RU2775800C2 - Cholestyramine pellets and their production methods - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics, namely to cholestyramine pellets, which can be obtained by molding. Pellets have high cholestyramine load and are sufficiently stable for the application of a shell of one or more shell layers. The invention also relates to a method for the production of such pellets and to a system for the delivery of particles of a drug, including such pellets.

EFFECT: pellets are suitable for oral administration, and they can be used for the treatment of hypercholesterolemia, hyperlipoproteinemia type II and diabetes mellitus type 2.

18 cl, 2 tbl, 3 ex

Description

The present invention relates to small pellets of cholestyramine, which can be obtained by molding. The pellets have a high cholestyramine load and are stable enough to be coated with one or more shell layers. The invention also relates to a method for producing such pills and a drug particle delivery system containing such pellets.

BACKGROUND OF THE INVENTION

Bile acid malabsorption is a condition characterized by an excess of bile acids in the colon, often leading to chronic diarrhea. Bile acids are steroid acids that are synthesized and conjugated in the liver. From the liver, they are excreted through 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 in the portal system 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 results in deconjugation and dehydroxylation of bile acids, producing secondary bile acid deoxycholate and 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 transit time through the colon. If present in excess, bile acids cause diarrhea with other gastrointestinal symptoms such as bloating, urination, and fecal incontinence. There have been several recent breakthroughs in understanding this condition 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 the inability of the distal ileum to absorb bile acids, 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 affect reabsorption of bile acids in the small intestine, such as treatment with inhibitors of bile acid absorption in the ileum (IBAT).

The current treatment for bile acid malabsorption aims to bind excess bile acids in the gastrointestinal tract, starting from the proximal small intestine, thus reducing the secretory action of bile acids. For this purpose, cholestyramine is commonly used as a bile acid sequestrant. Cholestyramine (or cholestyramine; CAS number 11041-12-6) is a highly alkaline anion exchange resin that is practically insoluble in water and is not absorbed from the gastrointestinal tract. Instead, it is absorbed and combined with bile acids in the intestine to form a soluble complex. The complex, which is formed when bile acids bind to the resin, is excreted in the faeces. Thus, the resin prevents the normal reabsorption of bile acids through the enterohepatic circulation, resulting in increased conversion of cholesterol to bile acids, removing them from reabsorption. This conversion lowers plasma cholesterol concentrations, primarily by lowering low-density lipoprotein (LDL) cholesterol.

Colestyramine is also used as a lipid-lowering agent in the treatment of hypercholesterolemia, type II hyperlipoproteinemia, and type 2 diabetes mellitus. It is also 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 dose of oral cholestyramine is 12-24 g per day administered as a single dose or up to 4 separate doses. In the treatment of pruritus, doses of 4 to 8 g are usually sufficient. Colestyramine may be administered gradually over 3 to 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 gallstone formation due to the increased concentration of cholesterol in bile. High doses can cause steatorrhea by interfering with gastrointestinal absorption of fats and concomitant reduced absorption of fat-soluble vitamins. Chronic administration may lead to increased bleeding tendency 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 rare 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 current treatment with cholestyramine is 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 to take other drugs at least 1 hour before or 4-6 hours after taking cholestyramine. Dosage adjustments of concomitant medications may still be necessary.

In light of these side effects, it is desirable that cholestyramine can be formulated as a colon-released composition, ie. to release cholestyramine in the proximal colon. Such a composition may require a lower dose of cholestyramine and should have better texture and taste properties and may therefore be better tolerated by patients. More importantly, the release of cholestyramine in the colon should not give interactions with other drugs and should not induce the risks of malabsorption of fat and fat-soluble vitamins, while still binding bile acids to reduce increased secretion and colonic motility. For patient adherence to treatment, it is further desirable that the amount of pellets taken be as low as possible. Therefore, each pellet should contain as much cholestyramine as possible.

EP 1273307 describes bile acid diarrhea prevention formulations comprising a bile acid adsorbent coated with a polymer so as to allow release of the bile acid adsorbent from the lower small intestine to the caecum. Colestyramine granules coated with HPMCAS-HF or ethyl cellulose have been shown to exhibit excessive swelling and rupture under conditions simulating a gastric environment.

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

Despite the progress made in this area, there is still a need for further improved cholestyramine compositions. In particular, there is a need for small particles of cholestyramine which have a high content of cholestyramine and remain stable during the coating process.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that small and stable cholestyramine cores can be obtained by pelletizing a mixture comprising cholestyramine and a vinylpyrrolidone-based polymer, or a combination of a vinylpyrrolidone-based polymer and an acrylate polymer. Such pellets have a high cholestyramine content and are stable enough to withstand the conditions commonly used to coat the cores with one or more shell layers.

