WO1994007503A1

WO1994007503A1 - Enteric preparations

Info

Publication number: WO1994007503A1
Application number: PCT/FI1993/000389
Authority: WO
Inventors: Kaija Kristiina Af Ursin; Markku Juho Ylermi ÄÄRIMAA; Harry Gösta JALONEN
Original assignee: Orion-Yhtymä Oy
Priority date: 1992-10-05
Filing date: 1993-09-29
Publication date: 1994-04-14
Also published as: FI924470A0; AU4821593A

Abstract

Enteric pharmaceutical preparations containing a disaccharide polysulfate complex, especially sucralfate, suitable for use in the treatment of intestinal disorders, which may be ulceration and/or inflammation in the intestine, especially in the distal small intestine and colon, and injury caused by radiotherapy or cytotoxic drugs.

Description

ENTERIC PREPARATIONS

This invention relates to enteric pharmaceutical preparations containing disaccharide polysulfate complexes, especially sucralfate, useful in the treatment of intestinal disorders. The intestinal disorders may be ulceration and/or inflammation in the intestine, particularly in the small intestine and colon, especially Crohn's disease and ulcerative colitis, and injury caused by radiotherapy or cytotoxic drugs.

Further this invention relates to the use of disaccharide polysulfate complexes, especially sucralfate, in the preparation of enteric pharmaceutical preparations useful in the treatment of intestinal disorders, especially ulceration and/or inflammation in the intestine, particularly in the small intestine and colon, more particularly Crohn's disease and ulcerative colitis, or injury caused by radiotherapy or cytotoxic drugs.

Sucralfate, a disaccharide polysulfate aluminium compound and more specifically alpha-D-glucopyranoside, beta-fructofuranosyl-, octakis (hydrogen sulfate), aluminium complex, is well known in the art as a basic aluminium sucrose sulphate complex which accelerates the healing of gastric and duodenal ulcers. The preparations on the market release sucralfate already in the stomach where it forms a gel-like mass interacting the mucous membrane in the stomach and is shown to have a healing effect on ulcers. The intestine is not targetted for treatment.

Sucralfate may be replaced by other disaccharide polysulfate complexes other than those of aluminium, for example an alkaline earth metal ( e.g. Ca, K or Mg) or Bi.

The term "enteric" means a medicinal preparation formulated to pass through the stomach unaltered and disintegrate in the intestine. No effective cure has been found for the group of patients suffering from ulceration and/or inflammation in the intestine, especially in the distal small intestine and colon, or injury caused by radiotherapy or cytotoxic drugs. The sucralfate preparations in the market are not suitable for the treatment of for example ileitis, Crohn's disease, ulcerative colitis and related colo-rectal lesions.

International specification WO 91/04034 proposes the use of topical sucralfate preparations for treatment of e.g. ulcerative colitis. The specification does not suggest enteric sucralfate preparations to treat the colon but a retention enema was proposed.

The present invention provides enteric disaccharide polysulfate complex, particularly sucralfate, preparations suitable for the treatment of intestinal disorders, especially ulceration and/or inflammation in the intestine, especially in the distal small intestine and colon, and injury caused by radiotherapy or cytotoxic drugs. In particular the present invention provides enteric disaccharide polysulfate complex, especially sucralfate, preparations for the treatment of Crohn's disease and ulcerative colitis.

The dissolution of the suitable enteric coating materials is dependent on pH.

The enteric coating material may be any material which inhibits disaccharide polysulfate complexes to be released in the stomach and disintegrate in the intestine or part of the intestine without altering their therapeutic effect. Enteric coating materials which may be used in preparations targetted for the treatment of the small intestine should be insoluble in gastric juice and be soluble in intestinal juice below pH 7. Enteric coating materials which may be used in preparations targetted for the treatment of the colon should be insoluble in gastric juice and intestinal juice below about pH 7 and be soluble in intestinal juice above about pH 7. The enteric coating material may also be a combination of two or more materials when it is desired to target preparations for a particular part of the intestine or for the treatment of both the small intestine and the colon. According to the invention it may be possible to treat the whole intestine with a single enteric preparation or only the part of the intestine desired.

