RU2783157C2 - Cholestyramine granules, oral cholestyramine compositions and their use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the field of medicine, namely to granules intended for being covered with a shell of one or more shell layers for targeted delivery of cholestyramine to the colon. In this case, each granule contains at least 70% wt./wt. of cholestyramine and i) a combination of at least 6% wt./wt. of a binder and at least 2% wt./wt. of acrylate copolymer; or ii) a combination of at least 5% wt./wt. of a binder and at least 3% wt./wt. of acrylate copolymer; or iii) a combination of at least 6% wt./wt. of a binder, at least 1% wt./wt. of acrylate copolymer, and from 5% to 15% wt./wt. of microcrystal cellulose. The binder includes cellulose ester, polymer based on vinylpyrrolidone, or a combination thereof. The invention also relates to a drug delivery system of a set of separate particles, including a set of cholestyramine granules. The invention also relates to an oral composition for targeted delivery of cholestyramine to the colon, including a) a set of granules, and b) a shell around the specified granules, providing release in the colon.

EFFECT: group of inventions provides cholestyramine granules, which are stable enough for application of one or more shell layers.

27 cl, 2 dwg, 1 tbl, 6 ex

Description

The invention relates to small granules containing cholestyramine. The granules have a high content of cholestyramine and are stable enough to be coated with one or more layers of the shell. The invention also relates to a multiparticulate drug delivery system comprising such granules. The invention further relates to an oral composition for targeted delivery of cholestyramine to the colon, comprising a plurality of cholestyramine granules that are coated for release in the colon. The invention also relates to the use of such a composition in the treatment of bile acid malabsorption and bile acid diarrhea.

BACKGROUND OF THE INVENTION

Bile acid malabsorption is a condition characterized by an excess of bile acids in the colon, often resulting in chronic diarrhea. Bile acids are steroid acids that are synthesized and conjugated in the liver. From the liver, they are excreted via the biliary tract into the small intestine, where they are involved in the dissolution and absorption of dietary lipids and fat-soluble vitamins. When they reach the ileum, the bile acids are reabsorbed into the portal circulation and returned to the liver. A small proportion of secreted bile acids are not reabsorbed in the ileum and reach the large intestine. Here, bacterial action leads to deconjugation and dehydroxylation of bile acids, giving secondary deoxycholate and bile acid lithocholate.

In the colon, bile acids (particularly the dehydroxylated bile acids chenodeoxycholate and deoxycholate) stimulate the secretion of electrolytes and water. This increases colonic motility and shortens colonic transit time. When present in excess, bile acids cause diarrhea with other gastrointestinal symptoms such as bloating, urgency, and fecal incontinence. There have been several recent advances in understanding this state of bile salt or bile acid malabsorption, or BAM (Pattni and Walters, Br. Med. Bull. 2009, vol 92, p. 79-93; Islam and Di Baise, Pract. Gastroenterol. 2012, 36(10), pp. 32-44). Depending on the cause of insufficient absorption of bile acids in the distal ileum, bile acid malabsorption can be divided into type 1, type 2, and type 3 BAM.

Diarrhea can also be the result of high concentrations of bile acids in the colon following treatment with drugs that increase bile acid production and/or interfere with reabsorption of bile acids in the small intestine, such as treatment with inhibitors of bile acid absorption in the ileum (IBAT).

Current treatment for bile acid malabsorption aims to bind excess bile acids in the gastrointestinal tract, starting from the proximal small intestine, thereby reducing the secretory actions of bile acids. Cholestyramine is commonly used for this purpose as a bile acid sequestrant. Cholestyramine (or cholestyramine; CAS Number 11041-12-6) is a strongly alkaline anion exchange resin that is practically insoluble in water and is not absorbed from the gastrointestinal tract. Instead, it absorbs bile acids and combines with them in the intestine to form an insoluble complex. The complex that forms when bile acids bind to the resin is excreted in the faeces. By doing so, the resin prevents the reabsorption of bile acids through the enterohepatic circulation, resulting in increased conversion of cholesterol to bile acids to replace those removed from the reabsorption process. This conversion lowers plasma cholesterol concentrations, primarily by lowering low-density lipoprotein (LDL) cholesterol.

Cholestyramine is also used as a lipid-lowering agent in the treatment of hypercholesterolemia, type II hyperlipoproteinemia, and type 2 diabetes mellitus. Moreover, it is used to relieve diarrhea associated with ileal resection, Crohn's disease, vagotomy, diabetic vagus neuropathy and radiation, and to treat pruritus in patients with cholestasis.

In the current treatment of hyperlipidaemias and diarrhea, the oral dose of cholestyramine is 12 to 24 g per day administered as a single dose or up to 4 separate doses. In the treatment of pruritus, doses of 4-8 g are usually sufficient. Cholestyramine can be administered gradually over 3-4 weeks to minimize gastrointestinal effects. The most common side effect is constipation, while other gastrointestinal side effects are bloating, abdominal discomfort and pain, heartburn, flatulence, and nausea/vomiting. There is an increased risk of gallstones due to the increased concentration of cholesterol in bile. High doses can cause steatorrhea by interfering with gastrointestinal fat absorption and concomitant reduced absorption of fat-soluble vitamins. Chronic administration may lead to an increased tendency to bleed due to hypoprothrombinemia associated with vitamin K deficiency, or may lead to osteoporosis due to impaired absorption of calcium and vitamin D. There are also isolated reports of skin rash and itching of the tongue, skin, and perianal area. . Due to poor taste and texture and various side effects, >50% of patients discontinue therapy within 12 months.

Another disadvantage of the current treatment with cholestyramine is the fact that this agent reduces the absorption of other drugs administered simultaneously, such as estrogens, thiazide diuretics, digoxin and related alkaloids, loperamide, phenylbutazone, barbiturates, thyroid hormones, warfarin and some antibiotics. Therefore, it is recommended that other drugs be taken at least 1 hour before or 4-6 hours after the administration of cholestyramine. In this case, it may still be necessary to adjust the doses of concomitantly taken drugs.

In light of these side effects, it would be desirable to formulate cholestyramine as a colonic release formulation, i. composition for the release of cholestyramine in the proximal part of the colon. Such a formulation may require a lower dose of cholestyramine and should have better texture and taste properties and therefore be better tolerated by patients. More importantly, the release of cholestyramine in the colon should be free from interactions with other drugs and should not induce risks of malabsorption of fat and fat-soluble vitamins while still binding bile acids to reduce increased secretion and colonic motility. For reasons of patient compliance with treatment regimens, it would furthermore be desirable that the number of tablets to be taken be as low as possible. Therefore, each tablet should contain as much cholestyramine as possible.

EP 1273307 describes preparations for the prevention of bile acid diarrhea comprising a bile acid absorbent coated with a polymer so as to allow release of the fatty acid absorbent from the lower small intestine to the caecum. It has been shown that cholestyramine granules coated with HPMCAS-HF or ethylcellulose exhibited excessive swelling and rupture under conditions simulating an intragastric environment.

Jacobsen et al. (Br. Med. J. 1985, vol. 290, p. 1315-1318) describes a study where 500 mg cholestyramine tablets coated with cellulose acetate phthalate (12 tablets per day) were administered to patients undergoing ileal resection. In five of the 14 patients in this study, the tablets did not break down at the desired site.

WO 2017/138876 describes granules containing at least 70% cholestyramine. Such granules contain lower amounts of vinylpyrrolidone-based polymer as a binder.

WO 2017/138877 and WO 2017/138878 describe oral compositions for targeted delivery of cholestyramine to the colon, wherein said compositions comprise a plurality of coated cholestyramine granules.

Despite progress in this area, there is still a need for further improved cholestyramine formulations. In particular, there is a need for fine cholestyramine particles that have a high cholestyramine content and are stable during the coating process.

