CH699302B1 - An oral pharmaceutical formulation for omeprazole containing a specific release layer. - Google Patents

Abstract

The invention relates to an enteric pharmaceutical formulation containing omeprazole, an (alkaline) alkaline salt of omeprazole, an enantiomer of omeprazole or an (alkaline) salt of an enantiomer of omeprazole, wherein the separating layer between active substance and enteric coating is a polyvinyl alcohol Polyethylene glycol graft copolymer and / or optionally modified pea starch contains.

Description

The invention relates to an enteric pharmaceutical formulation for omeprazole, an alkaline salt of omeprazole, an enantiomer of omeprazole or an alkaline salt of an enantiomer of omeprazole, containing a specific separation layer. The separating layer between the active substance and the coating contains a polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch.

Patent EP 5129 has substituted 2- (pyridylmethylsulfinyl) -1H-benzimidazoles, so-called prazoles, e.g. the commercially available omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole, and their properties as effective proton pump inhibitors. Esomeprazole is the name for the S-enantiomer of omeprazole, S-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole. Omeprazole acts as an inhibitor of gastric acid secretion and is suitable for use as an antiulcer and for the prevention and treatment of overproduction of gastric acid-related diseases in mammals, and particularly in humans. It is known that pyridylmethylsulfinylbenzimidazoles such as omeprazole are relatively unstable in the presence of moisture but also of organic solvents. They are particularly unstable in an acidic environment. One way to obtain derivatives with higher stability is the formation of (alkaline) alkaline salts, e.g. Sodium or magnesium salts, for example as described for omeprazole in the patent EP 124 495.

Omeprazole is usually provided with an enteric coating. It has been found to be advantageous to provide a separating layer between the active substance (in the form of the free base or in the form of an alkali or magnesium salt) and the enteric coating. European Patent EP 0 342 522 proposes to prepare an acid labile pyridylmethylsulfinylbenzimidazole first with a sparingly water soluble fines such as magnesium oxide, silicium anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, calcium stearate or sucrose-fatty acid ester and a low water-soluble film material, e.g. To coat ethyl cellulose or polyvinyl acetate. Thereafter, the usual enteric-coated film is applied, e.g. Hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid / methyl methacrylate copolymer or polyvinyl acetate phthalate. Compared with water-soluble coatings, these proposed release layers have advantages.

In EP 773 025 it is proposed to apply the acid-labile pyridylmethylsulfinylbenzimidazole mixed with hydroxypropylmethylcellulose and talcum to a core and then to coat it with a separating layer of hydroxypropylmethylcellulose and talcum (and optionally titanium oxide as white pigment). In addition, the enteric coating of methacrylic acid / methyl methacrylate copolymer and plasticizers, e.g. Triethyl citrate, applied.

In international patent application WO 2006/085335, it is proposed to use the acid-labile active ingredient with a separating layer of a water-insoluble polymer, e.g. Ethylcellulose, polyvinyl acetate, acrylic polymers and copolymers such as Eudragit RL, Eudragit L, Eudragit RS 30D or mixtures thereof. To this polymer is added an organic stabilizer, for example meglumine or tromethamine or mixtures thereof, optionally also plasticizer, e.g. Polyethylene glycol, castor oil, dibasic sebacate, triethyl citrate or mixtures thereof, and talc to prevent sticking. Thereafter, the enteric coating of cellulose acetate phthalate, hydroxymethyl cellulose, methacrylic acid / methyl methacrylate copolymer or shellack is applied.

Surprisingly, it has now been found that remarkably stable forms of tablets, minitablets, pellets, film-coated tablets, capsules and granules of omeprazole, for example of esomeprazole, are obtained when omeprazole, an (alkaline) alkaline salt of omeprazole, an enantiomer of omeprazole or an (alkaline) salt of an enantiomer of omeprazole with a specific separating layer between the active substance and the enteric coating, the separating layer containing a polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch.

A polyvinyl alcohol-polyethylene glycol graft copolymer is available, for example, under the trade name Kollicoat® IR. Kollicoat <®> IR has excellent film-forming properties, low viscosity in an over-spray solution of up to 25% polymer concentration, and the release layer remains flexible, does not stick, and gives a smooth surface without additional plasticizer.

Pea starch (optionally modified) is available, for example, under the trade name Lycoat <®>. Lycoat <®> also gives a flexible, non-sticky release layer and a smooth surface and is easy to spray onto drug cores. The viscosity can be easily adapted to existing sprayers.

The release layer may contain other adjuvants, e.g. Talc, silicas (Syloid <®>) and the like.

Both polyvinyl alcohol-polyethylene glycol graft copolymer and optionally modified pea starch are easy to apply and provide release liners of consistent quality that do not affect the properties of the drug, protect it from light, moisture and especially acid, but the dissolution of the drug in the intestine no way hindering.

The invention equally encompasses a process for the preparation of solid, enterically coated oral dosage forms containing omeprazole, an alkaline salt of omeprazole, an enantiomer of omeprazole, or an alkaline salt of an enantiomer of omeprazole, wherein the active ingredient optionally contains additives coated on a core, then coated with a release layer containing a polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch, and finally with an enteric coating containing cellulose acetate phthalate, hydroxymethylcellulose, methacrylic acid / methyl methacrylate copolymer and / or shellack.

