HU217587B - Pharmaceutical compositions containing ranitidine/bismuth carboxylate complex and basic salts - Google Patents

Abstract

Field of the Invention The present invention relates to solid unit dosage form pharmaceutical compositions for use in the treatment of guinea-pigs, which contain ranitidine and a lithium-acacia stone-stone complex or a potassium salt and a alkaline salt. The composition may be, for example, a tablet-head liver and may contain ranitidine business citrate and sodium carbonate. The disintegration and / or laceration of the preparation is better than known. ŕ

Description

FIELD OF THE INVENTION The present invention relates to an improved form of formulations of ranitidine derivatives having H 2 antagonist activity, particularly oral formulations. More particularly, the present invention relates to a pharmaceutical composition comprising as an active ingredient a salt of ranitidine with a bismuth carboxylic acid complex.

British Patent No. 2,220,937 A discloses a salt formed by ranitidine and a bismuth carboxylic acid complex, in particular tartaric acid, more preferably citric acid. These salts have the antisecretory properties of the H ₂ antagonist linked to ranitidine and are antibacterial against Helicobacter pylori (formerly Campylobacter pylori). In addition, these salts are cell protective, have activity against human gastric pepsin, and in particular inhibit the action of pepsin 1 and pepsin isozyme associated with peptic ulcers.

The salts disclosed in the above-mentioned patent have a particularly advantageous combination of properties which are useful in the treatment of gastrointestinal disorders, in particular peptic ulcers and other gastroduodenal conditions such as gastritis and non-ulcerative dyspepsia.

The same specification also discloses pharmaceutical compositions containing as active ingredient salts of ranitidine and a carboxylic acid complex of bismuth. These compositions are intended primarily for oral administration and may, for example, be tablets, capsules, solutions, syrups, suspensions, or dry products to be reconstituted with water or other vehicle before use.

One of the important properties of solid form pharmaceutical compositions for oral administration is that, once swallowed, they must be disintegrated and / or dissolved in order for the active ingredient to be released. It has been found that the disintegration and / or dissolution rates of such formulations, in particular the tablets containing salts of the type described in British Patent No. 2,220,937 A, may be significantly improved, particularly under acidic conditions, by providing an alkaline salt is incorporated into the composition. This increases the rate of release of the active ingredient from the formulation.

Thus, the present invention relates to solid dosage forms for oral administration containing as active ingredient a salt of ranitidine and a bismuth complex with a carboxylic acid, including tartaric or citric acid, and an alkaline salt.

The present invention also encompasses compositions comprising solvates, including hydrates, of ranitidine salts.

The ranitidine salt may be, for example, N - {{2 - {[[5 - [(dimethylamino) methyl] -2-furanyl} methyl]] thio} ethyl}} -N '-methyl-2-nitro-1,1- ethenediamine (2-hydroxy-1,2,3-propane tricarboxylate) bismuth (3 +) complex, also known as ranitidine bismuth citrate, or N - {{2 - {[[5 - [(dimethyl) -amino) -methyl] -2-furanyl} -methyl]] -thio} -ethyl}} -N '-methyl-2-nitro-1,1-ethenediamine [R- (R * R *)] - 2,3 -dihydroxybutanedioate bismuth (3 ⁺ ) complex, also known as ranitidine bismuth tartrate.

These salts may be prepared by reacting ranitidine with a suitable bismuth carboxylic acid complex, such as bismuth citrate or bismuth tartrate.

Particularly preferred are formulations containing ranitidine bismuth citrate as the active ingredient.

The alkaline salt may be, for example, a carbonate, bicarbonate, citrate, phosphate or acetate salt. It is preferred to use an alkali metal (e.g. sodium or potassium) or alkaline earth metal (e.g. magnesium or calcium) carbonate or bicarbonate salt or mixtures thereof. Sodium bicarbonate and / or sodium carbonate are particularly preferred, more preferably sodium carbonate, preferably in anhydrous form. Other examples of suitable alkaline salts include ammonium citrate, ammonium carbonate, ammonium phosphate, sodium acetate, sodium citrate, sodium phosphate, potassium acetate, potassium citrate and the like.

The amount of ranitidine bismuth carboxylate in the compositions of the invention is, for example, from 150 mg to 1.5 g, preferably from 200 to 800 mg.

The alkaline salt may, for example, be present in an amount of from 2 to 20% by weight, preferably from 2 to 8% by weight.