SUMMARY OF THE INVENTION

The invention provides fine and stable granules which have a cholestyramine content of at least 70% and which are stable enough to withstand the conditions commonly used to apply one or more coating layers. In particular, the invention provides a set of granules, each granule includes at least 70% wt./mass. cholestyramine and

i. at least 7% wt./mass. astringent; or

ii. a combination of at least 6% wt./mass. binder and at least 2% wt./mass. acrylate copolymer; or

iii. a combination of at least 5% wt./mass. astringent and at least 3% wt./mass. acrylate copolymer; or

iv. a combination of at least 6% wt./mass. astringent, at least 1% wt./mass. acrylate copolymer and from 5% to 15% wt./mass. microcrystalline cellulose.

The beads may be coated with one or more coat layers which prevent the release of cholestyramine before the beads reach the colon.

In another aspect, the invention provides a particulate drug delivery system comprising a plurality of cholestyramine beads as described herein, more specifically a drug delivery system wherein the cholestyramine beads are formulated for targeted delivery to the colon.

In yet another aspect, the invention provides an oral composition for targeted delivery of cholestyramine to the colon, comprising a plurality of beads as described herein, and a colonic release coat (colon release coat) around said beads. The combination of fine granules of cholestyramine and a colonic release coating allows the dose of cholestyramine to be reduced to, for example, 1.5 g twice daily. This dose of cholestyramine is believed to be sufficient to bind excess bile acids in the colon. Therefore, the composition can be used in the treatment or prevention of bile acid malabsorption and bile acid diarrhea.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the sequestration profiles for various compositions in a study simulating the pH of the stomach and small intestine. In FIG. 1A shows the results for compositions A, B and C for 6 hours at pH 5.5. In FIG. 1B shows the results for compositions A, B and C for 2 hours at pH 1 followed by 4 hours at pH 6.8.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that fine and stable cholestyramine granules can be obtained by granulating a mixture comprising cholestyramine and an appropriate astringent. Such granules have a high content of cholestyramine and are stable enough to withstand the conditions commonly used to apply one or more coat layers.

In the first aspect, the invention relates to a set of granules, each granule includes at least 70% wt./mass. cholestyramine and

i. at least 7% wt./mass. astringent; or

ii. a combination of at least 6% wt./mass. astringent and at least 2% wt./mass. acrylate copolymer; or

iii. a combination of at least 5% wt./mass. astringent and at least 3% wt./mass. acrylate copolymer; or

iv. a combination of at least 6% wt./mass. astringent, at least 1% wt./mass. acrylate copolymer and from 5% to 15% wt./mass. microcrystalline cellulose;

where the astringent includes an agent selected from the group consisting of cellulose ethers, polymers based on vinylpyrrolidone, sucrose, lactose, carrageenan, starch, alginic acid, sodium alginate, glyceryl behenate, polyethylene oxide, chitosan, carnauba wax, gelatin, gum arabic, guar gum and polyvinyl alcohol-polyethylene glycol graft copolymer, or combinations thereof.

As used in the present description, the term "granules" refers to granules obtained by wet granulation.

It is imperative that the granules are sufficiently stable to withstand mechanical stress during processing, such as during drying and coating of the granules. Granule stability can be expressed in terms of friability, which is the ability of a solid (such as a tablet, granule, spheres, or pellets) to be reduced to smaller particles, for example, by abrasion, fracture, or deformation. A low degree of brittleness means that the solid breaks down into small particles only to a small extent. As used herein, friability is defined as the reduction in weight of granules that occurs when granules are subjected to mechanical stress such as tumbling, vibration, plasticizing, etc. Methods for measuring friability are known in the art (e.g., European Pharmacopoeia 8.0, test 2.9.41 ).

The inclusion of lower amounts of binder and/or acrylate copolymer than stated above results in lower yield and more granular friability. The brittleness is preferably less than 3.5%, such as less than 3.0%, such as less than 2.5%, or, for example, less than 2.0%, more preferably less than 1.5%, even more preferably less than 1.0%, and even more preferably less than 0.5%.

In a preferred embodiment, the invention relates to a set of granules, each granule includes at least 70% wt./mass. cholestyramine, and

i. at least 7% w/w binder; or

ii. combinations of at least 6% wt./mass. astringent and at least 2% wt./mass. acrylate copolymer; or

iii. combinations of at least 5% wt./mass. astringent and at least 3% wt./mass. acrylate copolymer; or

iv. combinations of at least 6% wt./mass. astringent and at least 1% wt./mass. acrylate copolymer and from 5% to 15% wt./mass. microcrystalline cellulose;

wherein the binder comprises cellulose ether, a vinylpyrrolidone polymer, or a combination thereof.

The cellulose ether can be any cellulose ether that is suitable for pharmaceutical and oral use. Examples of suitable cellulose ethers include methylcellulose; ethylcellulose; ethyl methylcellulose; ethylhydroxyethylcellulose (etulose); hydroxyethylcellulose; hydroxyethylcemethylcellulose; hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC or hypromellose); carboxymethyl cellulose (CMC) or their sodium salt (NaCMC); and mixtures comprising two or more of the aforementioned cellulose ethers.

The vinylpyrrolidone-based polymer may be polyvinylpyrrolidone (povidone) or a vinylpyrrolidone-vinyl acetate copolymer (copovidone). Povidone is a water-soluble polymer composed of N-vinylpyrrolidone. Copovidone (also known as copovidone) is a linear, water-soluble copolymer of 1-vinyl-2-pyrrolidone (povidone) and vinyl acetate in a 6:4 ratio by weight. In a preferred embodiment of the invention, the vinylpyrrolidone-based polymer is copovidone.

In one embodiment of the invention, the binder is a cellulose ether (ie, the binder does not include a vinylpyrrolidone-based polymer). The cellulose ether is preferably methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose, or a mixture comprising two or more of these cellulose ethers.

In another embodiment of the invention, the binder is a vinylpyrrolidone polymer (ie, the binder does not include cellulose ether). The vinylpyrrolidone polymer is preferably copovidone.

In yet another embodiment of the invention, the binder comprises both a cellulose ether and a vinylpyrrolidone polymer. The cellulose ether is preferably methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose, or a mixture comprising two or more cellulose ethers and a vinylpyrrolidone-based polymer, preferably copovidone.

The acrylate copolymer may be a pharmaceutically acceptable copolymer comprising acrylate monomers. Examples of acrylate monomers include, without limitation, acrylate (acrylic acid), methyl acrylate, ethyl acrylate, methacrylic acid (methacrylate), methyl methacrylate, butyl methacrylate, trimethylammonioethyl methacrylate, and dimethylaminoethyl methacrylate. Several acrylate copolymers are known under the trade name Eudragit®.

Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) is a copolymer of ethyl acrylate, methyl methacrylate and a low content of trimethylammonioethyl methacrylate chloride (methacrylic acid ester with quaternary ammonium groups). The copolymer is also referred to as ammoniomethacrylate copolymer. It is insoluble, but the presence of ammonium salt groups renders the copolymer permeable. The copolymer is available as a 1:2:0.2 blend (Type A) or as a 1:2:0.1 blend (Type B). 30% aqueous dispersions of type A and type B are sold under the trade names Eudragit® RL 30 D and Eudragit® RS 30 D, respectively.

Poly(methylacrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 is a copolymer of methyl acrylate, methyl methacrylate and methacrylic acid. It is insoluble in an acidic environment, but dissolves to form a salt at pH above 7.0. A 30% aqueous dispersion is sold under the trade name Eudragit® FS 30 D.

Poly(methacrylic acid-co-ethyl acrylate) 1:1 copolymer is a copolymer of ethyl acrylate and methacrylic acid. It is insoluble in acidic environments below pH 5.5, but dissolves above this pH to form a salt. A 30% aqueous dispersion is sold under the trade name Eudragit® L 30 D-55.

Additional suitable acrylate copolymers include poly(ethyl acrylate-co-methyl methacrylate) 2:1, which is a water-insoluble copolymer of ethyl acrylate and methyl methacrylate. 30% aqueous dispersions are sold under the trade names Eudragit® NE 30 D and Eudragit® NM 30 D.