In a first aspect, the invention relates to pellets comprising at least 70% w/w cholestyramine and

i. at least 7% w/w polymer based on vinylpyrrolidone; or

ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or

iii. a combination of at least 5% w/w polymer based vinylpyrrolidone and at least 3% w/w acrylate copolymer; or

iv. a combination of at least 6% w/w polymer based on vinylpyrrolidone and at least 1% w/w acrylate copolymer and at least 10% w/w microcrystalline cellulose; or

v. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer and at least 20% w/w of microcrystalline cellulose.

As used herein, the term "pellets" refers to shaped pellets, i.e. pellets obtained by molding and spheronization. The production of shaped pellets typically includes the steps of mixing the powder with a liquid to form a wet mass, shaping the wet mass, spheronizing the extrudate, and drying the wet pellets.

The pellets need to be stable enough to withstand mechanical stress during processing, such as during drying and coating of the pellets. Pellet stability can be expressed as friability, which is the ability of a solid (such as a tablet, granule, sphere, or pellet) to be reduced to smaller pieces, for example, by abrasion, fracture, or deformation. A low degree of brittleness means that the solid is broken into smaller pieces only to a small extent. As used herein, friability is defined as the reduction in weight of pellets that occurs when pellets are subjected to mechanical stress such as dropping, vibration, fluidization, etc. Methods for assessing friability are known in the art (e.g., European Pharmacopoeia 8.0, tests 2.9.7 or 2.9.41).

Experiments have shown that the incorporation of lower amounts of vinylpyrrolidone-based polymer and/or acrylate copolymer than stated above results in lower yield and higher friability of the pellets. Although it is not possible to define an acceptable friability limit for pellets in general, friability values of <1.7% w/w are reported to be acceptable to counter the stresses associated with fluidized bed coating, processing and other processes (Vertommen and Kinget, Drug Dev. Ind. Pharm. 1997, vol. 23, pp. 39-46). For the cholestyramine pellets of the present invention, a friability of 2.1% was found to still be acceptable. Brittleness is preferably less than 2.0%, more preferably less than 1.5%, and even more preferably less than 1.0%.

The vinylpyrrolidone-based polymer may be polyvinylpyrrolidone (povidone) or a vinylpyrrolidone-vinyl acetate copolymer (copovidone). Povidone is a linear, water-soluble polymer composed of N-vinylpyrrolidone. Copovidone (also known as copolyvidone) 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.

The acrylate copolymer may be any pharmaceutically acceptable copolymer including 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 small amount 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 acidic conditions, 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 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.

Other suitable acrylate copolymers include poly(ethyl acrylate-co-methyl methacrylate) 2:1, which is a water insoluble copolymer of ethyl acrylate and methyl methacrylate. A 30% aqueous dispersion is 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-ethylacrylate) 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.

In one embodiment, the invention relates to pellets comprising at least 70% w/w cholestyramine and

i. at least 7% w/w polymer based on vinylpyrrolidone; or

ii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer.

In a more preferred embodiment, the invention relates to pellets comprising at least 70% w/w cholestyramine and

iii. at least 7% w/w copovidone; or

iv. a combination of at least 6% w/w copovidone and at least 2% w/w ammoniomethacrylate copolymer.

The pellets 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, the pellets comprise 0 to 20% w/w microcrystalline cellulose, eg 0 to 10% w/w microcrystalline cellulose. In a more preferred embodiment of the invention, the pellets include from 0 to 5% w/w microcrystalline cellulose.

In another embodiment of the invention, the pellets do not contain microcrystalline cellulose.

If cholestyramine pellets are used to bind excess bile acids in the colon, they must be formulated for colon-targeted delivery. This can be achieved by coating the cholestyramine pellets with one or more layers which delays the availability of cholestyramine to the contents of the small intestine until the pellets reach the colon. The coated pellets can then be administered orally, for example in the form of a capsule containing the coated pellets, or as a loose formulation that can be dispersed in a liquid or soft food. For the purpose of patient adherence to treatment, it is desirable that the total volume of the composition be kept as small as possible. The content of cholestyramine in pellets should therefore be as high as possible. The pellets of the invention contain at least 70% w/w cholestyramine, more preferably at least 75% w/w 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.