The amount of the active ingredient, i.e. the disaccharide polysulfate complex, especially sucralfate, in the enteric preparations should be sufficient to achieve a therapeutic effect in the intestine. Generally for example the amount of sucralfate administered may be up to about 4 g day which may be divided into two or more dosages if desired.

The enteric coating materials may be natural polymers, such as hydroxypropyl methylcellulose or its derivatives, such as hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate, or synthetic polymers, preferably (meth)acrylic acid and (meth)acrylic acid ester copolymers, such as EUDRAGIT polymers or their derivatives. Especially EUDRAGIT L which disintegrates in the pH value of below 7 may be used for preparations designed to treat the small intestine and EUDRAGIT S which disintegrates in the pH value above 7 for preparations designed to treat the colon.

The forms of administering the enteric disaccharide polysulfate complex, especially sucralfate, may include tablets, solid dispersions, granules, pellets, capsules, mixtures and any other dosage form which may be suitable for oral administration. The preparations may be made by conventional methods and coating techniques.

Tablets may be coated with an enteric coating material or they may be prepared using enteric coated granules or pellets. Enteric coated granules and pellets may also be used as such as a bulk material, packed into capsules suitable for oral administration and which dissolve in the stomage, e.g. gelatin capsules, or formed into multiple unit tablets by mixing with a disintegrant, such as Explotab, and when desired also other fillers, such as microcrystalline cellulose and tabletting in a suitable tabletting machine. Capsules and multiple unit tablets may still be coated with an enteric coating material if desired. In the case of solid dispersions or mixtures the disaccharide polysulfate complex granules or pellets may be mixed with an enteric coating material. The granulation may be performed by conventional methods, such as in a fluidized bed or high-shear granulator. Pellets may be produced by conventional methods, such as with extrusion/spheronization technique. Usually the pellets suitable for the preparations of the invention are about 0.5-1.5 mm diameter, especially about 1 mm diameter.

The active ingredient may also be granulated or pelleted using a solution or dispersion of an enteric coating material as a binder. In this case the enteric coating material acts as a matrix.

Enteric coated raw material particles or small agglomerates may be used in the preparation of dosage forms described above. Especially they are useful in preparing mixtures. They may also be used as a bulk material.

The enteric preparation may also be made of granules and/or pellets coated with different enteric coating materials to achieve a multicomponent preparation which releases the active ingredient according to pH gradient in the intestine.

It may also be possible to coat tablets, granules, pellets and particles/agglomerates with two or more successive layers of different enteric coating materials. One or more of the above layers may be replaced by a layer of a retarding agent, such as hydroxypropyl methylcellulose, methyl hydroxy- ethylcellulose, ethylcellulose, hydroxypropylcellulose, polyvidone, sodium carboxymethylcellulose, polyethylene glycols and acrylate polymers.

The enteric preparations of the invention may contain suitable pharmaceutically acceptable additives, such as fillers, binders, disintegrants, lubricants, plasticizers, solvents, etc..

The amount of enteric coating material required in the enteric preparations will depend on the dissolution properties of the particular enteric coating material and the planned dosage form in mind. Usually the amount of enteric coating material will be up to 25 % (dry weight gain). The enteric coating may be applied from solvent based solutions or aqueous dispersions. Suitable solvents are for example different alcohols, such as iso-propanol and ethanol, and acetone or their mixtures. The solvent based solutions may also contain water, usually at most one equivalent, and the aqueous dispersions may contain water misciple organic solvents. The enteric coating may contain additives, such as colouring agents, plasticizers, such as alkylphthalates (e.g. dibutylphthalate), polyethylene glycol, triacetin, citric acid esters and propylene glycol, auxiliary materials, e.g. talc, etc..

The coating to the preparations may be achieved by conventional coating techniques as defined above, such as by the use of spraying, fluidized bed, immersion tube and immersion bed techniques.

The following non-limiting examples illustrate the invention. The enteric preparations illustrated in the examples meet the requirements of the United States Pharmacopeia (USP) disintegration test for enteric coated tablets.

EXAMPLE 1

Tablet

Commercial ANTEPSIN® tablets which consist of 1 g of sucralfate are coated by a conventional spraying technique with a solution of 50 g of EUDRAGIT S100, 14 g of dibutylphtalat, 500 g of acetone and 500 g of iso-propanol. After the coating the tablets are allowed to dry. The amount of EUDRAGIT SI 00 per tablet is 42,2 mg.