Preferred acrylate copolymers are ammoniomethacrylate copolymer, poly(methylacrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1, and poly(methacrylic acid-co-ethyl acrylate) 1:1. More preferably the acrylate polymer is an ammoniomethacrylate copolymer and most preferably the acrylate polymer is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2.

The granules of alternatives i-iii may further include an excipient such as microcrystalline cellulose. Microcrystalline cellulose, or MCC, is purified, partially depolymerized cellulose with shorter crystalline polymer chains. Its binding properties make MCC one of the most commonly used excipients and binders in drug formulations. In one embodiment of the invention, the granules of alternative i-iii include up to 10% wt./mass. microcrystalline cellulose, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% wt./mass. microcrystalline cellulose. In another embodiment of the invention, the granules of alternatives i-iii include up to 5% wt./mass. microcrystalline cellulose. In another embodiment of the invention, the granules of alternatives i-iii do not contain microcrystalline cellulose.

Granules alternative iv include from 5% to 15% wt./mass. microcrystalline cellulose, and preferably include at least 10% wt./mass. microcrystalline cellulose, i.e. 10, 11, 12, 13, 14 or 15% w/w microcrystalline cellulose.

The granules are screened to obtain a granule fraction with a suitable size distribution. The diameter of the cholestyramine granules is preferably 500 µm to 3000 µm, more preferably 750 µm to 2000 µm, and even more preferably 1000 to 1600 µm. In the most preferred embodiment of the invention, the diameter of the granules is from 1000 to 1400 microns.

Due to its physical nature, cholestyramine powder is capable of absorbing large amounts of water, resulting in significant swelling of the material. In order to obtain a wet mass from dry cholestyramine, therefore, it is necessary to add more water than is usually used to obtain a wet mass from dry ingredients. Preferably, water is added to the dry ingredient mixture in an amount of at least 1.5 times the amount of cholestyramine (w/w), more preferably in an amount of at least 1.75 times the amount of cholestyramine (w/w), and even more preferably in an amount of 2 times the amount of cholestyramine (w/w).

Uncoated granules are rapidly destroyed in aqueous conditions. However, they are stable enough to withstand the conditions required to apply one or more coating layers to the pellets.

Since cholestyramine granules must bind excess bile acids in the colon, they must be formulated for colon-targeted delivery. This can be achieved by coating the cholestyramine beads with one or more layers that delay the release of the cholestyramine until the beads reach the colon.

Therefore, in another aspect, the invention relates to a single particle drug delivery system comprising a plurality of cholestyramine beads as described herein. In a preferred embodiment of the invention, the cholestyramine beads are formulated for delivery targeted to the colon. The beads are then coated with one or more coat layers which delay the release of cholestyramine from the beads until the coated beads reach the colon, in particular the proximal colon. In one embodiment of the invention, delivery targeted to the colon is based on enzyme controlled release of the granules. In another embodiment of the invention, colon-targeted delivery is based on pH or diffusion controlled release of the granules.

Due to its very low solubility, cholestyramine is not "released" from the composition comprising the coated cholestyramine granules, in which it dissolves from the composition and diffuses into the intestine. Instead, cholestyramine is likely to remain in the gradually degrading structure of the coated granules. Therefore, as used herein, the term “release” of cholestyramine refers to the availability of cholestyramine to intestinal contents to bind components (ie, bile acids) therein.

In another aspect, the invention relates to an oral composition for targeted delivery of cholestyramine to the colon, comprising

A) many granules, as described in the present description; and

b) Colon release coating around said granules.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine into the colon,

where more than 70% of cholestyramine is released in the colon.

In some embodiments of the invention, more than 75% of cholestyramine is released in the colon. In other embodiments, more than 80% of the cholestyramine is released in the colon. In other embodiments, more than 85% of the cholestyramine is released in the colon. In yet other embodiments, more than 90% of the cholestyramine is released in the colon.

In yet another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine into the colon,

where less than 30% of cholestyramine is released in the small intestine.

In some embodiments, less than 25% of the cholestyramine is released in the small intestine. In other embodiments, less than 20% of the cholestyramine is released in the small intestine. In other embodiments of the invention, less than 15% of cholestyramine is released in the small intestine. In yet another embodiment of the invention, less than 10% of cholestyramine is released in the small intestine.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine in the colon,

where the granules show a friability of less than 3.5% when measured using the European Pharmacopoeia 8.0, test 2.9.41.

In some embodiments, the granules exhibit less than 3.0% friability. In other embodiments, the granules exhibit less than 2.5% friability. In other embodiments of the invention, the granules exhibit a fragility of less than 2.0%. In other embodiments, the granules exhibit less than 1.5% friability. In other embodiments, the granules exhibit less than 1.0% friability. In still other embodiments, the granules exhibit less than 0.5% friability.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine into the colon,

where less than 30% of cholestyramine is released after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In some embodiments, less than 25% of cholestyramine is released after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, less than 20% cholestyramine is released after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, less than 15% cholestyramine is released after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In another embodiment, less than 10% cholestyramine is released after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine in the colon,

where the composition shows less than 30% sequestration of cholic acid after 6 hours at pH 5.5, as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In some embodiments, the composition exhibits less than 25% cholic acid sequestration after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits less than 20% cholic acid sequestration after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In yet other embodiments, the composition exhibits less than 15% cholic acid sequestration after 6 hours at pH 5.5 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine into the colon,

where the composition shows more than 30% sequestration of cholic acid after 2 hours at pH 1 followed by 4 hours at pH 6.8, as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In some embodiments, the composition exhibits greater than 35% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 6.8 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits greater than 40% sequestration of cholic acid after 2 hours at pH 1 followed by 4 hours at pH 6.8 as measured using USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3. In still other embodiments, the composition exhibits greater than 45% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 6.8 as measured using USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3. In yet other embodiments, the composition exhibits greater than 50% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 6.8 as measured using USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine in the colon,

where the composition shows less than 30% sequestration of cholic acid after 2 hours at pH 1, as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In some embodiments, the composition exhibits less than 25% cholic acid sequestration after 2 hours at pH 1 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits less than 20% cholic acid sequestration after 2 hours at pH 1 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits less than 15% cholic acid sequestration after 2 hours at pH 1 as measured using USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3. In yet other embodiments, the composition exhibits less than 10% cholic acid sequestration after 2 hours at pH 1 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In yet another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding said granules, wherein the shell is capable of targeting the release of cholestyramine in the colon,

where the composition shows more than 30% sequestration of cholic acid after 2 hours at pH 1 followed by 4 hours at pH 7.4, as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

In some embodiments, the composition exhibits greater than 35% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 7.4 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits greater than 40% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 7.4 as measured using USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3. In other embodiments, the composition exhibits greater than 45% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 7.4 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3. In yet other embodiments, the composition exhibits greater than 50% cholic acid sequestration after 2 hours at pH 1 followed by 4 hours at pH 7.4 as measured using USP Dissolution Apparatus 2 (blade) Ph. Eur. 2.9.3.

The colonic release coat should also prevent the rupture of the cholestyramine granules. When the water that diffuses through the shell is absorbed by the cholestyramine, the increasing volume of the cholestyramine causes the granules to swell. The shell of the granules must therefore be elastic enough to resist swelling of the granules. By preventing the rupture of the granules, the shell resists the premature release of cholestyramine.

The colonic release coating consists of one or more coating layers that delay the availability of cholestyramine to intestinal contents before the granules reach the desired portion of the colon. Techniques based on bacterial environment (i.e. enzyme controlled release) or pH (pH controlled release), based on gradual shell erosion (time controlled release), or based on diffusion through a permeable film (diffusion controlled release), or a combination of two or more of the above techniques can be used to control the site of release and the rate of release of the granules.