In one embodiment, the pellets comprise 70 to 92% w/w cholestyramine, 6 to 12% w/w vinylpyrrolidone polymer, 2 to 5% w/w acrylate copolymer, and 0 to 20% w/w microcrystalline cellulose. More preferably, the pellets comprise 80 to 92% w/w cholestyramine, 6 to 12% w/w vinyl pyrrolidone polymer, 2 to 5% w/w acrylate copolymer, and 0 to 5% w/w microcrystalline cellulose.

In another embodiment, the pellets comprise 70 to 92% w/w cholestyramine, 6 to 12% w/w copovidone, 2 to 5% w/w ammoniomethacrylate copolymer, and 0 to 20% w/w microcrystalline cellulose. More preferably, the pellets comprise 80 to 92% w/w cholestyramine, 6 to 12% w/w copovidone, 2 to 5% w/w ammoniomethacrylate copolymer, and 0 to 5% w/w microcrystalline cellulose.

In another embodiment, the pellets comprise 70 to 93% w/w cholestyramine, 7 to 12% w/w vinylpyrrolidone polymer, and 0 to 20% w/w microcrystalline cellulose. More preferably, the pellets comprise 70 to 93% w/w cholestyramine, 7 to 12% w/w copovidone, and 0 to 20% w/w microcrystalline cellulose.

In yet another embodiment, the pellets comprise 80 to 93% w/w cholestyramine, 7 to 12% w/w vinylpyrrolidone polymer, and 0 to 10% w/w microcrystalline cellulose. More preferably, the pellets comprise 80 to 93% w/w cholestyramine, 7 to 12% w/w copovidone, and 0 to 10% w/w microcrystalline cellulose.

The size of the pellets is initially determined by the size of the sieve used at the molding stage. After the shaping and spheronization step, the pellets can be screened to obtain a fraction of pellets with a narrow size distribution. The pellet diameter of cholestyramine 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 pellet diameter is between 1000 and 1400 µm.

In another aspect, the invention relates to a process for producing pellets comprising at least 70% w/w coolestyramine as described herein, comprising the steps of:

i) mixing dry ingredients;

ii) adding water and optionally an acrylate copolymer to obtain a wet mass;

iii) molding the wet mass;

iv) spheronizing the extrudate; and

v) drying the obtained pellets.

The dried pellets can then be sieved to obtain pellets of uniform size.

The dry ingredients in step i) include cholestyramine and vinylpyrrolidone polymer, and may optionally include an additional excipient such as microcrystalline cellulose.

In a preferred embodiment, the invention relates to a process for producing pellets comprising at least 70% w/w cholestyramine as described herein, comprising the steps of:

i) mixing dry cholestyramine and copovidone and optionally microcrystalline cellulose;

ii) adding water and optionally an ammoniomethacrylate copolymer to obtain a wet mass;

iii) molding the wet mass;

iv) spheronizing the extrudate; and

v) drying the obtained pellets.

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 at least 2 times the amount of cholestyramine (w/w).

Uncoated pellets are destroyed in water conditions. However, they are stable enough to withstand the conditions required to coat the pellets.

The cholestyramine pellets described herein can be formulated for targeted delivery to the colon. They are then coated with one or more layers that prevent cholestyramine from being available to the intestinal contents before the pellets reach the desired part of the colon. Techniques based on changing the 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 methods, can be used for controlled release and release rate of pellets.

For enzyme controlled release, pellets can be coated with polymers that are degraded by bacteria present in the colon, such as certain azopolymers and polysaccharides. Examples of bacterially degradable polysaccharides include chitosan, pectin, guar gum, dextran, inulin, starch and amylose, as well as their derivatives (Sinha and Kumria, Eur. J. Pharm. Sci. 2003, vol. 18, p. 3-18).

For pH controlled release, the pellets can be coated with a pH sensitive polymer. Such polymers are generally insoluble below but soluble above a certain pH. Therefore, the coating disappears from the pellets when the coated pellets reach the area of the gastrointestinal tract having a pH at which the polymer becomes soluble. Examples of such pH sensitive polymers include, without limitation, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly (methacrylic acid-co-ethyl acrylate) 1:1, poly(methylacrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1, polyvinyl acetate phthalate, shellac, sodium alginate and zein, and mixtures thereof.

For diffusion controlled release, the pellets can be coated with a polymer that is water insoluble at any pH but is permeable to water and small molecules dissolved in it. Examples of such polymers include, without limitation, ethylcellulose (eg, Surelease®); poly(vinyl acetate) (eg Kollicoat® SR 30 D); copolymers of ethyl acrylate, methyl methacrylate and aminoalkyl methacrylic acid ester such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit® RL 30 D) and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit® RS 30 D); and copolymers of ethyl acrylate and methyl methacrylate such as poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit® NE 30 D or Eudragit® NM 30 D).