The compositions of the present invention contain, for example, 20 to 95% by weight of ranitidine bismuth carboxylate, preferably 50 to 95% by weight, more preferably 80 to 95% by weight.

A preferred formulation comprises ranitidine bismuth citrate and sodium carbonate.

The compositions of the present invention are suitable for human or veterinary use.

The compositions may be administered, for example, 1 to 4 times daily, preferably 1 or 2 times daily. However, the dosage administered will depend on the nature and severity of the condition being treated and the dosage will be adjusted according to routine conditions depending on the age and weight of the patient.

The compositions may take such forms as tablets (including chewable tablets), capsules (hard or soft), powder or granules. Tablets are preferred.

The compositions of the invention may be formulated with additional physiologically acceptable carriers and / or other excipients as appropriate. Such additional carriers and excipients are, for example, binders (e.g., pregelatinised corn starch, polyvinylpyrrolidone) and hydroxypropylmethylcellulose], fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); glidants (for example, magnesium stearate, talc or silica); disintegrants (e.g., starch or sodium starch glycolate); and wetting agents (e.g., sodium lauryl sulfate). The tablets may also be coated in known manner. The compositions may also contain flavoring, coloring and / or sweetening agents as required.

The compositions of the present invention may be prepared by conventional procedures well known in the art of pharmaceutical solid dosage forms for oral administration. For example, ranitidine bismuth carboxylate and alkaline salt can be mixed with suitable excipients and

If desired, it may be granulated. Tablets may be prepared, for example, by compression of the mixture or granulate using a glidant as a tabletting aid.

The following examples illustrate tablets and capsules of the invention containing the active ingredient ranitidine bismuth citrate.

The tablets may be film-coated using suitable film-forming materials, such as hydroxypropylmethylcellulose, and conventional techniques.

Example 1 mg / tablet agent Anhydrous sodium carbonate 200.0 400.0 800.0 USNF 19.0 25.0 46.0 Microcrystalline cellulose Ph. Eur. 149.6 60.0 46.0 Poly (vinylpyrrolidone) 7.6 10.0 18.4 Magnesium stearate Ph. Eur. 3.8 5.0 9.2 Weight to be pressed 380.0 500.0 919.6

The active ingredient, sodium carbonate and microcrystalline cellulose are mixed, granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol and dried. The granules are mixed with magnesium stearate and compressed into tablets using suitable tools.

Example 2 mg / tablet

agent 400.0 400.0 Sodium bicarbonate USNF 85.0 21.7 Poly (vinylpyrrolidone) 10.0 8.7 Magnesium stearate Ph. Eur. 5.0 4.4 Weight to be pressed 500.0 434.8

The active ingredient and sodium bicarbonate are mixed, granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol and dried. The granules are mixed with magnesium stearate and compressed into tablets using suitable tools.

Example 3 mg / tablet agent 400.0 Anhydrous sodium carbonate USNF 2.5 Sodium bicarbonate USNF 22.5 Microcrystalline Cellulose Ph. Eur. 60.0 Poly (vinylpyrrolidone) 10.0 Magnesium stearate Ph. Eur. 5.0 Weight to be pressed 500.0

Tablets were prepared as described in Example 1 except that sodium bicarbonate was used in addition to sodium carbonate.

Example 4 mg / tablet

Active ingredient 600.0

Anhydrous sodium carbonate USNF 36.0

Lactose 60.0 mg / tablet

Poly (vinylpyrrolidone) 15.0

Magnesium stearate 8.0

Weight to be pressed 719.0

The active ingredient, sodium carbonate and lactose are mixed, granulated using a solution of polyvinylpyrrolidone in ethyl alcohol and dried. The granules are mixed with magnesium stearate and compressed into tablets using suitable tools.

Example 5 mg / tablet agent 600.0 Sodium bicarbonate USNF 36.0 Lactose 60.0 Poly (vinylpyrrolidone) 15.0 Magnesium stearate 8.0 Weight to be pressed 719.0

The active ingredient, sodium bicarbonate, and lactose are mixed, granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol and dried. The granulate is mixed with magnesium stearate and compressed into tablets using appropriate tools.