Coated for Enzyme Controlled Release

In one embodiment of the invention, the colonic release shell around the beads allows for enzyme controlled release of cholestyramine in the colon. The shell layer includes a biodegradable polymer that is degraded by bacterial enzymes present in the colon, but which is not degraded by human enzymes present in the gastrointestinal tract. The release of cholestyramine from the beads is therefore triggered by changes in the bacterial environment and is essentially prevented before the coated beads reach the colon.

The biodegradable polymer can also be an azo polymer or a polysaccharide. Examples of bacterially degradable polysaccharides include chitosan, pectin, guar gum, dextran, inulin, starch and amylose and their derivatives (Sinha and Kumria, Eur. J. Pharm. Sci. 2003, vol. 18, p. 3-18). The colonic release shell preferably includes starch.

The starch structure typically comprises 20-30% (w/w) amylose, which is more difficult to degrade by the intestinal microbiota, and 70-80% (w/w) amylopectin, which is readily degraded by the intestinal microbiota. Therefore, depending on the specific amounts of amylose and amylopectin present in the structure, different types of starch have different degradation profiles. Resistant starch has a high amylose content and is not normally digested in the small intestine. Such starch is instead digested by bacteria in the colon. Depending on the natural source of starch and its processing, resistant starch can be divided into four types (RS1-RS4), each with different properties. Type 2 resistant starch (RS2), such as high amylose maize starch (or high amylose corn starch) is less accessible to enzymes due to the conformation of the starch. The colonic release coat around the cholestyramine granules includes resistant starch type 2 (RS2). When RS2 is cooked or heated, the rearrangement of the crystal structures of amylose and amylopectin occurs in a process called retrogradation, resulting in type 3 resistant starch (RS3).

In addition to the biodegradable polymer, the shell layer includes one or more additional organic polymers. Examples of suitable organic polymers include, without limitation, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit® FS 30 D), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1: 2:0.2 (Eudragit® RL 30 D), poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit® RS 30 D), poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit ® NE 30 D or Eudragit® NM 30 D) and poly(vinyl acetate) (eg Kollicoat® SR 30 D). Preferably the organic polymer is poly(methylacrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 (Eudragit® FS 30 D).

Shell controlled by pH and diffusion

In another embodiment of the invention, the colonic release shell allows pH and diffusion controlled release of cholestyramine in the colon. The shell includes an inner layer of the shell controlled by diffusion around the granules and enteric (pH-controlled) outer layer of the shell.

The inner layer of the shell, controlled by diffusion, provides a modified release of cholestyramine, i.e. cholestyramine is not immediately available, but over a long period of time. The shell includes one or more polymers which are insoluble at any pH but which are permeable to water and the small molecules dissolved therein. Examples of such polymers include, without limitation, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2 :0.1 (Eudragit® RS 30 D), poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit® NE 30 D or Eudragit® NM 30 D) and polyvinyl acetate (Kollicoat® SR 30 D). The inner layer of the diffusion controlled shell preferably comprises poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1 :2:0.1 (Eudragit® RS 30 D) or a combination thereof and most preferably poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1.

The enteric coating layer includes a pH-sensitive polymer that is stable and insoluble at acidic pH values in the stomach (pH ~ 1-3), but rapidly degrades or becomes soluble at less acidic pH values, such as pH values in the small intestine (pH ~ 6-7). Examples of such pH sensitive polymers include, without limitation, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, poly(methacrylic acid-co-methyl methacrylate) 1:1 (Eudragit® L 100), poly(methacrylic acid-co-methyl methacrylate ) 1:2 (Eudragit® S 100), poly(methacrylic acid-co-ethylacrylate) 1:1 (Eudragit® L 100-55), poly(methylacrylate-co-methylmethacrylate-co-methacrylic acid) 7:3: 1 (Eudragit® FS 30 D), polyvinyl acetate phthalate, shellac, sodium alginate, and zein, and mixtures thereof. The enteric coating preferably comprises a pH sensitive polymer selected from the group consisting of poly(methacrylic acid-co-methyl methacrylate) 1:1, hydroxypropyl methylcellulose acetate succinate and poly(methacrylic acid-co-methyl methacrylate) 1:2. The enteric coating most preferably comprises hydroxypropyl methylcellulose acetate succinate.

When water is absorbed by cholestyramine, the increasing volume of cholestyramine causes the granules to swell. The enzyme controlled shell layer or the diffusion controlled inner shell layer must therefore be elastic (ie have a high elongation at break). Due to the elasticity of the shell layers, the shell is able to withstand such swelling. Therefore, granule rupture and premature release of cholestyramine are avoided. The elasticity of the shell may result from the elasticity of the organic polymer(s) as such, or may be induced by the addition of a plasticizer. Examples of suitable plasticizers include, without limitation, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, and dibutyl sebacate.

In order to improve adhesion of the shell layer to the cholestyramine beads, or to minimize interaction between the shell layer(s) and the cholestyramine in the beads, an additional barrier shell layer may optionally be present between the bead and the shell layer. A barrier layer of the shell may also be present when two different layers of the shell are to be physically separated from each other. A particularly suitable material for the barrier layer of the shell is hydroxypropyl methylcellulose (HPMC).

The controlled release shell layer(s) and optional barrier shell layer(s) may include one or more additives such as acids and bases, plasticizers, glidants, and surfactants. Examples of suitable acids include organic acids such as citric acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid. , glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid and oxalic acid, and inorganic acids such as hydrochloric acid , hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Examples of suitable bases include inorganic bases such as sodium bicarbonate, sodium hydroxide and ammonium hydroxide. Examples of suitable plasticizers include triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, and dibutyl sebacate. Examples of suitable glidants include talc, glyceryl monostearate, oleic acid, medium chain triglycerides and colloidal silicon dioxide. Examples of suitable surfactants include sodium dodecyl sulfate, polysorbate 80, and sorbitol monooleate.

A thin layer of non-tacky agent may eventually be applied to the coated beads. Such an outer layer prevents the coated granules from sticking together, for example during storage. Examples of suitable non-tacky materials include colloidal silicon dioxide, talc and magnesium stearate.

Coating layers can be applied to the cholestyramine beads by methods known in the art, for example, by film coating, including perforated bowls and fluidized substrates.

The colonic release coating essentially prevents the release of cholestyramine from the granules before they reach the colon. Preferably, there should be no exposure to cholestyramine in the small intestine, while exposure should be rapid as individual particles pass through the ileocecal valve. In one embodiment of the invention, less than 30% of the cholestyramine is released in the small intestine, such as less than 20%, such as less than 10%. In a more preferred embodiment of the invention, less than 5% of the cholestyramine is released in the small intestine. In another embodiment of the invention, more than 70% of the cholestyramine is released in the colon, eg more than 80%, eg more than 90%. In a more preferred embodiment of the invention, more than 95% of the cholestyramine is released in the colon.

The colonic release coating adds extra bulk and bulk to the pellets. The smaller the granule size, the greater the contribution of the shell to the volume of the final composition. However, due to patient adherence to treatment, it is desirable that the total volume of the composition be kept as low as possible. Therefore, the sheath layer(s) should be as thin as possible. Preferably, the amount of shell in the final composition (based on dry weight) is less than 50% w/w, more preferably less than 45% w/w, more preferably less than 40% w/w. and even more preferably less than 35% wt./mass.

The content of cholestyramine granules should be as high as possible. Therefore, uncoated granules preferably contain at least 75% wt./mass. cholestyramine, more preferably at least 80% w/w cholestyramine, even more preferably at least 85% w/w cholestyramine, and most preferably at least 90% w/w. cholestyramine. The cholestyramine content of the final composition (based on dry weight) is preferably at least 50% wt./mass., and more preferably at least 55% wt./mass.

The oral composition described herein may be administered to a patient in various forms, depending on factors such as the age and general physical condition of the patient. For example, the composition may be administered in the form of one or more capsules containing coated granules. Such capsules typically include a degradable material such as gelatin, hydroxypropyl methylcellulose (HPMC), pullulan, or starch, which is easily broken down by the acidic conditions of the stomach. The coated granules are thereby rapidly released in the stomach. Therefore, in one aspect, the invention relates to a capsule comprising an oral composition as described herein.