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

The release control shell(s) and optional barrier shell 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-acetoxybenzoic 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.

Shells can be applied to the cholestyramine cores by methods known in the art, such as film coating, including perforated trays and a fluidized bed.

In another aspect, the invention relates to a particle delivery system comprising a plurality of coated pills of cholestyramine. In a preferred embodiment, cholestyramine pellets are formulated for colon-targeted delivery. In such an embodiment, the pellets are coated with one or more layers that delay the release of the cholestyramine pellets before the coated pellets reach the colon. In one embodiment of the invention, colon-targeted delivery is based on enzyme-controlled release of pellets. In another embodiment of the invention, colon-targeted delivery is based on pH- and diffusion-controlled pellet release.

Due to its very low solubility, cholestyramine is not "released" from the composition comprising the coated pellets of cholestyramine, in which it dissolves from the composition and diffuses into the intestine. Instead, cholestyramine likely remains in the gradually degrading structure of the coated pellets. 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.

The low solubility of cholestyramine in an aqueous medium prevents the release of cholestyramine from a composition comprising coated pellets of cholestyramine for direct measurement. The availability of cholestyramine to the intestinal contents over time and 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 involves measuring the reduced amount of free bile acids (ie, the compound that is being sequestered) in a liquid medium representative of the gastrointestinal tract. See also the official monograph for cholestyramine resin (USP 40, page 3404).

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

EXAMPLES

Example 1

Molding experiments

All experiments were performed on a 100-200 g scale. The dry ingredients (colestyramine, vinylpyrrolidone polymer and/or microcrystalline cellulose) were mixed in the amounts indicated below. Water was added in portions of 50-100 grams with 3 minutes of mixing between additions. When the acrylate copolymer was included in the experiment, it was added as a 2% w/w copolymer dispersion in water (20 g of acrylate copolymer (30% aqueous dispersion) added to 300 g of water). A final portion of pure water was added as needed. In each experiment, the total amount of added liquid was from 1.7 to 2.3 times the amount of solid material (w/w).

The wet mass was transferred to a molder equipped with a 1.5 mm screen, processed at 25 rpm (revolutions per minute) and the extrudate was collected on a stainless steel tray. Approximately 100 g of the extrudate was run into the spheronizer for 1 minute at 730 rpm. The spheronized material was then transferred to stainless steel trays, placed in a drying oven and dried for 16 hours at 50°C. Yield was calculated as the fraction of pellets that passed through the 1.6 mm sieve but were retained by the 1.0 mm sieve.

The fragility study was carried out using the equipment and methodology described in the European Pharmacopoeia 8.0, test 2.9.7. The pellets were screened through a 500 µm sieve to remove any loose dust before weighing.

Results using Copovidone and Eudragit® RL 30 D are shown in Table 1 and results using Povidone and other Eudragit® copolymers are shown in Table 2.

Table 1

Input Quantity (% w/w) Exit (%) Brittleness (%) Colestyramine Copovidone MSS Eudragit® RL 30 D one 100 0 0 0 * * 2 90 0 ten 0 * * 3 70 0 thirty 0 39 1.6 four 70 6 24 0 * * 5 70 0 26 four * * 6 70 6 twenty four 85 0.1 7 80 3 fifteen 2 * * eight 85 7.5 4.5 3 92 0.6 9 90 6 four 0 * * ten 90 0 6 four * * eleven 90 0 0 ten * * 12 90 6 0 four 85 1.4 13 90 ten 0 0 87 1.2 fourteen 91 9 0 0 82 0.5 fifteen 92 eight 0 0 83 1.5 16 93 7 0 0 78 1.0 17 94 6 0 0 * * eighteen 91 6 0 3 84 0.3 19 92 6 0 2 82 1.6 twenty 93 6 0 one * * 21 85 6 eight one 81 3.5 22 80 6 13 one 85 0.8 23 92 5 0 3 70 2.0 24 93 5 0 2 * * 25 85 5 eight 2 54 7.1 26 80 5 13 2 73 9.1

0*=molding followed by spheronization did not produce pellets.

table 2

Input Quantity (% w/w) Exit (%) Brittleness (%) Colestyramine Copovidone MSS Eudragit® RL 30 D one 85 7.5 4.5 3% w/w FS 30D 79 0.2 2 85 7.5 4.5 3% w/w L 30 D-55 24 0.8 3 85 7.5 4.5 3% w/w NE 30 D 88 0.5 four 85 7.5 4.5 3% w/w NM 30 D 96 0.9 5 85 7.5 4.5 3% w/w RS 30 D 82 0.8