The coated sucralfate tablets resist 0,1 M HC1 solution, which resembles the conditions in the stomach. All the tested tablets disintegrated in pH 7,2 in about 9 to 53 minutes.

The disintegration of the coated ANTEPSIN® tablets was tested in vitro in ERWEKA ZT3 dissolution apparatus in phosphate buffer pH 7,2 in 37 °C according to European Pharmacopoeia 2nd edition. These conditions resemble the conditions in colon. EXAMPLE 2

Granule

Sucralfate is granulated in fluidized bed granulator using Kollidon 30 solution (20 %) as a binder. The amount of Kollidon in final dry granules is 8 %. Dry sucralfate granules are coated using aqueous dispersion of EUDRAGIT L 30 D. The composition of the coating dispersion is as follows:

60 g of coating liquid is needed for 100 g of granules.

EXAMPLE 3

Multiple unit tablet

Multiple unit tablets are prepared by mixing enteric coated granules (90 %) prepared in Example 2 with a disintegrant EXPLOTAB (10 %). The mixture is tabletted with a single punch tabletting machine to give multiple unit tablets weighing 0,5 grams.

EXAMPLE 4

Granule with an enteric coating material as a matrix

Sucralfate is granulated in fluidized bed granulator using EUDRAGIT L 30 D water dispersion as a binder. The binder dispersion composed of EUDRAGIT L 30 D (50 %), triacetin (1,5 %) and water (48,5 %). The amount of dry substances of binder dispersion in final granules is 13 %. EXAMPLE 5

Pellet

Sucralfate (80 %) and microcrystalline cellulose (20 %) are granulated with distilled water (80 % of dry substances) for further production of extrudate and pellets with extrusion/spheronization technique. The pellets are dried and coated with enteric coating in fluidized bed equipment. The composition of coating solution is the same as in Example 2 and 4. The amount of dry substances of the coating dispersion in final pellets is 10 %.

EXAMPLE 6

Mixture

Sucralfate particles are coated with EUDRAGIT L 30 D water dispersion as described in Example 2. Coated particles are used for the preparation of a mixture as follows:

coated sucralfate particles 19 % water 63 % glycerol (85 %) 17,5 % xanthan gum 0,5 %

Claims

1. Pharmaceutical preparation suitable for use in the treatment of intestinal disorders which comprises a disaccharide polysulfate complex in combination with an enteric coating material.

2. Pharmaceutical preparation according to claim 1 wherein the disaccharide polysulfate complex is sucralfate.

3. Pharmaceutical preparation according to claims 1 and 2 wherein the enteric coating material includes a synthetic polymer.

4. Pharmaceutical preparation according to claim 3 wherein the synthetic polymer is a copolymer of (meth)acrylic acid and (meth)acrylic acid ester.

5. Pharmaceutical preparation according to claim 4 wherein the synthetic polymer is EUDRAGIT S.

6. Pharmaceutical preparation according to claim 4 wherein the synthetic polymer is EUDRAGIT L.

7. Pharmaceutical preparation according to claims 1 and 2 wherein the enteric coating material includes a natural polymer.

8. Pharmaceutical preparation according to claims 1 to 7 wherein the preparation is in the form of a tablet

9. Pharmaceutical preparation according to claims 1 to 7 wherein the preparation is in the form of a capsule.

10. Pharmaceutical preparation according to claims 1 to 7 wherein the preparation is in the form of a multicomponent preparation.

11. Use of a disaccharide polysulfate complex for the preparation of an enteric pharmaceutical preparation suitable for use in the treatment of intestinal disorders.

12. Use of a disaccharide polysulfate complex according to claim 11 wherein the pharmaceutical preparation is used in the treatment of ulceration and/or inflammation in the intestine.

13. Use of a disaccharide polysulfate complex according to claim 12 wherein the pharmaceutical preparation is used in the treatment of ulceration and/or inflammation in the colon.

14. Use of a disaccharide polysulfate complex according to claim 12 wherein the pharmaceutical preparation is used in the treatment of ulceration and/or inflammation in the small intestine.

15. Use according to claims 11 to 14 wherein the disaccharide polysulfate complex is sucralfate.