Alternatively, the coated granules can be administered as a spray composition, the content of which can be dispersed in a liquid or soft food. Such a composition does not require the swallowing of larger capsules and is therefore particularly beneficial to infants and young children as well as older adults. Therefore, in another aspect, the invention relates to a sprayable composition comprising an oral composition as described herein. In such a composition, the coated granules may be contained in a capsule, sachet or stick pack.

The oral composition described herein provides some advantages over other compositions. The fine coated granules (individual particles) of the present invention are able to easily pass through the gastrointestinal tract. This eliminates the risk that the composition is temporarily retained in the gastrointestinal tract, eg in the stomach or in the ileocecal valve, which is sometimes the case with monolithic compositions (such as tablets or capsules that do not break down in the stomach). Moreover, cholestyramine becomes available to the intestinal contents only when the colonic release coat begins to break down in the lower gastrointestinal tract, in particular the colon. The contents of the stomach and small intestine are therefore effectively protected from cholestyramine, which is a major improvement over compositions that directly release cholestyramine in the stomach or small intestine. Since cholestyramine becomes available to intestinal contents only after reaching the colon, the oral composition described herein also reduces undesirable interactions of cholestyramine with other components in the gastrointestinal tract, such as other drugs or nutrients.

The low solubility of cholestyramine in an aqueous environment prevents the release of cholestyramine from the composition for direct measurement. The availability of cholestyramine to intestinal contents over time at various pH values can instead be determined in vitro, for example by measuring the sequesterability of the composition under simulated gastrointestinal conditions. Such a method includes measuring the reduced amount of free bile acids (ie, the compound that is being sequestered) in a liquid medium characteristic of the gastrointestinal tract, as described in the experimental section. See also Official Monograph for cholestiramine resin (USP 40, page 3404).

For example, the sequestering capacity of cholestyramine compositions can be studied using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) developed by ProDigest (Ghent, Belgium). As described in more detail in the experimental section, this model allows in vitro evaluation of the bile acid binding capacity of cholestyramine formulations under physiological conditions characteristic of the fasting stomach, small intestine, and proximal colon. Bile acids such as cholic acid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acid (DCA) may be used in such studies, or a mixture of two or more of these bile salts. A 40:40:20 (w/w) mixture of CA, CDCA and DCA is preferably used as a representative mixture of human bile salts. Experiments with cholestyramine formulations should be run in parallel with a control experiment to which no cholestyramine is added in order to monitor the degradation of bile acids under the conditions used in the assay. For each experiment, samples are obtained at selected intervals and the concentration of bile acids in the samples is determined, for example, by HPLC. From these data, the percentage of bile acids remaining in each test sample can be calculated as the ratio of test sample value to control sample value at the appropriate incubation time:

A graph of the percentage of bile acids remaining over time will show the decrease in bile acids, i.e. sequestration of bile acids by cholestyramine compositions during incubation in the small intestine and colon.

In another aspect, the invention relates to an oral composition comprising:

a) a plurality of granules, each granule comprising cholestyramine; and

b) a shell surrounding each granule, where the shell is capable of targeting the release of cholestyramine in the colon;

wherein the oral composition as used herein exhibits greater than about 30% sequestration of one or more of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours of enteric incubation as measured by the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model.

In some embodiments, the oral composition exhibits less than about 25% sequestration of one or more of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours of incubation in the small intestine, as measured by the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model. In other embodiments, oral compositions exhibit less than about 20% sequestration of one or more of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours of incubation in the small intestine, as measured by the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model. In yet other embodiments, the oral compositions exhibit less than about 15% sequestration of one or more of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours of incubation in the small intestine, as measured by the Simulator of the Human Intestinal Microbial Ecosystem (SHIME).

In another aspect, the invention relates to a composition described herein for use in the treatment or prevention of bile acid malabsorption.

The invention also relates to the use of a composition described herein in the preparation of a medicament for the treatment or prevention of bile acid malabsorption, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of the composition described herein.

Bile acid malabsorption can be classified into three different types, depending on the cause of the inability of the distal ileum to absorb bile acids. Type 1 BAM is the result of disease (terminal) of the ileum (such as Crohn's disease) or resection or anastomosis of the (terminal) ileum. BAM type 2 is often referred to as idiopathic bile acid malabsorption or primary bile acid diarrhea (BAD) and is thought to be the result of excess bile acid production or caused by defective feedback inhibition of bile acid synthesis in the liver. This feedback regulation in humans is mediated by the ileal hormone fibroblast growth factor 19 (FGF19). Finally, type 3 BAM can result from cholecystectomy, vagotomy, small bowel bacterial overgrowth (SIBO), celiac disease, pancreatic insufficiency (chronic pancreatitis, cystic fibrosis), pancreatic transplantation, radiation enteritis, collagenous colitis, microscopic colitis, lymphocytic colitis, ulcerative colitis or irritable bowel syndrome (IBS-D)).

The composition may also be used in combination with an ileal bile acid absorption inhibitor (IBAT). Treatment with IBAT inhibitors, e.g. in the treatment of liver diseases, disorders of fatty acid metabolism, or disorders of glucose utilization, may lead to elevated levels of bile acids and/or affect the reabsorption of bile acids by the small intestine, leading to a high concentration of bile acids in the colon and thus causing diarrhea. Such a side effect of treatment with IBAT inhibitors can be cured or prevented by treatment with a composition as described herein. The composition and the IBAT inhibitor may be administered simultaneously, sequentially or separately.

Therefore, in another aspect, the invention provides a composition as described herein for use in the treatment or prevention of diarrhea following oral administration of an IBAT inhibitor.

The invention also relates to the use of the composition described herein in the preparation of a medicament for the treatment or prevention of diarrhea upon oral administration of an IBAT inhibitor. The invention further relates to a method for treating or preventing diarrhea upon oral administration of an IBAT inhibitor, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of an IBAT inhibitor and a composition described herein.

In a preferred embodiment, the invention provides a composition as described herein for use in the treatment or prevention of bile acid diarrhea in the treatment of liver diseases such as cholestatic liver disease, comprising oral administration of an IBAT inhibitor. In particular, the invention relates to a composition described herein for use in the treatment or prevention of diarrhea in the treatment of Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, cholestatic pruritus, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH) involving oral administration of an IBAT inhibitor.

In another embodiment, the invention relates to a method of treating or preventing diarrhea of bile acids in the treatment of liver disease, comprising oral administration of an IBAT inhibitor, comprising administering to a mammal in need of such treatment or prevention, a therapeutically effective amount of a composition described herein. In particular, the invention relates to such a method for treating or preventing diarrhea, wherein the liver disease is Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, cholestatic pruritus, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

Liver disease, as defined herein, is any bile acid dependent disease of the liver and associated organs such as the pancreas, portal vein, liver parenchyma, intrahepatic bile ducts, extrahepatic bile ducts, and gallbladder. Liver diseases include, without limitation, hereditary metabolic liver diseases; congenital disorders of the synthesis of bile acids; congenital anomalies of the biliary tract, biliary atresia; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; secondary defect in BA synthesis; Zellweger's syndrome; cystic fibrosis (manifestations in the liver); alpha-1 antitrypsin deficiency; Alagille syndrome (ALGS); Bieler's syndrome; primary defect in bile acid synthesis (BA); progressive familial intrahepatic cholestasis (PFIC) including PFIC-1, PFIC-2, PFIC-3 and unspecified PFIC; benign recurrent intrahepatic cholestasis (BRIC) including BRIC1, BRIC2 and unspecified BRIC; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; general cholestasis; jaundice during pregnancy; jaundice due to drugs; intrahepatic cholestasis; extrahepatic cholestasis; primary sclerosing cholangitis (PSC); gallstones and choledocholithiasis; malignant neoplasms that cause obstruction of the biliary tract; itching due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnant women; medicinal hepatitis; iron overload disorders; hepatic fibrosis; hepatic cirrhosis; amyloidosis; viral hepatitis; and problems associated with cholestasis due to tumors and neoplasms of the liver, biliary tract and pancreas.