Particularly preferred is the formulation in which the active ingredient is the magnesium salt of esomeprazole, in particular in the form of its hydrates such as dihydrate and trihydrate.

Very particularly preferred is the formulation wherein the active ingredient is esomeprazole magnesium dihydrate.

As solid oral dosage forms tablets, minitablets, pellets, film-coated tablets, capsules, for example soft gelatin capsules, granules and related forms are considered.

The dosage forms are in addition to omeprazole, an alkaline salt of omeprazole, an enantiomer of omeprazole or an alkaline salt of an enantiomer of omeprazole optionally also from the following optimizers or so-called excipients which form pharmaceutically acceptable oral dosage forms:

Contemplated excipients for solid oral dosage forms are excipients (eg, microcrystalline cellulose, silica, xanthan gum, guar gum, silica, magnesium aluminum silicate, calcium silicate, calcium and magnesium phosphates), alumina, titania, thinner (eg, calcium carbonate, calcium sulfate, hydrogenated vegetable oil , Kaolin, magnesium carbonate, talc, sodium chloride), binders (eg guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, tragacanth, alginate, carboxymethylcellulose-calcium or sodium, carrageenan, xanthan), disintegrants (eg croscarmellose, crospovidone (cross-linked polyvinylpyrrolidone ), colloidal silica, sodium starch glycolate, sodium carboxymethyl starch), lubricants (eg, colloidal silica, starch, tribasic calcium phosphate, talc), and mold release agents (eg, calcium stearate, zinc stearate, magnesium stearate, stearic acid, fumaric acid, Glycerol monostearate, glycerol palmitostearate, mineral oil, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated castor oil, hydrogenated castor oil).

Film-coated tablets optionally additionally contain film formers (for example carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, gelatin, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), ethylcellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) , Polymethacrylate, microcrystalline wax, shellac, talc, titanium dioxide), suspending agents (eg fumed silica, kaolin, talc), lubricants (eg calcium stearate, magnesium stearate, glycerol monostearate, glycerol palmitostearate, mineral oil, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, hydrogenated Castoröl) and color pigments (eg titanium dioxide, iron oxides, indigotin verlackt, erythrosin verlackt).

Further contemplated excipients are polyhydroxy compounds, for example ethylene glycol, propylene glycol or butylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and polyethylene glycol, glycerol or partially etherified with ethylene oxide glycerol derivatives. These liquid excipients are used only in amounts such that the active ingredient remains in a powdered state.

Nitrogen-containing basic organic compounds may also be added, for example lysine, arginine, histidine, ethylenediamine, ethanolamine, propanolamine, N, N-dibenzylethylenediamine, meglumine, tromethamine, choline, procaine (4-aminobenzoic acid diethylaminoethyl ester), chloroprocaine or procainamide.

Sugars are also suitable excipients for omeprazole, for example, mannitol, sorbitol, dextrins, maltodextrins, inositol, isomalt, lactitol, maltitol and xylitol, or the above-mentioned amino sugar meglumine.

One or more of the above-mentioned additives, instead of the active ingredient or in addition to the active ingredient and the separating layer of polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch may be added, for example, silica, titanium dioxide, talc or a color pigment. It is also possible to add a base to the separation layer, for example an inorganic base such as sodium hydroxide or an organic base, for example one of the abovementioned organic amines.

Softgels, hard gelatin, HPMC, polysaccharide or starch capsules, for example, as capsules, welded or glued capsules of different size, color and water content come into consideration as capsules.

Granules, for example, bottled in sachets or bottles and the like, usually contain the above thinners, binders, disintegrants and lubricants.

Preference is given to the methods and products described in the examples.

The following examples illustrate the invention, but do not constitute a limitation of the subject invention.

example 1

[0026] <tb> Pos. <sep> Material <sep> Quantity [kg] <Tb> 1 <sep> Active ingredient pellets <sep> 150.00 <tb> 2 <sep> Kollicoat IR <sep> 27.00 <Tb> 3 <sep> sodium hydroxide <sep> 00:10 <Tb> 4 <sep> Talc <sep> 11:40 <tb> 5 <sep> Silica, fumed <sep> 8.00 <Tb> 6 <sep> dioxide <sep> 3:50 <Tb> 7 <sep> Water <sep> 340.00 <tb> <sep> total amount of pellets after isolation <sep> 200.00

Sodium hydroxide is dissolved in 90 kg of water with stirring; Subsequently, talcum, silicon dioxide and titanium dioxide are suspended in the solution. This suspension is stirred into a solution of Kollicoat IR in 250 kg of water. With the resulting coating liquid, the active substance pellets are coated with a film in a fluidized bed coating apparatus. The product temperature during coating should be between 35 and 40 ° C. After coating, the pellets are further dried for 2 hours at 60 ° C supply air.

