 5 grams of a copolymer according to Claim 2 or Claim 3. 22. The pharmaceutical composition of Claim 20 in unit dosage form for lowering the blood cholesterol level of a mammal, said composition comprising a dosage of about 2 to about 5 grams of a copolymer according to Claim 2 or Claim 3. 23. A pharmaceutical composition of Claim 20 for inhibiting diarrhea in a mammal, said composition comprising a copolymer according to Claim 4 or Claim 5 or Claim 10.

Inventors: BUYNISKI, JOSEPH P., COMER, WILLIAM T., JOHNSON, PORTER C., PIRCIO, ANTHONY W.
Applicants: BRISTOL-MYERS COMPANY
Application year: 1985
Main classification: C08F8
IPC codes: C08F8, A61K31