Example 6 mg / tablet agent 400.0 Anhydrous sodium carbonate USNF 2.5 Sodium bicarbonate USNF 22.5 Microcrystalline Cellulose Ph. Eur. 57.5 Poly (vinylpyrrolidone) 10.0 Magnesium stearate 5.0 Silicon dioxide 2.5 filling Weight 500.0

The active ingredient, sodium carbonate, sodium bicarbonate and microcrystalline cellulose are mixed, granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol and dried. The granules are mixed with magnesium stearate and silica and filled into suitable size hard gelatin capsules using a conventional capsule filling device.

Example 7 mg / tablet

Active ingredient 400.0

Anhydrous sodium carbonate USNF 25.0

Microcrystalline cellulose 72.5

Silica 2.5

Filling weight 500.0

The microcrystalline cellulose and silica are mixed into a premix and then mixed with the active ingredient and sodium carbonate. The resulting mixture is filled into suitable size hard gelatin capsules using a conventional capsule filling apparatus.

Example 8 mg / tablet

Active ingredient 800.0

Anhydrous sodium carbonate USNF 46.0

HU 217 587 Β mg / tablet

Microcrystalline Cellulose Ph. Eur. 46.0

Poly (vinylpyrrolidone) 18.4

Magnesium stearate 9.2

918 ^ 6

The active ingredient, sodium carbonate and microcrystalline cellulose are mixed, granulated using a 90:10 solution of polyvinylpyrrolidone in isopropyl alcohol / water and dried. The granulate is mixed with magnesium stearate and compressed into tablets using appropriate tools.

Example 9 mg / tablet agent 750.0 N atrium carbonate 45.0 Lactose 78.0 Poly (vinylpyrrolidone) 18.0 Magnesium stearate 9.0 900.0

The active ingredient, sodium carbonate and lactose are mixed, granulated with a solution of polyvinylpyrrolidone in isopropyl alcohol and dried. The granulate is mixed with magnesium stearate and compressed into tablets using appropriate tools.

Claims (13)

PATENT CLAIMS A pharmaceutical composition in solid unit dosage form for oral administration comprising a salt formed by ranitidine and a bismuth-carboxylic acid complex including a bismuth-tartaric acid complex or a bismuth-citric acid complex and an alkaline salt. Composition according to claim 1, comprising 200 to 800 mg of ranitidine bismuth carboxylate per unit dose. A composition according to claim 1 or 2, comprising 2 to 20% by weight of an alkaline salt. Composition according to claim 1 or 2, comprising 2-8% by weight of alkaline salt. 5. A composition according to any one of claims 1 to 5, comprising 50 to 95% by weight of ranitidine bismuth carboxylate. 6. A composition according to any one of claims 1 to 6, wherein the ranitidine salt is N - {{2 - {[[5 - [(dimethylamino) methyl] -2-furanyl} methyl]] thio} ethyl}} -N'-methyl-2nitro-1. , 1-ethenediamine (2-hydroxy-1,2,3-propane tricarboxylate) -bismuth (3 ⁺ ) complex or N - {{2 - {[[5 - [(dimethylamino) methyl] -2- furanyl} -methyl]] -thio} -ethyl}} -N '-methyl-2-nitro-1,1-ethenediamine [R- (R * R *)] - 2,3-dihydroxybutanedioate bismuth (3 ⁺ ) complex. 7. A composition according to any one of claims 1 to 3, wherein the alkaline salt is a carbonate, bicarbonate, citrate, phosphate or acetate salt. 8. A composition according to any one of claims 1 to 6, which comprises as the alkali salt the carbonate or bicarbonate of an alkali metal or alkaline earth metal or a mixture thereof. 9. A composition according to any one of claims 1 to 3, wherein the alkaline salt is sodium carbonate and / or sodium bicarbonate. 10. A composition according to any one of claims 1 to 3, wherein the ranitidine bismuth carboxylate is N {{2 - {[[5 - [(dimethylamino) methyl] -2-furanyl} methyl]] thio} ethyl}} -N '-methyl Contains -2-nitro-1,1-ethenediamine (2-hydroxy-1,2,3-propane tricarboxylate) bismuth (3 ⁺ ) complex, sodium carbonate as the basic salt. 11. A composition according to any one of claims 1 to 4 which is formulated as a tablet. 12. A composition according to any one of claims 1 to 3, further comprising one or more physiologically acceptable carriers and / or other excipients. 13. Methods 1 to 12. Pharmaceutical compositions according to any one of claims 1 to 3, characterized in that the ranitidine bismuth carboxylate and the alkaline salt are formulated in a solid unit dosage form suitable for oral administration.