Fatty acid metabolism disorders and glucose utilization disorders include, without limitation, hypercholesterolemia, dyslipidemia, metabolic syndrome, obesity, fatty acid metabolism disorders, glucose utilization disorders, disorders involving insulin resistance, and type 1 and type 2 diabetes mellitus.

IBAT inhibitors are often referred to by various names. As used herein, the term "IBAT inhibitors" is to be understood as also encompassing compounds known in the literature as sodium apical bile acid transporter inhibitors (ASBTI's), bile acid transporter (BAT) inhibitors, inhibitors of the ileal sodium/biliary bile acid cotransporter system. gut, sodium-bile acid apical cotransporter inhibitors, sodium-dependent bile acid transport inhibitors in the ileum, bile acid reabsorption inhibitors (BARI's), and sodium bile acid transporter inhibitors (SBAT).

IBAT inhibitors that may be used in combination with the bile acid sequestrant composition described herein include, without limitation, benzothiazepines, benzothiepines, 1,4-benzothiazepines, 1,5-benzothiazepines, and 1,2,5-benzothiazepines.

Suitable examples of IBAT inhibitors that can be used in combination with the bile acid sequestrant composition described herein include, without limitation, the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188 WO 96/08484 WO 96/16051 WO 97/33882 WO 98/03818 WO 98/07449 WO 98/40375 WO 99/35135 WO 99/64409 WO 99/64410 WO 00/47568 , WO00/61568, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68096, WO 02/32428, WO 03/061663, WO 2004/006899, Wo 2007/009655, Wo 2007/009656, DE 19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP 624593, EP 624594, EP 624595, EP 624596, EP 0864582, EP 1173205 and EP 1535913.

Particularly suitable IBAT inhibitors are those described in WO 01/66533, WO 02/50051, WO 03/022286, WO 03/020710, WO 03/022825, WO 03/022830, WO 03/091232, WO 03/106482 and WO 2004/076430, and especially compounds selected from the group consisting of:

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4 ,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)- hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxypropyl)carbamoyl]-4- hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl] -4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine;

or their pharmaceutically acceptable salts.

Other particularly suitable IBAT inhibitors are those described in WO99/32478, WO00/01687, WO01/68637, WO03/022804, WO 2008/058628 and WO 2008/058630, and especially compounds selected from the group consisting of:

1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxydo-1-benzothiepine -5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octanemethanesulfonate;

1-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxydo-1-benzothiepin-5-yl ]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicycloo[2.2.2]octane chloride;

1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1 -dioxydo-1-benzothiepin-5-yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol; and

potassium ((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy -1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]ureido}-3,5-dihydroxy-tetrahydropyran-2-ylmethyl)sulfate, ethanolate, hydrate.

An effective amount of a cholestyramine composition of the invention may be any amount containing greater than or equal to about 100 mg of cholestyramine, such as greater than or equal to about 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg or 2000 mg cholestyramine. For example, an effective amount of cholestyramine may be 100 mg to 5000 mg, such as 250 mg to 2500 mg, 250 mg to 2000 mg, 500 mg to 2500 mg, 500 mg to 2000 mg, or 750 mg to 2000 mg. .

A unit dose of a cholestyramine composition of the invention may include 200 to 300 mg of cholestyramine, eg 220 to 280 mg of cholestyramine, eg 240 to 260 mg of cholestyramine. The unit dose preferably includes about 250 mg of cholestyramine. The daily dose may be administered in a single dose or divided into one, two, three or more unit doses.

The frequency of administration of the composition as described herein can be any frequency that reduces the bile acid malabsorption condition without causing any significant adverse events or toxicity to the patient. The frequency of administration may vary from once or twice a week to several times a day, such as once a day or twice a day. The frequency of administration may, moreover, remain constant or change during the course of treatment.

Several factors can influence the frequency of administration and the effective amount of the composition to be used for a particular application, such as the severity of the condition being treated, the duration of treatment, and the age, body weight, sex, diet, and general medical condition of the patient being treated.

The invention is further illustrated by the following examples, which do not limit the invention in any way. All cited documents and references are incorporated herein by reference.

EXAMPLES

Example 1

Receiving granules

All experiments were performed in a 200 g volume. The dry ingredients (cholestyramine and copovidone; see amounts in Table 1 below) were mixed in Kenwood Patissier for 1 minute. When Eudragit® RL 30 D (30% aqueous dispersion) was included in the experiment, the appropriate amount of the dispersion was diluted with water to a total weight of about 300 grams. The water or diluted Eudragit dispersion was then added to the dry ingredients in three portions of about 100 grams with 3 minutes of stirring after each addition. Thereafter, an additional portion of pure water (60 to 100 g) was added, so that the total amount of water added was about 2.1 times the amount of cholestyramine (w/w). After mixing for 1 minute, the wet mass was transferred to a stainless steel tray and dried in a drying oven at 50° C. overnight.

The dried material was ground in a Quadro Comil U5 equipped with a 4 mm sieve and operated at 1000 rpm (revolutions per minute). The granules were sieved and a fraction of 1.0 to 1.6 mm was collected. The fraction that was greater than 1.6 mm was returned to the mill and ground again.

Friability testing was carried out using the equipment and procedure described in European Pharmacopoeia 8.0, test 2.9.41. The granules were sieved on a 500 µm sieve to remove any dust before weighing. The results are shown in Table 1 below.

Table 1

Entrance Quantity (% w/w) Exit (%) fragility Cholestyramine Copovidone MSS Eudragit® RL 30 D* one 85 7.5 4.5 3 45 1.5 2 93 7 0 0 43 2.0 3 92 6 0 2 46 1.7 four 92 5 0 3 46 0.8 5** 83 6 ten one 49 3.1

* Quantity refers to the weight of dry polymer

** The total amount of water was about 2.4 times the amount of cholestyramine (w/w)

Coating experiments (such as in Examples 3 and 4 below) confirmed that the resulting pellets were sufficiently stable to be coated with one or more shell layers.

Example 2

Cholestyramine Granule Destruction Study

The granules of example 1 (10 g) were added to 400 ml of phosphate buffer (50 mm, pH 6.8) with stirring at 300 rpm using a propeller stirrer. The time until complete destruction of the granules was measured.

Example 3

Compositions A-C for Enzyme Controlled Release

The cholestyramine granules of example 1 entry 1 were formulated with a colonic release coating based on Eudragit® FS 30 D and natural high amylose maize starch.

The composition of the granules for a standard dose comprising 250 mg of cholestyramine is shown below.

Ingredient Amount (mg/dose) Cholestyramine 250 Copovidone (Kollidon® VA64 small) 22.1 Microcrystalline cellulose (Avicel® PH102) 13.2 Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D) 8.8 Total 294.1

For the shell, a glycerol monostearate (GMS) emulsion containing GMS, polysorbate 80 and triethyl citrate was prepared according to the general instructions from Evonik. The emulsion was then mixed with Eudragit® FS 30 D (30% aqueous dispersion). The composition of the Eudragit FS 30 D coating dispersion based on dry weight is shown below. The concentration based on dry weight is 19.8% (w/w).

Ingredient Amount (mg/dose) Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylic acid) 7:3:1 (Eudragit® RL 30 D) 90.4 triethyl citrate 4.5 Glycerin monostearate 45-55 (Kolliwax® GMS II) 3.6 Polysorbate 80 (Tween® 80) 1.5

The pH of the dispersion was adjusted with 0.3 M NaOH solution to 5.5. The dispersion was mixed with a suspension of natural starch granules containing 12.9% starch, 0.1% Kolliphor® SLS fine and water. The Eudragit® dispersion was mixed with the starch slurry so that the ratio between polymer film and starch in the final film was 60% starch to 40% Eudragit® FS 30 D film. The sheath composition based on dry weight is shown below. The concentration, based on the dry weight of the dispersion used, is 15% (w/w).