Example 2

[0028] <tb> Pos. <sep> Material <sep> Quantity [kg] <Tb> 1 <sep> Active ingredient pellets <sep> 140.00 <tb> 2 <sep> Kollicoat IR <sep> 20.00 <Tb> 3 <sep> Talc <sep> 10:00 <Tb> 4 <sep> dioxide <sep> 3:00 <Tb> 5 <sep> Water <sep> 280.00 <tb> <sep> total amount of pellets after isolation <sep> 173.00

Talc and titanium dioxide are suspended in 80 kg of water. This suspension is stirred into a solution of Kollicoat IR in 200 kg of water. With the resulting coating liquid, the active substance pellets are coated with a film in a fluidized bed coating apparatus. The product temperature during coating should be between 25 and 30 ° C. After coating, the pellets are further dried for 2 hours at 50 ° C supply air.

Example 3

[0030] <tb> Pos. <sep> Material <sep> Quantity [kg] <Tb> 1 <sep> Active ingredient pellets <sep> 150.00 <tb> 2 <sep> Lycoat RS 780 (modified pea starch) <sep> 27.00 <Tb> 3 <sep> Talc <sep> 13:00 <Tb> 4 <sep> dioxide <sep> 5:00 <Tb> 5 <sep> Water <sep> 350.00 <tb> <sep> total amount of pellets after isolation <sep> 195.00

Talc and titanium dioxide are suspended in 80 kg of water. This suspension is stirred into a solution of Lycoat RS 780 in 270 kg of water. With the resulting coating liquid, the active substance pellets are coated with a film in a fluidized bed coating apparatus. The product temperature during coating should be between 35 and 40 ° C. After coating, the pellets are further dried for 2 hours at 55 ° C supply air.

Example 4

[0032] <tb> Pos. <sep> Material <sep> Quantity [kg] <Tb> 1 <sep> Active ingredient pellets <sep> 150.00 <tb> 2 <sep> Lycoat RS 780 (modified pea starch) <sep> 17.00 <Tb> 3 <sep> Talc <sep> 8:00 <Tb> 4 <sep> dioxide <sep> 3.75 <tb> 5 <sep> iron oxide red <sep> 1.25 <Tb> 6 <sep> Water <sep> 200.00 <tb> <sep> total pellets after isolation <sep> 180.00

Talc, red iron oxide and titanium dioxide are suspended in 50 kg of water. This suspension is stirred into a solution of Lycoat RS 780 in 150 kg of water. With the resulting coating liquid, the active substance pellets are coated with a film in a fluidized bed coating apparatus. The product temperature during coating should be between 35 and 40 ° C. After coating, the pellets are further dried for 2 hours at 55 ° C supply air.

Example 5

[0034] <tb> Pos. <sep> Material <sep> Quantity [kg] <Tb> 1 <sep> Active ingredient pellets <sep> 120.00 <tb> 2 <sep> Kollicoat IR <sep> 5.50 <tb> 3 <sep> Lycoat RS 780 (modified pea starch) <sep> 5.50 <Tb> 4 <sep> Talc <sep> 5:50 <Tb> 5 <sep> dioxide <sep> 3:50 <Tb> 6 <sep> Water <sep> 110.00 <tb> <sep> total amount of pellets after isolation <sep> 140.00

Talc and titanium dioxide are suspended in 40 kg of water. This suspension is stirred into a solution of Lycoat RS 780 and Kollicoat IR in 110 kg of water. With the resulting coating liquid, the active substance pellets are coated with a film in a fluidized bed coating apparatus. The product temperature during coating should be between 40 and 45 ° C. After coating, the pellets are further dried for 2 hours at 60 ° C supply air.

Claims (11)

An enteric-coated oral pharmaceutical formulation containing omeprazole, an (alkaline) alkaline salt of omeprazole, an enantiomer of omeprazole, or an (alkaline) salt of an enantiomer of omeprazole, wherein the active-material release coating layer is a polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch. 2. Formulation according to claim 1, wherein the separating layer between the active substance and the coating comprises a polyvinyl alcohol-polyethylene glycol graft copolymer. 3. Formulation according to claim 1, wherein the separating layer between active substance and coating contains modified pea starch. 4. Formulation according to claim 1, containing omeprazole. 5. A formulation according to claim 1, containing an (alkaline) alkaline salt of omeprazole. 6. Formulation according to claim 1, containing esomeprazole. 7. A formulation according to claim 1, containing an (alkaline) alkaline salt of esomeprazole. 8. A formulation according to claim 1, containing the magnesium salt of esomeprazole. 9. A formulation according to claim 1 containing esomeprazole magnesium dihydrate. 10. A formulation according to any one of claims 1 to 9 as an agent for controlling ulcer and for the prevention and control of overproduction of gastric acid-related diseases in mammals and in particular in humans. 11. A process for the preparation of solid enteric coated oral dosage forms containing omeprazole, an oleic salt of omeprazole, an enantiomer of omeprazole or an (alkaline) salt of an enantiomer of omeprazole, wherein the active ingredient is optionally supplemented applied to a core, then coated with a release layer containing a polyvinyl alcohol-polyethylene glycol graft copolymer and / or optionally modified pea starch and finally with an enteric coating containing cellulose acetate phthalate, hydroxymethyl cellulose, methacrylic acid / methyl methacrylate copolymer and / or shellack is provided.