Example 2

Getting the pills

Pellets with the composition according to table 1, input 8, were produced in a batch size of 200 g at the molding stage and 100 g at the spheronization stage. 170 g of cholestyramine, 15 g of copovidone and 9 g of microcrystalline cellulose were loaded into a planetary mixer. The mixer was turned on at an intermediate speed and the liquid was slowly added in portions with agitation between each addition. The first 300 g of water with 20 g of Eudragit® RL 30 D (30% dry weight) was added in three equal parts with mixing for 3 minutes between each addition. Finally, 40 g of pure water was added and stirring was carried out for an additional 30 seconds. The wet mass was then transferred to an extruder. The extruder equipped with a 1.5 mm screen was turned on at 25 rpm and the extrudate was collected on a stainless steel tray. Approximately 100 g of the extrudate was run into the spheronizer for 1 minute at 730 rpm. The spheronized material was then transferred to stainless steel trays, placed in a drying oven and dried for 16 hours at 50°C. Dry pellets were sieved and a fraction between 1 mm and 1.6 mm was collected.

Example 3

Colestyramine Pellet Stability Study

Pellets 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 mixer. Pellets of table 1, input 8 were completely destroyed within 1 min 25 s, and pellets of table 2, input 1 were completely destroyed within 1 min 50 s.

Claims (29)

1. Stable extruded pellets designed to be coated with one or more layers of the shell and targeted delivery of cholestyramine to the colon, while the pellets contain at least 70% wt./mass. cholestyramine and i) at least 7% wt./mass. polymer based on vinylpyrrolidone; or ii) a combination of at least 6% wt./mass. polymer based on vinylpyrrolidone and at least 2% wt./mass. acrylate copolymer; or iii) a combination of at least 5% wt./mass. polymer based on vinylpyrrolidone and at least 3% wt./mass. acrylate copolymer; or iv) a combination of at least 6% wt./mass. polymer based on vinylpyrrolidone, at least 1% wt./mass. acrylate copolymer and at least 10% wt./mass. microcrystalline cellulose; or v) a combination of at least 5% wt./mass. polymer based on vinylpyrrolidone, at least 2% wt./mass. acrylate copolymer and at least 20% wt./mass. microcrystalline cellulose, where the vinylpyrrolidone-based polymer is copovidone or povidone. 2. Pellets according to claim 1, wherein the pellets also include microcrystalline cellulose. 3. Pellets according to claim 1, wherein the pellets do not contain microcrystalline cellulose. 4. Pellets according to claim 1, where the pellets include at least 85% wt./mass. cholestyramine. 5. Pellets according to claim 1, where the pellets include at least 90% wt./mass. cholestyramine. 6. Pellets according to claim 1, wherein the vinylpyrrolidone-based polymer is copovidone. 7. Pellets according to claim 1, wherein the acrylate copolymer is an ammoniomethacrylate copolymer. 8. Pellets under item 1, where the pellets include from 80 to 92% wt./mass. cholestyramine, from 6 to 12% wt./mass. copovidone, from 2 to 5% wt./mass. ammoniomethacrylate copolymer and from 0 to 5% wt./mass. microcrystalline cellulose. 9. Pellets under item 1, where the pellets include from 80 to 93% wt./mass. cholestyramine, from 7 to 12% wt./mass. copovidone and from 0 to 10% wt./mass. microcrystalline cellulose. 10. Pellets according to claim. 1, where the diameter of the pellets is from 1000 microns to 1400 microns. 11. Pellets according to any one of paragraphs. 1-10 formulated for delivery targeted to the colon. 12. The method of obtaining pellets according to any one of paragraphs. 1-10, including stages: i) mixing dry ingredients; ii) adding water to obtain a wet mass; iii) molding the wet mass; iv) spheronizing the extrudate and v) drying the obtained pellets. 13. The method of claim 12, wherein step ii) also includes the addition of an acrylate copolymer. 14. The method according to p. 12, where water is added to the mixture of dry ingredients in an amount of at least 1.75 times. the amount of cholestyramine (w/w). 15. A multi-particulate composition for targeted delivery to the colon, comprising a plurality of cholestyramine pellets according to any one of paragraphs. 1-10. 16. The formulation of claim 15, wherein the cholestyramine pellets are formulated for colon-targeted delivery. 17. The formulation of claim 16 wherein the colon-targeted delivery is based on enzyme controlled release. 18. The formulation of claim 16 wherein the colon-targeted delivery is based on pH and diffusion controlled release.