Ingredient Amount (mg/dose) Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylic acid) 7:3:1 (Eudragit® RL 30 D) 36.0 High amylose maize starch (Hylon® VII) 59.7 triethyl citrate 1.8 Glycerin monostearate 45-55 (Kolliwax® GMS II) 1.4 Polysorbate 80 (Tween® 80) 0.6 Sodium lauryl sulfate (Kolliphor® SLS fine) 0.5 NaOH Qs pH 5.5

The shell layer was applied using a Huttlin Kugelcoater HKC005. The initial batch size was 65 g. The coating process was carried out with an inlet air temperature of 47-52°C, resulting in a product temperature of 27-29°C. The air flow was adjusted to achieve adequate fluidization of the pellets during coating.

The shell was applied to the granules of cholestyramine so as to obtain a weight gain of ~50% (composition A), ~75% (composition B) or ~100% (composition C). After coating, the granules were heat treated at 40° C. for 2 hours.

Coated granules may be encapsulated in capsules, such as hard gelatin capsules. Details of the final compositions (based on dry weight) are shown below:

Composition A Composition B Composition C Dose mass 441 mg 515 mg 588 mg Cholestyramine 250 mg (57%) 250 mg (49%) 250 mg (43%) Shell 147 mg (33%) 221 (43%) 294 mg (50%)

Example 4

D-F formulations for pH and diffusion controlled release

The cholestyramine granules of Example 1 were formulated with a colonic release coating comprising a diffusion controlled poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) inner coating and an enteric outer coating based on hydroxypropyl methylcellulose acetate succinate.

Three compositions were prepared with different amounts of poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in the inner shell, as follows:

Composition D: 100% Eudragit® RL 30 D Composition E: 50% Eudragit® RL 30 D+50% Eudragit® RS 30 D Composition F: 100% Eudragit® RS 30 D

The composition of the granules for a standard dose comprising 250 mg of cholestyramine is shown below.

Ingredient Amount (mg/dose) Cholestyramine 250 Copovidone (Kollidon® VA64 small 22.1 Microcrystalline cellulose (Avicel® PH102) 13.2 Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D) 8.8 Total 294.1

Inner shell

An emulsion of glycerol monostearate (GMS) containing GMS, polysorbate 80 and triethyl citrate was prepared according to the general instructions from Evonik. The emulsion was mixed with a dispersion of Eudragit RL30D/RS30D (30% w/w). The composition of the inner film shell based on dry weight is shown below. The concentration based on the dry weight of the applied dispersion is 19.8% (w/w).

Ingredient Amount (mg/dose) Inner shell Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D) or 1:2:0.1 (Eudragit® RS 30 D) 90.4 triethyl citrate 4.5 Glycerol monostearate 45-55 (Kolliwax® GMS II) 3.6 Polysorbate 80 (Tween ® 80) 1.5

The sheath layer is applied using a Huttlin Kugelcoater HKC005; batch size 75 g. The coating process was carried out with an inlet air temperature of 45°C, giving a product temperature of 27-29°C. The air flow is adjusted to achieve proper lyophilization of the pellets during coating. The shell is applied to the granules so as to obtain a weight gain of 10%. After coating the shell, the granules were treated with heat at 40°C for 24 hours.

Outer shell

Enteric shell was obtained by mixing 7% wt./mass. hypromellose acetate succinate, 2.45% w/w triethylcitrate, 2.1% w/w talc, 0.21% w/w sodium lauryl sulfate and 88.24% wt./mass. water for 30 min with an overhead stirrer at a low temperature <15°C. The composition of the outer film coat, based on dry weight, is shown below. The liquid shell was kept below 15° C. during the coating process.

Ingredient Quantity (w/w) Outer shell Hypromellose acetate succinate (AQOAT AS HF) 59.5 triethyl citrate 20.8 Talc, micronized 17.9 Sodium lauryl sulfate (Kollipor® SLS fine) 1.8

The shell layer was applied using a Huttlin Kugelcoater HKC005; batch size 75 g. The coating process was carried out with an inlet air temperature of 55°C, giving a product temperature of 32°C. The air flow was adjusted to achieve proper lyophilization of the pellets during coating. The enteric coating was applied to the granules so as to obtain a weight gain of 40% (based on the weight of the coated granules after application of the inner coating). After coating, the pellets were heated at 40° C./75% RH for 48 hours.

Coated granules may be encapsulated in capsules, such as hard gelatin capsules. Details for final compositions (based on dry weight) are shown below:

Dose weight 452.9 mg Cholestyramine 25 mg (55%) Inner shell 29.4 mg Outer shell 129.4 mg Whole shell 158.8 mg (35%)

Example 5

Sequestration analysis

The sequestering abilities of compositions A, B and C were determined in a simplified analysis simulating the pH of the stomach and small intestine. Sequestration was determined by measuring the decreasing amount of cholic acid in aqueous solution. Used USP Dissolution Apparatus 2 (bladed) Ph. Eur. 2.9.3.

Sequestration at pH 5.5

An amount of composition A, B, or C corresponding to 250 mg of cholestyramine was added to a vessel containing 500 ml of cholic acid buffer (0.192 mg/ml), pH 5.5, and the contents were stirred at 75 rpm for 6 hours. Solution samples were taken at various time points and analyzed for cholic acid by HPLC using a Thermo Hypersil Gold column, 50 mm x 2.1 mm, particle size 1.9 µm; column temperature 60°C; mobile phase 30:70 acetonitrile: phosphate buffer (pH 3.0); flow rate 0.75 ml/min. 3 samples were analyzed for each composition and the average values were calculated.

Sequestration at pH 6.8

An amount of composition A, B, or C corresponding to 250 mg of cholestyramine was added to a vessel containing 250 ml of 0.1 M hydrochloric acid solution (pH 1) and the contents were stirred at 75 rpm for 2 hours. 250 ml of a solution of cholic acid in potassium chloride/potassium phosphate buffer solution was then added to the vessel, giving a buffer solution of cholic acid (0.192 mg/ml) with a pH of 6.8. After 1 minute of stirring, the first sample was removed. The pH was then confirmed and, if necessary, adjusted to 6.8 by adding an appropriate amount of 0.1 M potassium hydroxide solution. The solution was then stirred for an additional 6 hours. Solution samples were taken at various time points and analyzed for cholic acid by HPLC using a Thermo Hypersil Gold column, 50 mm x 2.1 mm, particle size 1.9 µm; column temperature 60°C; mobile phase 30:70 acetonitrile: phosphate buffer (pH 3.0); flow rate 0.75 ml/min. 3 samples were analyzed for each formulation and averages were calculated.

The sequestration profiles for formulations A-C are shown in FIG. 1. The pH of 5.5 is slightly lower than the pH normally seen in the duodenum, although it may be found in some patients and healthy individuals. This pH sequestration is limited for all compositions (Fig. 1A). Sequestration at pH 6.8 is characteristic of the condition in the ileum. At this pH, composition A gave 49% sequestration after 4 hours, composition B gave 34% sequestration and composition C gave 25% sequestration (FIG. 1B).

Example 6

In vitro determination of the sequestering capacity of cholestyramine compositions under simulated conditions of the gastrointestinal tract.

The sequestering capacity of cholestyramine compositions was tested in the Gut Microbiome Ecosystem Simulator (SHIME®) developed by ProDigest (Ghent, Belgium). The simulator is adapted to assess the sequestering capacity of bile salt binding under physiological conditions typical of the fasting stomach, small intestine, and proximal colon. The fluid environment characteristic of the fasting stomach and small intestine was previously described by Marzorati et al. (LWT-Food Sci. Technol. 2015, vol. 60, p. 544-551). Proximal Colon Liquid Medium includes a SHIME® matrix containing a stable microbial community characteristic of the human intestine. A method for obtaining a stable microbial community in the human gut is described by Possemiers et al. (FEMS Microbiol. Ecol. 2004, vol. 49, p. 495-507) and references therein. Sequestration was determined by measuring the decreasing amount of bile acids in an aqueous solution. A 40:40:20 (w/w) mixture of cholic acid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acid (DCA) was used as a representative mixture of human bile salts (Carulli et al., Aliment. Pharmacol. Ther. 2000, vol. 14, issue supplement s2, pp. 14-18).

A comparative experiment was also carried out, to which pure (not included) cholestyramine powder was added. A control experiment, to which no cholestyramine was added, was performed to monitor the degradation of bile salts under the colonic conditions used in the assay.

Each experiment was performed in triplicate to assess biological variation.

Stomach on an empty stomach

The amounts of formulations A, B and C corresponding to 91 mg of cholestyramine and pure cholestyramine (91 mg) were administered in 14 ml of fasting gastric fluid (pH 1.8). Digestible substances were incubated for 1 hour at 37°C.

Small intestine

After one hour of incubation in the stomach, 5.6 ml of pancreatic juice (pH 6.8) containing a 40:40:20 mixture of bile acids (46.7 mM) was added. Digestibles from the small intestine were incubated for 2 hours at 37° C. and samples were taken at 0, 60 and 120 minutes.

proximal colon

After two hours of incubation in the small intestine, 42 ml of complete SHIME® matrix (pH 6.0) derived from the ascending colon of the SHIME® system was added. Digested residues in the colon were incubated for 24 hours at 37°C and samples were collected every hour for the first 6 hours and then after 19 hours and after 24 hours.

Sample analysis

The concentration of free bile salts in the samples was assessed by HPLC. The calibration curve was used to calculate the concentrations in the CA, CDCA and DCA samples. One ml of each sample was centrifuged for 2 min at 5000 g. 500 µl of the supernatant was mixed with 500 µl of an 80:20 (v:v) mixture of methanol and phosphate buffer, shaken thoroughly, filtered through a 0.2 µm PTFE filter and injected into a Hitachi Chromaster HPLC equipped with a UV-Vis detector. The three bile salts were separated on a C18 reverse phase column (Hydro-RP, 4 μm, 80 A, 250×4.6 mm, Synergi). The separation was carried out under isocratic conditions at room temperature using an 80:20 (v:v) mixture of methanol and phosphate buffer as the mobile phase. The analysis was carried out at 0.7 ml/min for 23 minutes and bile salts were determined at 210 nm. The injection volume was set to 20 μl for stomach and small intestine samples and 50 μl for colon samples.

The complete SHIME® matrix used for colonic incubation contains (degraded) bile salts derived from BD Difco™ Oxgall, dehydrated fresh bovine bile extract (catalog number 212820). Although the exact composition of this mixture is unknown, higher amounts of free bile salts can be expected in colon samples. Basis values (i.e. a blank sample where no bile salt mixture is added) are therefore subtracted from each sample to account for the 'basic' free bile acids present in the total SHIME® matrix.

The measured concentrations of various bile acids in a colon sample will show the effect and duration of microbial salt metabolism in the intestine (eg, deconjugation, dehydrogenation and dehydroxylation), especially in the colon. A sudden and large decrease in the concentrations of CA, CDCA and DCA in the control sample can be observed during the transition from small intestine to colonic incubation.

The percentage of remaining bile acids in each test sample can be calculated as the ratio of the value of the test sample to the value of the control sample at the corresponding incubation time. A graph of the percentage of bile acids remaining over time will show the decrease in bile acids, i.e. sequestration of bile acids by cholestyramine compositions during enteric and colonic incubation.

Claims (36)

1. Granules designed to be coated with one or more shell layers for targeted delivery of cholestyramine to the colon, where each granule contains at least 70% wt./mass. cholestyramine and i) a combination of at least 6% wt./mass. binder and at least 2% wt./mass. acrylate copolymer; or ii) a combination of at least 5% wt./mass. binder and at least 3% wt./mass. acrylate copolymer; or iii) a combination of at least 6% wt./mass. binder, at least 1% wt./mass. acrylate copolymer and from 5% to 15% wt./mass. microcrystalline cellulose; wherein the binder comprises cellulose ether, a vinylpyrrolidone polymer, or a combination thereof. 2. Granules according to claim 1, where the astringent is cellulose ether. 3. Granules according to claim 1, where the binder is a polymer based on vinylpyrrolidone. 4. Granules according to claim 1, wherein the binder comprises a combination of a cellulose ether and a polymer based on vinylpyrrolidone. 5. Granules according to any one of paragraphs. 1, 2 and 4, where the cellulose ether is methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose, or a mixture comprising two or more of such cellulose ethers. 6. Granules according to any one of paragraphs. 1, 3 and 4, where the vinylpyrrolidone-based polymer is copovidone. 7. Granules according to any one of paragraphs. 1-6, where the acrylate copolymer is an ammoniomethacrylate copolymer. 8. Granules according to any one of paragraphs. 1-7, where the granules include at least 85% wt./mass. cholestyramine. 9. Granules according to any one of paragraphs. 1-8, where the diameter of the granules is from 1000 µm to 1600 µm. 10. Granules according to any one of paragraphs. 1-9 formulated for delivery targeted to the colon. 11. A drug delivery system from a plurality of individual particles, comprising a plurality of cholestyramine granules according to any one of paragraphs. 1-10. 12. The drug delivery system of claim 11, wherein the cholestyramine beads are formulated to be delivered to the colon. 13. The drug delivery system of claim 12, wherein the colon-targeted delivery is based on enzyme controlled release. 14. The drug delivery system of claim 12, wherein the colon-targeted delivery is based on pH and diffusion controlled release. 15. Oral composition for targeted delivery of cholestyramine to the colon, comprising a) a plurality of granules according to any one of paragraphs. 1-9; and b) a sheath around said granules for release in the colon. 16. The composition of claim 15, wherein the colonic release shell is elastic. 17. A composition according to claim 15 or 16, wherein the colonic release shell contains starch. 18. The composition of claim 17 wherein the starch is type 2 resistant starch (RS2). 19. The composition according to claim 15 or 16, wherein the colonic release coating comprises an inner diffusion controlled coating layer and an outer enteric coating layer. 20. The composition according to claim 19, where the inner layer of the shell, controlled by diffusion, includes poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in ratios of 1:2:0.2, 1:2:0.1, or in their combinations. 21. The composition of claim 19 or 20, wherein the outer enteric coating layer comprises hydroxypropyl methylcellulose acetate succinate. 22. The composition according to any one of paragraphs. 15-21 for use in the treatment or prevention of bile acid malabsorption. 23. A composition for use according to claim 22, wherein the bile acid malabsorption is the result of an ileal disease such as Crohn's disease; resection of the ileum or anastomosis of the ileum; the result of excessive bile acid production or defective feedback inhibition of bile acid synthesis in the liver; or the result of cholecystectomy; vagotomy; overgrowth of bacteria in the small intestine (SIBO); celiac disease; pancreatic insufficiency such as chronic pancreatitis or cystic fibrosis; pancreatic transplantation; radiation enteritis; membranous colitis; microscopic colitis; lymphocytic colitis; ulcerative colitis or irritable bowel syndrome (IBS-D). 24. The composition according to any one of paragraphs. 15-21 for use in the treatment or prevention of bile acid diarrhea. 25. The composition according to any one of paragraphs. 15-21 for use in the treatment or prevention of bile acid diarrhea following oral administration of an IBAT inhibitor. 26. The composition according to any one of paragraphs. 15-21 for use in the treatment or prevention of diarrhea of bile acids in the treatment of cholestatic liver disease, including oral administration of an IBAT inhibitor. 27. The composition for use according to claim 26, where the IBAT inhibitor is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine; or their pharmaceutically acceptable salts.

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